Instructions Enap 20 HL tablets 20 mg + 12.5 mg blister No. 20
Composition
active ingredient: 1 tablet contains enalapril maleate 20 mg and hydrochlorothiazide 12.5 mg;
excipients: sodium bicarbonate, lactose monohydrate, corn starch, pregelatinized starch, talc, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: round, flat, white tablets with a beveled edge and a notch on one side.
Pharmacotherapeutic group
Combined ACE inhibitor drugs. Enalapril and diuretics. ATC code C09B A02.
Pharmacological properties
Pharmacodynamics.
Enap® 20 HL is a combination of an angiotensin-converting enzyme (ACE) inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide).
Enalapril maleate
ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I 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. Enalapril can also block the breakdown of bradykinin, a potent vasodepressor peptide. However, the role of this fact in the therapeutic effects of enalapril remains unknown. While the mechanism by which enalapril lowers blood pressure is primarily associated with inhibition 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.
Two large randomized controlled trials (ONTARGET (Ongoing International Trial of Telmisartan Alone and in Combination with Ramipril), VA NEPHRON-D (US Department of Veterans Affairs Diabetic Nephropathy Study) studied the use of a combination of an ACE inhibitor with an angiotensin II receptor blocker.
ONTARGET is a study conducted in patients with a history of cardiovascular or cerebrovascular disease or patients 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 a significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while there was an increased risk of hyperkalemia, acute kidney injury and/or hypotension compared with monotherapy. Given their similar pharmacodynamic properties, these results can also be applied 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 in Type 2 Diabetes with Cardiovascular and Renal Endpoints) is a study designed to test the benefit 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 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.
Hydrochlorothiazide is a diuretic and antihypertensive agent that increases plasma renin activity.
Non-melanoma skin cancer (NMSC)
Based on available epidemiological data, a cumulative dose-dependent association between hydrochlorothiazide and NMSC has been observed. One study included a population consisting of 71,533 basal cell carcinoma (BCC) and 8,629 squamous cell carcinoma (SCC) cases, which were compared with 1,430,833 and 172,426 control subjects, respectively. High doses of hydrochlorothiazide (≥ 50,000 mg cumulative dose) were associated with an adjusted HR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose-response relationship was observed for BCC and SCC. Another study showed a possible association between lip cancer (LC) and hydrochlorothiazide exposure: 633 cases of lip cancer were compared with 63,067 controls using a random sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted HR of 2.1 (95% CI: 1.7-2.6), increasing to HR of 3.9 (3.0-4.9) for high doses (25,000 mg) and HR of 7.7 (5.7-10.5) for the highest cumulative dose (100,000 mg) (see section 4.4).
The antihypertensive effects of the two components are additive and usually last for 24 hours. Although enalapril alone has a hypotensive effect even in patients with low-renin hypertension, concomitant use with hydrochlorothiazide in such patients results in a greater reduction in blood pressure.
The enalapril component of the drug usually attenuates the decrease in potassium caused by taking hydrochlorothiazide.
Pharmacokinetics.
Enalapril maleate
After oral administration, enalapril is rapidly absorbed, reaching maximum serum concentrations (Cmax) within 1 hour. Based on urinary excretion, the extent of absorption of enalapril after oral administration is approximately 60-70%.
After absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Cmax of enalaprilat in serum is reached 3-4 hours after oral administration of enalapril maleate. Enalapril is excreted mainly by the kidneys. The main components in the urine are enalaprilat, which accounts for approximately 40% of the dose, and unchanged enalapril; except for 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 on the 4th day of oral administration of enalapril. The effective half-life of enalaprilat accumulation after multiple oral administration of enalapril is 11 hours. Food intake does not affect the absorption of enalapril from the gastrointestinal tract. The extent of absorption and hydrolysis of enalapril are similar when taking different doses within the recommended therapeutic range.
Hydrochlorothiazide
When monitoring plasma levels of hydrochlorothiazide for at least 24 hours, the elimination half-life was 5.6-14.8 hours. Hydrochlorothiazide is not metabolized but is rapidly excreted by the kidneys. When administered orally, at least 61% of the dose is excreted unchanged within 24 hours. Hydrochlorothiazide crosses the placental barrier and does not cross the blood-brain barrier.
Enalapril maleate/hydrochlorothiazide
Multiple simultaneous administration of enalapril and hydrochlorothiazide has little or no effect on the bioavailability of these drugs. The combination tablet is bioequivalent to its individual components when administered simultaneously.
Indication
Arterial hypertension in patients for whom combination therapy is indicated.
Contraindication
Hypersensitivity to any of the components of the drug or to other drugs that are derivatives of sulfonamides.
History of angioedema associated with previous treatment with ACE inhibitors, as well as hereditary or idiopathic angioedema.
Severe liver dysfunction.
Renal artery stenosis.
Severe renal impairment (creatinine clearance ≤30 ml/min).
Anury.
Treatment-resistant hypokalemia or hyperkalemia.
Refractory hyponatremia.
Symptomatic hyperuricemia (gout).
Pregnant women or women planning to become pregnant (see section “Use during pregnancy or breastfeeding”).
Concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 ml/min/1.73 m2) (see sections “Pharmacodynamics” and “Special warnings and precautions for use”).
Concomitant use with sacubitril/valsartan therapy due to increased risk of angioedema. Enap® 20 NL should not be used within 36 hours after the last dose of sacubitril/valsartan, a drug containing a neprilysin inhibitor, or after switching from it to another drug (see sections “Interaction with other medicinal products and other types of interactions” and “Special precautions for use”).
Interaction with other medicinal products and other types of interactions
Enalapril maleate – hydrochlorothiazide
Dual blockade of RAAS
Clinical studies have shown that dual blockade of the RAAS with the simultaneous use of ACE inhibitors, angiotensin II receptor antagonists 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 5.1, 5.2 and 5.4).
Other antihypertensive agents
Concomitant use of these drugs may enhance the hypotensive effect of enalapril. Concomitant use with nitroglycerin, other nitrates, or other vasodilators may further reduce blood pressure.
The combination of enalapril maleate and beta-blockers, methyldopa, or calcium channel blockers improves the effectiveness of lowering blood pressure.
Ganglioblockers or adrenoblockers in combination with enalapril should only be used with careful monitoring of the patient's condition.
Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant use of lithium and ACE inhibitors. Concomitant use of thiazide diuretics and ACE inhibitors may further increase lithium levels and increase the risk of lithium toxicity.
The use of the drug simultaneously with lithium preparations is not recommended, but if such a combination is necessary, the level of lithium in the blood serum should be carefully monitored (see section "Special instructions").
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid > 3 g/day, and nonselective NSAIDs
NSAIDs, including selective COX-2 inhibitors, may attenuate the effects of diuretics and other antihypertensive drugs. For this reason, the antihypertensive effect of angiotensin II receptor antagonists, ACE inhibitors or diuretics may be attenuated by the use of NSAIDs, including selective COX-2 inhibitors.
Concomitant use of NSAIDs (including COX-2 inhibitors) and angiotensin II receptor antagonists or ACE inhibitors has shown an additive effect on serum potassium levels and may lead to renal dysfunction. These effects are usually reversible. Rarely, renal failure may develop, particularly in patients with impaired renal function (e.g. elderly patients or patients with dehydration, including patients receiving diuretics). Therefore, this combination should be administered with caution to patients with impaired renal function.
Enalapril
Potassium-sparing diuretics or 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 enalapril is used concomitantly 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-mentioned 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").
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 may be reduced by discontinuing the diuretic, increasing salt intake, or initiating therapy with a low dose of enalapril.
Tricyclic antidepressants/neuroleptics/anesthetics/hypnotics
Concomitant administration of certain anesthetics, tricyclic antidepressants and neuroleptics with ACE inhibitors may lead to an additional decrease in blood pressure (see section "Special warnings and precautions for use").
Gold preparations
Rare cases of nitritoid reactions (facial flushing, nausea, vomiting and hypotension) have been reported in patients receiving injectable gold (sodium aurothiomalate) concomitantly with an ACE inhibitor, including enalapril.
Mammalian target of rapamycin (mTOR) inhibitors
Concomitant use with mTOR inhibitors (such as temsirolimus, sirolimus, everolimus) may increase the risk of angioedema (see section "Special warnings and precautions for use").
Neprilysin inhibitors
Concomitant use with neprilysin inhibitors (e.g. sacubitril, racecadotril) may increase the risk of angioedema. Sacubitril/valsartan should not be initiated until 36 hours after the last dose of enalapril therapy. Enalapril therapy should not be initiated until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.4).
Cyclosporine: Concomitant use of cyclosporine may increase hyperuricemia, which may precipitate gout attacks in patients with asymptomatic disease.
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Alcohol
Alcohol potentiates the hypotensive effect of ACE inhibitors.
Antidiabetic drugs (oral hypoglycemic drugs and insulin)
Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic medicinal products (insulins, oral hypoglycaemic agents) may lead to a decrease in blood glucose levels 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 sections 4.4 and 4.8).
Acetylsalicylic acid, thrombolytics and β-blockers
Enalapril can be safely used concomitantly with acetylsalicylic acid (in cardiological doses), thrombolytics, and β-blockers.
Non-depolarizing muscle relaxants
Thiazides may increase susceptibility to tubocurarine.
Alcohol, barbiturates, or narcotic analgesics potentiate the development of orthostatic hypotension.
Anticholinergics (e.g., antropine, biperiden)
Due to the weakening of gastrointestinal motility and a decrease in the rate of evacuation from the stomach, the bioavailability of thiazide-type diuretics increases.
Carbamazepine
Given the risk of symptomatic hyponatremia, clinical and biological monitoring is necessary.
Antidiabetic drugs (oral hypoglycemic drugs and insulin)
During treatment with thiazides, glucose tolerance may be impaired. When using antidiabetic drugs and thiazide diuretics, it may be necessary to change the dosage of the antidiabetic drug. Metformin should be used with caution, taking into account the risk of lactic acidosis due to possible functional renal failure associated with hydrochlorothiazide.
Antigout drugs (probenecid, sulfinpyrazone, allopurinol)
Dose adjustment of uricosuric agents may be necessary, as hydrochlorothiazide may increase serum uric acid levels. Increased doses of probenecid or sulfinpyrazone may be required. Concomitant use of thiazides may increase the incidence of hypersensitivity reactions to allopurinol.
Cholestyramine and colestipol resins
The absorption of hydrochlorothiazide is reduced in the presence of anion exchange resins. A single dose of cholestyramine or colestipol resin binds to hydrochlorothiazide and reduces its absorption from the gastrointestinal tract by 85% and 43%, respectively.
Prostaglandin synthase inhibitors – in some patients, their use may reduce the diuretic, natriuretic, and antihypertensive effects of diuretics.
QT prolongation (e.g., quinidine, procainamide, amiodarone, sotalol)
Increases the risk of torsades de pointes.
Drugs that cause changes in serum potassium levels
Periodic monitoring of serum potassium and ECG is recommended if hydrochlorothiazide is taken concomitantly with drugs that cause changes in serum potassium (e.g. digitalis glycosides and antiarrhythmic drugs) and drugs that cause torsades de pointes (ventricular tachycardia), since hypokalemia is a factor in the development of torsades de pointes:
class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide);
class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide);
some neuroleptics (thioridazine, chlorpromazine, levomepromazine, trifluoroperazine, cyamemazine, sulpiride, sultopride, amisulpiride, tiapride, pimozide, haloperidol, droperidol);
other medicines (bepridil, cisapride, diphemanil, erythromycin for intravenous administration, galafantrine, mizolastine, pentamidine, terfenadine, vincamine for intravenous administration).
Digitalis glycosides
Hypokalemia or hypomagnesemia may potentiate or exacerbate the cardiac response to the toxic effects of digitalis (e.g., increased ventricular excitability).
Corticosteroids, ACTH
Electrolyte imbalance, particularly hypokalemia, is increasing.
Kaliuretic diuretics (e.g., furosemide), carbenoxolone, or laxative abuse
Hydrochlorothiazide may increase potassium and/or magnesium losses.
Pressor amines (e.g., adrenaline)
The effect of pressor amines may be reduced (see section "Interaction with other medicinal products and other types of interactions").
Cytostatic drugs (e.g. cyclophosphamide, methotrexate)
Thiazides may reduce the renal excretion of cytotoxic drugs and enhance their myelosuppressive effects.
Salicylates
When using high doses of salicylates, hydrochlorothiazide may enhance their toxic effect on the central nervous system.
Methyldopa
Isolated cases of hemolytic anemia have been reported with the concomitant use of hydrochlorothiazide and methyldopa.
Calcium salts
Thiazide diuretics increase serum calcium levels by decreasing its excretion. If calcium supplements are required, serum calcium levels should be monitored and the calcium dose adjusted accordingly.
Iodine-containing contrast agents
In case of diuretic-induced dehydration, the risk of acute renal failure increases, especially when using high doses of iodinated contrast media. Patients need to be rehydrated before the administration of iodinated contrast media.
Amphotericin B (for parenteral administration), stimulant laxatives
Hydrochlorothiazide increases electrolyte imbalance, mainly hypokalemia.
β-blockers and diazoxide
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with β-blockers may increase the risk of hyperglycemia. Thiazide diuretics may potentiate the hyperglycemic effect of diaxozide.
Amantadine
Thiazides, including hydrochlorothiazide, may increase the risk of side effects caused by amantadine.
Children
Drug interaction studies have only been conducted in adult patients.
Application features
Dual blockade of RAAS
Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to isolated cases with close monitoring of blood pressure, renal function, and electrolytes. In several studies, in patients with established atherosclerotic vascular disease, heart failure, or diabetes with end-organ damage, dual blockade of the RAAS 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 a single RAAS-acting agent. Enalapril should not be used with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.3 and 4.4).
ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.
Hypotension and electrolyte/water imbalance
As with other antihypertensive drugs, symptomatic hypotension may occur in some patients. Symptomatic hypotension has also been reported in patients with heart failure with or without renal insufficiency. Symptomatic hypotension has been reported more frequently in patients with more severe heart failure, those receiving higher doses of loop diuretics, those with hyponatremia, or those with impaired renal function. In such patients, treatment should be initiated under medical supervision.
Patients should be monitored for clinical signs of fluid and electrolyte imbalance, such as dehydration, hyponatremia, hypochloremic alkalosis, which may induce hepatic encephalopathy or hepatic coma; hypomagnesemia or hypokalemia, which may result from diarrhea or vomiting. Serum electrolyte levels should be monitored periodically in such patients.
Particular care should be taken in the treatment of patients with ischemic heart disease or cerebrovascular disease, since excessive reduction in blood pressure can lead to myocardial infarction or stroke. If hypotension develops, the patient should be placed on his back and, if necessary, 0.9% sodium chloride solution should be administered intravenously. Transient hypotension is not a contraindication to the use of subsequent doses of the drug. Treatment with the drug can be started only after effective normalization of circulating blood volume and blood pressure, and therapy can be resumed in reduced doses or with the use of each of the components of the drug separately.
In some patients with heart failure with normal or low blood pressure, Enap® 20 HL may further reduce blood pressure. This reaction to the drug is expected and is usually not a reason to stop treatment. If hypotension becomes resistant to treatment, the dose should be reduced and/or the diuretic and/or the drug should be discontinued.
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. It may be necessary to reduce the dose of enalapril and/or discontinue the diuretic. In such cases, the possibility of renal artery stenosis should be considered.
Hyperkalemia
With the combined use of enalapril and a diuretic in low doses, the possibility of developing hyperkalemia cannot be excluded.
Lithium
Concomitant use of enalapril and lithium is generally not recommended (see section "Interaction with other medicinal products and other types of interactions").
Children
The safety and effectiveness of the drug in children have not been established.
Enalapril maleate
Aortic stenosis/hypertrophic cardiomyopathy
As with all vasodilators, ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction and outflow tract obstruction; they should be avoided in cardiogenic shock and hemodynamically significant obstruction.
Kidney dysfunction
Renal failure has been reported with enalapril, predominantly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. With prompt diagnosis and appropriate treatment, renal failure with enalapril is usually reversible (see Dosage and Administration).
In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, increases in blood urea and serum creatinine have been observed during treatment with ACE inhibitors, which are usually reversible upon discontinuation of the drug. Therapy in such patients should be initiated under close medical supervision with low doses, careful titration, and monitoring of renal function.
Patients undergoing hemodialysis
Enalapril is contraindicated in patients requiring dialysis for renal failure. Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g. AN 69®) and treated concomitantly with ACE inhibitors. In such patients, a different type of dialysis membrane or a different class of antihypertensive drug should be used.
Kidney transplantation
There is no experience in patients who have recently undergone kidney transplantation. Therefore, treatment with enalapril is not recommended in these patients.
Liver failure
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 is rare in patients with normal renal function and in the absence of other complicating factors. Enalapril should be used with caution in patients with collagen vascular disease who are receiving immunosuppressive therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing renal impairment. Some such patients have developed serious infections, some of which have not responded to intensive antibiotic therapy. Periodic monitoring of white blood cell counts is recommended when enalapril is prescribed to such patients, and patients should report any signs of infection.
Hyperkalemia
Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including enalapril. Risk factors for hyperkalaemia include renal insufficiency, decreased renal function, age >70 years, diabetes mellitus, intercurrent conditions including dehydration, acute cardiac decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene or amiloride), potassium-containing supplements or salt substitutes, or other medicinal products that may increase serum potassium (e.g. heparin, trimethoprim or co-trimoxazole, also known as trimethoprim/sulfamethoxazole, and especially aldosterone antagonists or angiotensin receptor blockers). The use of potassium supplements, potassium-sparing diuretics or salt substitutes containing potassium, or other drugs that may increase serum potassium levels, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium levels. Hyperkalemia may cause serious and even fatal arrhythmias. If the concomitant use of perindopril and any of the above substances is considered appropriate, they should be used with caution, with close monitoring of renal function and plasma potassium levels (see section "Interaction with other medicinal products and other forms of interaction").
Hypoglycemia
Diabetic patients taking oral antidiabetic agents or insulin and starting an ACE inhibitor should be advised to monitor their blood sugar levels closely, especially during the first month of combination therapy (see section 4.5).
Hypersensitivity/angioedema
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported with ACE inhibitors, including enalapril. These reactions may occur at any time during treatment. In such cases, treatment with Enap® 20 HL should be discontinued immediately and the patient should be closely monitored to ensure complete resolution of symptoms before discharge. Even in cases where only tongue swelling occurs without respiratory distress, prolonged monitoring of the patient is necessary, as treatment with antihistamines and corticosteroids may be inadequate.
Black patients taking ACE inhibitors had a higher incidence of angioedema compared to non-black patients.
Patients with a history of angioedema unrelated to ACE inhibitors may be at increased risk of developing angioedema while receiving ACE inhibitors (see section 4.3).
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Sacubitril/valsartan should not be initiated until 36 hours after the last dose of enalapril therapy. Enalapril therapy should not be initiated until 36 hours after 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 may lead to an increased 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 with hymenoptera venom
Rarely, patients receiving ACE inhibitors have developed life-threatening anaphylactoid reactions during hymenoptera venom desensitization. Such reactions can be avoided by temporarily stopping the ACE inhibitor before desensitization.
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis
Life-threatening anaphylactoid reactions have been reported rarely in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. These reactions can be avoided by temporarily discontinuing the ACE inhibitor prior to each apheresis session.
Cough
Cough has been reported with ACE inhibitors. The cough is usually non-productive, persistent, and resolves after discontinuation of the drug. Cough associated with ACE inhibitors should be considered in the differential diagnosis of cough.
Surgical interventions/anesthesia
During major surgery or during anaesthesia with agents that produce hypotension, enalapril blocks the formation of angiotensin II secondary to compensatory renin release. Hypotension due to this mechanism can be corrected by volume expansion (see section 4.5).
Pregnancy
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.8).
Ethnic differences
As with other ACE inhibitors, enalapril is less effective in lowering blood pressure in black patients than in non-black patients. This may be due to a higher prevalence of low-renin systems in black hypertensive patients.
Hydrochlorothiazide
Kidney dysfunction
Thiazides may cause
