Enalapril n-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Enalapril H-Teva (Enalapril H-Teva)

Composition:

Active substances: enalapril maleate, hydrochlorothiazide;

One tablet contains enalapril maleate 10 mg and hydrochlorothiazide 25 mg;

Excipients: lactose monohydrate, corn starch, pregelatinized starch, sodium bicarbonate, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, slightly convex tablets, with embossing "EL", "10" and a break line on one side, smooth on the other.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors and diuretics. ATC code C09BA02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. The medicinal product Enalapril N-Teva exerts both antihypertensive and diuretic effects. Enalapril and hydrochlorothiazide can be used for the treatment of arterial hypertension both separately and in combination. The antihypertensive effect of both components is approximately additive. Enalapril may attenuate the potassium loss observed during hydrochlorothiazide administration. The antihypertensive effect of Enalapril N-Teva usually lasts for 24 hours.

Enalapril maleate

Enalapril maleate is hydrolyzed in the liver to enalaprilat, which is an inhibitor of angiotensin-converting enzyme (ACE). ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to angiotensin II, a vasoconstrictive substance. Inhibition of ACE leads to a reduction in the formation of vasoconstrictive angiotensin II in tissues and plasma, resulting in decreased aldosterone secretion and increased serum potassium concentration. Increased plasma renin activity is associated with the inhibition of the negative feedback of angiotensin II on renin release.

Since ACE also cleaves bradykinin (a vasodilatory peptide), ACE inhibition also leads to increased activity of the circulating and local kallikrein-kinin system (and thus to activation of the prostaglandin system). This mechanism may contribute to the hypotensive effect of ACE inhibitors and partially cause some adverse effects.

Administration of enalapril to patients with arterial hypertension leads to a reduction in blood pressure in both supine and upright positions without compensatory increase in heart rate.

In hemodynamic studies, enalapril significantly reduces peripheral arterial resistance. This usually does not lead to clinically significant changes in renal plasma flow or glomerular filtration rate.

The onset of antihypertensive activity in most patients usually occurs within 1 hour after oral administration of enalapril, with maximum effect achieved within 4–6 hours. The maximum antihypertensive effect of a given enalapril dose is observed approximately after 3–4 weeks.

With administration of the recommended daily dose, the antihypertensive effect persists even during long-term therapy. Short-term discontinuation of enalapril does not lead to a rapid rebound increase in blood pressure (rebound effect).

Hydrochlorothiazide

Hydrochlorothiazide is a derivative of benzothiadiazine. Thiazides act directly on the kidneys, enhancing excretion of sodium chloride and water. The main clinically significant site of action is the proximal portion of the distal tubule. Thiazides inhibit the electroneutral cotransport of sodium and chloride across the luminal membrane of tubular epithelial cells. Excretion of potassium and magnesium increases, while calcium excretion decreases. Hydrochlorothiazide causes low bicarbonate excretion, and chloride excretion exceeds sodium ex游戏副本

Clinical characteristics.

Indications.

Treatment of arterial hypertension in patients in whom blood pressure cannot be adequately controlled with enalapril monotherapy.

Contraindications.

• Hypersensitivity to enalapril and to other angiotensin-converting enzyme inhibitors (ACE inhibitors), thiazides, or to other sulfonamides (cross-reactivity possible), or to any other components of the medicinal product.
• History of angioedema (e.g., associated with previous ACE inhibitor therapy), as well as hereditary or idiopathic angioedema (see section "Special precautions").
• Severe renal impairment (creatinine clearance less than 30 mL/min) or patients undergoing dialysis.
• Clinically significant electrolyte disturbances (hypercalcemia, hyponatremia, hypokalemia).
• Severe hepatic dysfunction (hepatic precoma/coma).
• Pregnancy (see sections "Special precautions" and "Use in pregnancy or lactation").
• Breastfeeding period (see section "Use in pregnancy or lactation").
• Concomitant use with sacubitril/valsartan. Treatment with Enalapril N-Teva may be initiated only 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Enalapril + hydrochlorothiazide

Other antihypertensive agents

Concomitant use of these agents may potentiate the hypotensive effect of enalapril and hydrochlorothiazide. Concomitant use with nitroglycerin, other nitrates, or other vasodilators may additionally reduce blood pressure.

Lithium

Reversible increases in serum lithium concentrations and lithium toxicity have been reported during concomitant use of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may further increase lithium levels and increase the risk of lithium toxicity when an ACE inhibitor is administered. Concomitant use of this medicinal product with lithium-containing medicines is not recommended; however, if such combination is necessary, serum lithium levels should be closely monitored (see section "Special precautions").

Nonsteroidal anti-inflammatory drugs (NSAIDs)

During prolonged use of NSAIDs, the antihypertensive effect of ACE inhibitors may be reduced, and the diuretic, natriuretic, and antihypertensive effects of diuretics may also be diminished.

NSAIDs and ACE inhibitors have an additive effect on increasing serum potassium levels and may lead to worsening of renal function. These effects are usually reversible. In rare cases, acute renal failure may develop, particularly in patients with impaired renal function (e.g., elderly patients or those with dehydration).

Enalapril

Diuretics (thiazide or loop diuretics)

Prior treatment with high-dose diuretics may lead to reduced blood volume and increase the risk of arterial hypotension at the start of enalapril therapy. The hypotensive effect can be mitigated by discontinuing the diuretic, increasing fluid volume, increasing salt intake, or initiating therapy with low doses of enalapril.

Tricyclic antidepressants/neuroleptics/anesthetics/narcotics

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

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Antidiabetic agents

Epidemiological studies indicate that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may lead to reduced blood glucose levels with a risk of hypoglycemia. This effect is more likely during the first weeks of concomitant therapy and in patients with impaired renal function.

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytic agents, and β-blockers

Enalapril can be safely used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytic agents, and β-blockers.

Gold preparations

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

Medicinal products that increase the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions"). Concomitant use of ACE inhibitors with racecadotril, mammalian target of rapamycin (mTOR) inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (see section "Special precautions").

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

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving this medicinal product. Potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium levels. Caution should also be exercised when enalapril is used concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of enalapril with the above-mentioned medicinal products is not recommended. If concomitant use is indicated, treatment should be administered with caution and regular monitoring of serum potassium levels is required.

Cyclosporine

Hyperkalemia may occur when ACE inhibitors are used concomitantly with cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin

Hyperkalemia may occur when ACE inhibitors are used concomitantly with heparin. Monitoring of serum potassium levels is recommended.

Hydrochlorothiazide

Antihypertensive agents (e.g., other diuretics, beta-blockers), nitrates, vasodilators, barbiturates, phenothiazines, tricyclic antidepressants, alcohol

Enhancement of the hypotensive effect of hydrochlorothiazide.

Analgesics, anti-inflammatory agents, salicylic acid derivatives, indomethacin, other NSAIDs

Weakening of the antihypertensive and diuretic effects; when salicylates are taken at high doses – enhanced central nervous system toxicity of salicylates. Acute renal failure may occur in the presence of hypovolemia.

Table salt

Weakening of the antihypertensive effect.

Potassium-wasting diuretics (e.g., furosemide), glucocorticoids, ACTH, carbenoxolone, amphotericin B, penicillin G, salicylates, or laxative abuse

Enhanced excretion of potassium and/or magnesium.

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

Increased risk of ventricular tachycardia torsades de pointes.

Cardiac glycosides (e.g., digoxin)

The effect and adverse reactions of cardiac glycosides may be enhanced in the presence of hypokalemia and/or hypomagnesemia.

Catecholamines (e.g., adrenaline)

Reduced effect due to hydrochlorothiazide.

Sedatives, narcotics, anesthetics

Significant reduction in blood pressure (anesthesiologists should be informed about treatment with Enalapril N-Teva).

Allopurinol, immunosuppressants, systemic corticosteroids, procainamide

Reduced white blood cell count, leukopenia.

Cytoxan (e.g., cyclophosphamide, fluorouracil, methotrexate)

Enhanced bone marrow toxicity (especially granulocytopenia).

Oral antidiabetic agents (e.g., sulfonylureas, biguanides), insulin, and uric acid-lowering agents

Weakened effect due to hydrochlorothiazide.

Cholestyramine and colestipol

Reduced absorption of hydrochlorothiazide.

Curare-like muscle relaxants

Enhanced or prolonged muscle-relaxing effect due to hydrochlorothiazide (anesthesiologists should be informed about treatment with Enalapril N-Teva).

Methyldopa

Isolated cases of hemolysis due to formation of antibodies against hydrochlorothiazide.

Special precautions.

Enalapril + hydrochlorothiazide

Arterial hypotension and electrolyte imbalance

In rare cases, symptomatic arterial hypotension may occur in patients with uncomplicated arterial hypertension. The likelihood of symptomatic arterial hypotension is higher in patients with arterial hypertension receiving enalapril + hydrochlorothiazide who have reduced circulating blood volume, for example due to diuretic therapy, a low-salt diet, or in cases of diarrhea or vomiting (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects"). In such patients, serum electrolyte levels should be monitored regularly at defined intervals. Symptomatic arterial hypotension has been observed in patients with hypertensive heart disease and heart failure, regardless of concomitant renal insufficiency. It occurs more frequently in patients with more severe degrees of heart failure, as evidenced by the use of high doses of loop diuretics, hyponatremia, or impaired renal function. Therapy in such patients should be initiated under medical supervision, and patients should be closely monitored when adjusting the dose of this medicinal product and/or diuretic. A similar approach should be applied to patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, 0.9% sodium chloride solution should be administered intravenously. Transient hypotensive response is not a contraindication for continuing treatment with the medicinal product, which can be resumed after blood pressure has increased following restoration of blood volume.

Renal function impairment

The medicinal product Enalapril N-Teva should not be prescribed to patients with renal insufficiency (creatinine clearance <80 ml/min and >30 ml/min) until enalapril titration has established that the patient requires precisely the dose contained in this medicinal form (see section "Method of administration and dosage").

In some patients with arterial hypertension who have no history of kidney disease, increased blood urea nitrogen and serum creatinine concentrations have been observed during concomitant use of enalapril and diuretics (see section "Special precautions. Hydrochlorothiazide. Renal function impairment"). In such cases, treatment with the medicinal product should be discontinued. These cases may indicate the presence of renal artery stenosis (see section "Special precautions. Enalapril. Renovascular hypertension").

Hyperkalemia

The combined use of enalapril and low-dose diuretics may not exclude the possibility of hyperkalemia development (see section "Special precautions. Enalapril. Hyperkalemia").

Lithium

Generally, lithium is not recommended to be used in combination with enalapril and diuretics (see section "Interaction with other medicinal products and other forms of interaction").

Enalapril

Aortic stenosis/hypertrophic cardiomyopathy

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

Renal function impairment

Renal insufficiency associated with enalapril use has been reported, occurring predominantly in patients with severe heart failure or underlying kidney disease, including renal artery stenosis. When diagnosed promptly and appropriately treated, enalapril-associated renal insufficiency is usually reversible.

Renovascular hypertension

The risk of developing arterial hypotension and renal insufficiency increases when treating patients with bilateral renal artery stenosis or stenosis of the renal artery of a single functioning kidney with ACE inhibitors. In such cases, renal function impairment may be accompanied by only minor changes in serum creatinine concentration. For such patients, treatment with the medicinal product should be initiated with low doses under strict medical supervision, with careful dose titration and monitoring of renal function.

Kidney transplantation

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

Hepatic insufficiency

In isolated cases, the use of ACE inhibitors has been associated with a syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant hepatic necrosis, sometimes with fatal outcome. The mechanism of this syndrome remains unclear. If patients treated with ACE inhibitors develop jaundice or marked elevation of liver enzymes, ACE inhibitor therapy should be discontinued and appropriate medical supervision provided.

Neutropenia/agranulocytosis

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia occurs rarely in patients with normal renal function and absence of other complicating factors. Enalapril should be prescribed with particular caution to patients with collagen vascular disease involving vessels, those receiving immunosuppressants, allopurinol, procainamide, or a combination of these factors, especially in patients with pre-existing renal function impairment. Serious infections have been observed in some of these patients, which in some cases do not respond to intensive antibiotic therapy. Periodic monitoring of white blood cell count and informing patients about the need to report any signs of infection are recommended when prescribing enalapril to such patients.

Hypersensitivity/angioedema

Cases of angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been reported in patients receiving ACE inhibitors, including enalapril, which may develop at any time during treatment. In such cases, enalapril should be discontinued immediately, and appropriate monitoring of the patient should be initiated to ensure complete resolution of symptoms. Even when only tongue swelling occurs without respiratory distress, patients may require prolonged monitoring, as treatment with antihistamines and corticosteroids may be insufficient.

Very rare cases of fatal outcomes due to laryngeal or tongue angioedema have been reported. In patients with swelling of the tongue, glottis, or larynx, obstruction of the airways may occur, especially in patients with a history of surgical treatment of the airways. In case of angioedema of the tongue, glottis, or larynx capable of causing airway obstruction, appropriate therapy should be initiated immediately, which may include subcutaneous administration of 1:1000 epinephrine solution (0.3–0.5 ml) and/or measures to ensure airway patency.

According to reports, angioedema occurs more frequently in individuals of non-black race compared to patients of other races receiving ACE inhibitors.

The risk of developing angioedema during ACE inhibitor therapy may be higher in patients with a history of angioedema unrelated to ACE inhibitor use (see section "Contraindications").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema development. Treatment with sacubitril/valsartan may be initiated only 36 hours after the last dose of enalapril. Treatment with enalapril may be initiated only 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with racemase inhibitors, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may lead to an increased 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 racemase inhibitors, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving an ACE inhibitor.

Anaphylactoid reactions during desensitization therapy for insect venom

In isolated cases, life-threatening anaphylactoid reactions have been observed in patients receiving ACE inhibitors during desensitization therapy for insect venom. The development of such reactions can be prevented by temporarily discontinuing ACE inhibitor therapy before each desensitization procedure.

Anaphylactoid reactions during LDL apheresis

In isolated cases, life-threatening anaphylactoid reactions have been observed in patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis using dextran sulfate. The development of such reactions can be prevented by temporarily discontinuing ACE inhibitor therapy before each apheresis procedure.

Patients undergoing hemodialysis

Cases of anaphylactoid reactions have been reported in patients undergoing hemodialysis with high-flux membranes (e.g., AN 69®) while concurrently receiving an ACE inhibitor. For such patients, dialysis membranes of another type should be used or antihypertensive agents of another class (see section "Contraindications").

Patients with diabetes mellitus

Patients with diabetes mellitus who are taking oral antidiabetic agents or insulin and start taking an ACE inhibitor should be advised to carefully monitor their blood glucose levels, especially during the first month of therapy (see section "Interaction with other medicinal products and other forms of interaction").

Cough

Cough has been reported during ACE inhibitor therapy. This cough is usually non-productive, persistent, and resolves after discontinuation of treatment. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgical procedures/anesthesia

During major surgical procedures or anesthesia with agents causing arterial hypotension, enalapril blocks the formation of angiotensin II due to compensatory renin release. Arterial hypotension arising through this mechanism can be corrected by increasing circulating blood volume (see section "Interaction with other medicinal products and other forms of interaction").

Hyperkalemia

Elevated serum potassium levels have been observed in individual patients treated with ACE inhibitors, including enalapril. Risk factors for hyperkalemia include renal insufficiency, diabetes mellitus, concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, or amiloride), potassium-containing preparations, potassium salt substitutes, or concomitant use of other drugs causing increased serum potassium concentration (e.g., heparin). Hyperkalemia may cause serious and even fatal arrhythmias. If concomitant administration of enalapril and any of the above-mentioned drugs is necessary, these drugs should be used with caution and serum potassium levels should be monitored regularly (see section "Interaction with other medicinal products and other forms of interaction").

Serum potassium

ACE inhibitors may cause hyperkalemia as they suppress aldosterone release. This effect is usually insignificant in patients with normal renal function. However, in patients with impaired renal function and/or in patients taking potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim or co-trimoxazole (also known as trimethoprim/sulfamethoxazole), and particularly aldosterone antagonists or angiotensin receptor blockers, hyperkalemia may occur. Caution should be exercised when using potassium-sparing diuretics and angiotensin receptor blockers in patients taking ACE inhibitors. In such patients, serum potassium levels and renal function should be monitored (see section "Interaction with other medicinal products and other forms of interaction").

Ethnic characteristics

Like other ACE inhibitors, enalapril shows lower efficacy in reducing blood pressure in patients of non-black race compared to individuals of other races, possibly related to the higher prevalence of low-renin forms of arterial hypertension in individuals of this race.

Hydrochlorothiazide

Renal function impairment

The medicinal product Enalapril N-Teva may be used in patients with moderate renal function impairment (creatinine clearance 30–60 ml/min) only after a careful benefit-risk assessment and under strict monitoring of renal function. In patients with kidney disease, thiazides may cause azotemia. Cumulative effects of the medicinal product may occur in patients with impaired renal function. If worsening renal insufficiency occurs, characterized by increased blood total nitrogen without protein nitrogen, the continuation of diuretic therapy should be critically reconsidered. Discontinuation of diuretic therapy should be considered (see section "Contraindications").

Hepatic function impairment

Thiazide preparations should be used with caution in patients with hepatic insufficiency or progressive liver disease, as even minor changes in water-electrolyte balance may lead to the development of hepatic coma (see sections "Contraindications" and "Special precautions. Enalapril. Hepatic insufficiency").

Metabolic and endocrine effects

Thiazide group preparations may impair glucose tolerance. Patients with diabetes mellitus may require adjustment of insulin or oral hypoglycemic agent doses. Latent diabetes mellitus may manifest during thiazide diuretic therapy.

Increased cholesterol and triglyceride levels may be associated with thiazide diuretic therapy. Thiazide diuretic therapy may cause hyperuricemia and/or exacerbation of gout in some patients. This effect on hyperuricemia is dose-dependent. Enalapril may increase urinary uric acid excretion and thereby attenuate the hyperuricemic effect of hydrochlorothiazide.

Electrolyte imbalance

As in other patients receiving diuretic therapy, serum electrolyte levels should be monitored regularly at defined intervals.

Thiazides (including hydrochlorothiazide) may cause disturbances in water or electrolyte balance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Signs indicating disturbances in water-electrolyte balance include dry mouth, thirst, weakness, lethargic sleep, drowsiness, restlessness, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, and gastrointestinal disorders such as nausea or vomiting.

Although hypokalemia may develop during thiazide diuretic use, concomitant therapy with enalapril may reduce diuretic-induced hypokalemia. The highest risk of hypokalemia occurs in patients with liver cirrhosis, patients with accelerated diuresis, inadequate oral intake of electrolytes, and patients receiving concomitant therapy with corticosteroids or ACTH (see section "Interaction with other medicinal products and other forms of interaction").

Hyponatremia may occur in patients with edema during hot weather. Chloride deficiency is usually insignificant and does not require treatment.

Thiazide preparations may reduce calcium excretion in urine and cause a transient slight increase in serum calcium levels in the absence of calcium metabolism disorders. Marked hypercalcemia may be a sign of occult hyperparathyroidism. Thiazide preparations should be discontinued before testing parathyroid function.

It has been established that thiazide preparations can enhance magnesium excretion in urine, potentially leading to hypomagnesemia.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative exposure dose of hydrochlorothiazide was noted in two epidemiological studies based on data from the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for NMSC development.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin changes. To reduce the risk of skin cancer, patients should be advised to take preventive measures such as limiting exposure to sunlight and ultraviolet radiation, or using appropriate protective measures when exposed to solar or ultraviolet rays. Suspicious skin lesions should be examined immediately, if necessary with histological examination of biopsy material. The use of hydrochlorothiazide should be reconsidered in patients with a history of NMSC (see also section "Side effects").

Anti-doping test

Hydrochlorothiazide contained in this medicinal product may cause a positive reaction in anti-doping tests.

Pregnancy

Women planning pregnancy should be switched to an alternative antihypertensive agent with an established safety profile for use during pregnancy. Upon confirmation of pregnancy, hydrochlorothiazide therapy must be discontinued immediately and, if necessary, alternative treatment initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

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

Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defect, transient myopia, and acute angle-closure glaucoma.

Acute respiratory toxicity

Very rare cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide intake. Pulmonary edema usually develops within minutes or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening lung condition, and hypotension. If ARDS is suspected, the medicinal product Enalapril N-Teva should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after hydrochlorothiazide intake.

Other

Hypersensitivity reactions may occur during thiazide preparation use, regardless of a history of allergy or bronchial asthma. Cases of systemic lupus erythematosus exacerbation or transition to an active phase have been reported.

Lactose. This medicinal product contains monohydrate lactose. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not use this product.

Sodium. This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

The use of ACE inhibitors and hydrochlorothiazide during pregnancy is contraindicated (see sections "Contraindications" and "Special precautions").

ACE inhibitors

If pregnancy is confirmed, ACE inhibitor therapy should be discontinued immediately and, if possible, alternative therapy initiated. It is known that ACE inhibitor use during the second and third trimesters of pregnancy may cause fetotoxicity (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal insufficiency, hypotension, hyperkalemia). If ACE inhibitors were used during the second trimester of pregnancy, ultrasound examination of embryonic kidney function and embryonic skull is recommended.

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

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide use during pregnancy, especially in the first trimester. 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 disrupt fetoplacental circulation and cause jaundice in the fetus or newborn, electrolyte imbalance, and thrombocytopenia.

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

Period of breastfeeding

The medicinal product Enalapril N-Teva should not be used during breastfeeding. Enalapril and hydrochlorothiazide pass into breast milk.

During breastfeeding, a decrease or even suppression of lactation has been observed in women associated with thiazide use. Due to the possibility of serious adverse reactions in the infant, a decision should be made to discontinue breastfeeding or discontinue treatment.

If the use of the medicinal product Enalapril N-Teva is considered necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving vehicles or operating machinery.

The possibility of dizziness and weakness should be considered when driving vehicles or operating machinery. Treatment with this medicinal product requires regular medical monitoring. Due to the possibility of individual reactions to the drug, reaction ability may change to such an extent that it may impair the ability to actively participate in road traffic, operate machinery, or work without reliable support. This is particularly relevant at the beginning of treatment, dose increase, drug change, and when combined with alcohol.

Method of Administration and Dosage

In general, treatment of arterial hypertension should be initiated with a single active ingredient at a low dose (with gradual dose escalation). The use of the fixed-dose combination drug Enalapril H-Teva is recommended only after prior individual dose adjustment (dose titration) of the separate components (i.e., enalapril and hydrochlorothiazide). When clinically appropriate, transition from monotherapy to the fixed combination may be made directly.

The medicinal product Enalapril H-Teva can be taken independently of food intake. The prescribed daily dose should be taken in the morning with a large amount of fluid. The break line is intended solely to facilitate tablet splitting for easier swallowing and does not ensure equal dose division.

Dosage

The usual daily dose for patients requiring combination therapy is 1 tablet of Enalapril H-Teva (containing 10 mg enalapril maleate and 25 mg hydrochlorothiazide) once daily.

Note: Since excessive reduction in arterial pressure may occur when switching from enalapril monotherapy to the combination Enalapril H-Teva, particularly in patients with salt and/or fluid depletion (e.g., due to vomiting, diarrhea, prior diuretic therapy), severe heart failure, severe arterial hypertension, or renal hypertension, such patients should be monitored for approximately 8 hours.

Dosage for Patients with Renal Impairment (creatinine clearance 30–60 mL/min) and Elderly Patients (over 65 years of age)

Dose adjustment should be performed with particular caution (titration of individual components).

Elderly Patients

A more pronounced reduction in arterial pressure may occur in elderly patients after taking Enalapril H-Teva compared to younger patients, as renal function impairment is more common in elderly patients. Therefore, appropriate dose adjustment is required in elderly patients. In patients aged 65 years and older, monitoring of blood pressure and renal function is recommended.

Children.

The safety and efficacy of Enalapril H-Teva in children have not been sufficiently established; therefore, administration of this medicinal product to children is not recommended.

Overdose.

There is no specific information available regarding treatment of overdose with Enalapril H-Teva. Treatment is symptomatic and supportive. Administration of Enalapril H-Teva should be discontinued and careful monitoring of the patient’s condition ensured. Recommended measures include induction of emesis, administration of activated charcoal and laxatives if the tablets were recently ingested, as well as correction of dehydration, electrolyte imbalances, and arterial hypotension according to established procedures.

Enalapril

The main signs of overdose known to date are profound arterial hypotension, beginning approximately 6 hours after tablet ingestion, accompanied by blockade of the renin-angiotensin system and stupor. Symptoms associated with overdose of ACE inhibitors may include circulatory shock, disturbances in electrolyte balance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Serum enalapril levels 100 and 200 times higher than normal therapeutic levels have been reported after ingestion of 300 mg and 440 mg of enalapril, respectively.

Recommended treatment of overdose is intravenous infusion of physiological saline. If arterial hypotension occurs, the patient should be placed in a shock position. If possible, infusion of angiotensin II and/or intravenous administration of catecholamines may also be considered. If tablets were ingested recently, measures aimed at eliminating enalapril should be undertaken (e.g., emesis, gastric lavage, administration of adsorbents and sodium sulfate). Enalaprilat may be removed from systemic circulation by hemodialysis. In cases of bradycardia resistant to treatment, cardiac pacing is indicated. Continuous monitoring of vital functions, serum electrolyte levels, and serum creatinine is required.

Hydrochlorothiazide

The most common signs and symptoms result from electrolyte depletion (hypokalemia, hypochloremia, hyponatremia), seizures, somnolence, confusion, circulatory shock, and renal failure due to dehydration from excessive diuresis. If digoxin is also being administered, hypokalemia may exacerbate cardiac arrhythmias.

Side effects

Adverse reactions are classified by system organ class and frequency. Within each group, adverse reactions are listed in order of decreasing severity: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders: uncommon – anaemia (including aplastic and haemolytic anaemia due to G-6-PD deficiency); rare – neutropenia, decreased haemoglobin and haematocrit, thrombocytopenia, agranulocytosis, bone marrow suppression, leucopenia, pancytopenia, lymphadenopathy, autoimmune disorders.

Metabolism and nutrition disorders: common – hypokalaemia, increased cholesterol levels, increased triglyceride levels, hyperuricaemia (up to gout attacks); uncommon – hypoglycaemia (see section "Special precautions"); hypomagnesaemia; rare – hyperglycaemia, glucosuria; very rare – hypercalcaemia. With prolonged continuous use, hydrochlorothiazide commonly causes disturbances in fluid and electrolyte balance, namely hypokalaemia and hyponatraemia, as well as hypermagnesuria, hypomagnesaemia, hypochloraemia and hypercalcaemia. As a consequence of electrolyte and fluid loss, metabolic alkalosis may develop.

Nervous system disorders: common – headache, depression; uncommon – confusion and seizures due to dehydration and excessive diuresis, drowsiness, insomnia, nervousness, decreased libido, peripheral neuropathy with paraesthesia, vertigo; rare – abnormal dreams, sleep disorders, clouding of consciousness, paralysis and muscle weakness (due to hypokalaemia).

Eye disorders: very common – blurred vision; rare – decreased tear production; frequency not known – choroidal effusion.

Ear and labyrinth disorders: uncommon – tinnitus.

Cardiac and vascular disorders: very common – dizziness; uncommon – arterial hypotension (including orthostatic hypotension), syncope, chest pain, cardiac rhythm disturbances, angina pectoris, tachycardia, orthostatic hypotension, palpitations, myocardial infarction or cerebrovascular stroke (possibly due to excessive blood pressure reduction in patients at increased risk); rare – Raynaud's syndrome, thrombosis and embolism (due to haemoconcentration, particularly in elderly patients and those with venous disorders), vasculitis.

Respiratory, thoracic and mediastinal disorders: very common – dry cough; common – dyspnoea; uncommon – rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma; rare – pulmonary infiltrates, respiratory distress (including pneumonitis and pulmonary oedema with shock symptoms), rhinitis, allergic alveolitis/eosinophilic pneumonia; very rare – acute respiratory distress syndrome.

Gastrointestinal disorders: very common – nausea; common – diarrhoea, abdominal pain, taste disturbances (transient taste loss); uncommon – flatulence, intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, loss of appetite, gastric mucosal irritation, dry mouth, peptic ulcer; rare – stomatitis/aphthous ulcers, glossitis; very rare – angioneurotic oedema of the intestine.

Hepatobiliary disorders: rare – hepatic failure, liver necrosis (may be fatal), hepatitis (hepatocellular or cholestatic), cholestatic jaundice, cholecystitis (particularly in patients with pre-existing gallstone disease).

Skin and subcutaneous tissue disorders: common – rash (exanthema), hypersensitivity/angioedema (angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported); uncommon – increased sweating, pruritus, urticaria, alopecia; rare – polymorphic erythema, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, purpura, cutaneous lupus erythematosus, erythroderma, bullous dermatosis.

A syndrome complex has been reported which may include some or all of the following symptoms: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibody test, elevated ESR, eosinophilia and leucocytosis. Skin rashes, photosensitivity or other dermatological manifestations may occur. During ACE inhibitor therapy, psoriasiform skin changes and onycholysis have been observed.

Musculoskeletal and connective tissue disorders: uncommon – muscle cramps.

Renal and urinary disorders: uncommon – renal dysfunction, renal failure (due to hypovolaemia), proteinuria; rare – oliguria, interstitial nephritis.

Reproductive system and breast disorders: uncommon – impotence; rare – gynaecomastia.

Benign, malignant and unspecified neoplasms (including cysts and polyps): frequency not known – non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma). Non-melanoma skin cancer: epidemiological studies have shown an association between the occurrence of non-melanoma skin cancer and cumulative dose of hydrochlorothiazide (see section "Special precautions").

General disorders and administration site conditions: very common – weakness; common – fatigue; uncommon – flushing, malaise, fever.

Investigations: common – hyperkalaemia, increased serum creatinine; uncommon – increased blood urea, hyponatraemia; rare – increased liver enzymes, increased serum bilirubin concentration.

Reporting of suspected adverse reactions. All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of reach and sight of children.

Packaging. 10 tablets in a blister; 2, 3, 5, 6 or 10 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Teva Pharmaceutical Works Private Limited Company.

Manufacturer's address and place of business.

Unit 1; Pallagi str. 13, H-4042 Debrecen, Hungary.