Enalapril 10/hydrochlorothiazide 12,5 krka: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENALAPRIL 10/ HYDROCHLOROTHIAZIDE 12.5 KRKA ENALAPRIL 10/ HYDROCHLOROTHIAZIDE 25 KRKA ENALAPRIL 20/ HYDROCHLOROTHIAZIDE 12.5 KRKA (Enalapril 10/ hydrochlorothiazide 12.5 KRKA Enalapril 10/ hydrochlorothiazide 25 KRKA Enalapril 20/ hydrochlorothiazide 12.5 KRKA)

Composition:

Active substances: enalapril; hydrochlorothiazide;

1 tablet contains enalapril maleate 10 mg and hydrochlorothiazide 12.5 mg

or enalapril maleate 10 mg and hydrochlorothiazide 25 mg,

or enalapril maleate 20 mg and hydrochlorothiazide 12.5 mg;

Excipients: sodium hydrocarbonate, lactose monohydrate, maize starch, pregelatinized starch, talc, magnesium stearate, quinoline yellow dye (E 104) – only in Enalapril 10/ hydrochlorothiazide 25 KRKA.

Pharmaceutical form. Tablets.

Main physicochemical properties:

ENALAPRIL 10/ HYDROCHLOROTHIAZIDE 12.5 KRKA: round, flat tablets of white color with bevelled edges and a score line on one side;

ENALAPRIL 20/ HYDROCHLOROTHIAZIDE 12.5 KRKA: round, flat tablets of white color with bevelled edges and a score line on one side;

ENALAPRIL 10/ HYDROCHLOROTHIAZIDE 25 KRKA: round, flat tablets of yellow color with bevelled edges and a score line on one side.

Pharmacotherapeutic group. Combined preparations of ACE inhibitors. Enalapril and diuretics. ATC code C09B A02.

Pharmacological properties.

Pharmacodynamics.

Enalapril maleate

Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I into the pressor substance angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a reduction in plasma angiotensin II levels, resulting in increased plasma renin activity (due to suppression of the negative feedback on renin release) and reduced aldosterone secretion.

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

Mechanism of action

Although the mechanism by which enalapril reduces blood pressure is primarily attributed to inhibition of the renin-angiotensin-aldosterone system, which plays a key role in blood pressure regulation, enalapril may exert antihypertensive effects even in patients with low-renin hypertension.

Enalapril maleate – hydrochlorothiazide

Hydrochlorothiazide is a diuretic and antihypertensive agent that increases plasma renin activity. Although enalapril exerts antihypertensive effects even in patients with low-renin hypertension, concomitant administration of hydrochlorothiazide contributes to greater blood pressure reduction in these patients.

Dual blockade

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

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

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

Therefore, ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a trial designed to evaluate the benefits of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was prematurely terminated due to an increased risk of adverse outcomes. Cardiovascular mortality and stroke rates were higher in the aliskiren group than in the placebo group, and adverse events and serious adverse events (hyperkalemia, hypotension, and renal dysfunction) occurred more frequently in the aliskiren group than in the placebo group.

Hydrochlorothiazide

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

Non-melanoma skin cancer

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

Pharmacokinetics.

Enalapril

Absorption

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

Following absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent inhibitor of angiotensin-converting enzyme. Peak serum concentrations of enalaprilat are reached 3–4 hours after oral administration of enalapril maleate. Enalapril is primarily eliminated by the kidneys. The main components in urine are enalaprilat, accounting for approximately 40% of the dose, and unchanged enalapril. 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, likely due to binding to ACE. In individuals with normal renal function, steady-state serum concentrations of enalaprilat are achieved by day 4 of enalapril administration. Food intake does not affect gastrointestinal absorption of enalapril. The extent of absorption and hydrolysis of enalapril is similar across different doses within the recommended therapeutic range.

Distribution

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

Biotransformation

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.

Elimination

Enalaprilat is primarily eliminated by the kidneys. The main urinary components of the drug are enalaprilat, accounting for approximately 40% of the dose, and unchanged enalapril. The effective half-life for accumulation of enalaprilat after multiple oral doses of enalapril maleate is 11 hours. In studies measuring plasma concentrations of hydrochlorothiazide over at least 24 hours, the plasma elimination half-life ranged from 5.6 to 14.8 hours. Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys. After oral administration, at least 61% of the dose is excreted unchanged within 24 hours.

Renal impairment

Enalaprilat is removed from the general circulation by hemodialysis.

Lactation

After a single oral dose of 20 mg in five postpartum women, the mean peak concentration of enalapril in breast milk was 1.7 µg/L (range: 0.54–5.9 µg/L) 4–6 hours after dosing. The mean peak concentration of enalaprilat was 1.7 µg/L (range: 1.2–2.3 µg/L), with peaks observed at various times over 24 hours. Based on peak milk concentrations, the calculated maximum dose received by a breastfed infant is approximately 0.16% of the maternal dose normalized to body weight. A woman taking 10 mg of enalapril orally daily for 11 months had a peak milk concentration of enalapril of 2 µg/L at 4 hours post-dose and a peak enalaprilat concentration of 0.75 µg/L approximately 9 hours post-dose. The total amount of enalapril and enalaprilat detected in breast milk over 24 hours was 1.44 µg/L and 0.63 µg/L of milk, respectively. Enalaprilat concentration in breast milk was undetectable (< 0.2 µg/L) 4 hours after a single 5 mg dose in one woman and 10 mg in two women; enalapril levels were not detected.

Clinical characteristics.

Indications.

The medicinal product is indicated for the treatment of mild to moderate hypertension in patients whose condition has been stabilized during therapy with the individual components in the same proportions (see sections “Pharmacodynamic properties”, “Contraindications”, “Special precautions for use”, and “Interaction with other medicinal products and other forms of interaction”).

Contraindications.

Hypersensitivity to enalapril and other angiotensin-converting enzyme (ACE) inhibitors, hydrochlorothiazide and other sulfonamide derivatives, or to any other component of the medicinal product.
History of angioedema associated with previous treatment with ACE inhibitors.
Hereditary or idiopathic angioedema.
Patients with severe renal impairment (creatinine clearance less than 30 mL/min or serum creatinine levels exceeding 265 µmol/L (3 mg/100 mL)).
Refractory hypokalemia or hyperkalemia.
Refractory hyponatremia.
Renal artery stenosis.
Hemodialysis period.
Clinical condition following kidney transplantation.
Severe hepatic impairment.
Anuria, primary hyperaldosteronism.
Symptomatic hyperuricemia (gout).
Pregnancy or planned pregnancy, breastfeeding (see section “Use during pregnancy or lactation”).
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”, “Special precautions for use”).
Concomitant use with sacubitril/valsartan therapy – due to increased risk of angioedema. The medicinal product must not be administered within 36 hours after the last dose of sacubitril/valsartan – a drug containing a neprilysin inhibitor – or following transition from it to another medicinal product (see sections “Special precautions for use” and “Interaction with other medicinal products and other forms of interaction”).

Interaction with other medicinal products and other forms of interaction.

Enalapril maleate – hydrochlorothiazide

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

Clinical studies have demonstrated that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant administration of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased risk of adverse events such as hypotension, hyperkalemia, and worsening renal function (including acute renal failure), compared to treatment with a single RAAS-blocking agent (see sections “Pharmacodynamic properties”, “Contraindications”, “Special precautions for use”).

Other antihypertensive agents

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

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

Lithium

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

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

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, may attenuate the effects of diuretics and other antihypertensive agents. For this reason, the antihypertensive effect of angiotensin II receptor antagonists, ACE inhibitors, or diuretics may be diminished when NSAIDs, including selective COX-2 inhibitors, are administered.

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

Enalapril

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

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving enalapril. The use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), as well as potassium-containing dietary supplements or salt substitutes, may lead to a significant increase in serum potassium levels. Caution should also be exercised when combining enalapril with other 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 agents is not recommended. If the above-mentioned agents are indicated due to hypokalemia, they should be used cautiously with regular monitoring of serum potassium levels (see section “Special precautions for use”).

Diuretics (thiazide or loop diuretics)

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

Tricyclic antidepressants/antipsychotics/narcotics

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

Gold preparations

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

mTOR inhibitors (mammalian target of rapamycin inhibitors)

Concomitant use with mTOR inhibitors (such as temsirolimus, sirolimus, everolimus) may increase the risk of angioedema (see section “Special precautions for use”).

Neprilysin inhibitors

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

Cyclosporine

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

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Alcohol

Alcohol potentiates the hypotensive effect of ACE inhibitors.

Antidiabetic agents

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

Acetylsalicylic acid, thrombolytics, beta-blockers

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

Hydrochlorothiazide

Non-depolarizing muscle relaxants

Thiazide diuretics may potentiate the response to tubocurarine.

Alcohol, barbiturates, narcotic analgesics

Orthostatic hypotension may be potentiated.

Antidiabetic agents (oral hypoglycemic agents and insulin)

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

Cholestyramine and colestipol resins

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

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

Increased risk of torsades de pointes tachycardia.

Digitalis glycosides

Hypokalemia may potentiate or exacerbate cardiac reactions to digitalis toxicity (e.g., increased ventricular excitability).

Corticosteroids, adrenocorticotropic hormone

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

Potassium-wasting 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 forms of interaction”).

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

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

Children

Drug interaction studies have been conducted only in adult patients.

Special precautions for use.

Enalapril and hydrochlorothiazide

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

Dual blockade (e.g., adding an ACE inhibitor to an angiotensin II receptor antagonist) should be restricted only to selected cases with careful monitoring of blood pressure, renal function, and electrolyte levels. Several studies have reported that in patients with established atherosclerotic vascular disease, heart failure, or diabetes with target organ damage, dual RAAS blockade is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to treatment with a single agent acting on the renin-angiotensin-aldosterone system. Do not use enalapril with aliskiren in patients with diabetes or impaired renal function (eGFR < 60 mL/min/1.73 m²) (see sections "Contraindications" or "Special precautions for use").

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

Hypotension and fluid and electrolyte imbalance

Symptomatic arterial hypotension is rarely observed in patients with uncomplicated arterial hypertension. Among patients receiving enalapril/hydrochlorothiazide, arterial hypotension occurs more frequently in patients with salt depletion/volume depletion, e.g., due to diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting (see sections "Interaction with other medicinal products and other forms of interaction", "Undesirable effects"). Regular monitoring of serum electrolyte levels is required in such patients. Symptomatic arterial hypotension has been observed in patients with heart failure, with or without renal insufficiency. Hypotension occurs more frequently in patients with severe forms of heart failure who are receiving higher doses of loop diuretics, have hyponatremia, or impaired renal function. Such patients should start treatment under medical supervision. Particular care is required when adjusting the dose of enalapril/hydrochlorothiazide and/or diuretic. Similarly, patients with ischemic heart disease or cerebrovascular disease should be closely monitored, as a sudden drop in blood pressure may lead to myocardial infarction or stroke.

In case of developing arterial hypotension, the patient should be placed in a supine position and, if necessary, 0.9% sodium chloride solution should be administered intravenously. Transient arterial hypotension during treatment is not a contraindication for continuing therapy, which may be resumed after normalization of blood pressure and restoration of fluid volume.

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

Renal function impairment

Renal function impairment has been reported with enalapril, particularly in patients with severe heart failure or kidney disease, including renal artery stenosis. If diagnosed promptly and treated appropriately, renal failure associated with enalapril therapy is usually reversible.

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

In some patients with arterial hypertension without renal insufficiency, administration of enalapril with a diuretic may lead to increased serum urea and creatinine levels. Dose reduction of enalapril and/or discontinuation of the diuretic may be required. In such cases, the possibility of renal artery stenosis should be considered.

Hyperkalemia

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

Lithium

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

Elderly patients

The efficacy and tolerability of enalapril maleate and hydrochlorothiazide administered together are similar in elderly patients and younger adults with arterial hypertension.

Enalapril

Aortic or mitral stenosis/hypertrophic cardiomyopathy

Like all vasodilators, ACE inhibitors should be used with caution in patients with mitral valve stenosis or left ventricular outflow tract obstruction. Their use should be avoided in cardiogenic shock and obstruction of the left ventricular outflow tract.

Renal function impairment

Renal failure associated with enalapril use has been reported, occurring predominantly in patients with severe heart failure or underlying kidney disease, including renal artery sten游戏副本

Dosage and Administration.

Arterial Hypertension

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

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

The dosage regimen should be individualized depending on the patient's condition and severity of arterial hypertension. Treatment should be initiated with low doses, gradually increasing as needed. The drug is administered orally, independent of food intake. The established daily dose should be taken in the morning with a large amount of fluid.

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

Fixed-dose combination tablets of 10 mg/25 mg and 20 mg/12.5 mg may replace therapy consisting of separate administration of 10 or 20 mg enalapril and 25 or 12.5 mg hydrochlorothiazide, respectively, in patients whose condition has been stabilized on individual component therapy.

Prior Diuretic Therapy. Symptomatic hypotension may occur at the beginning of enalapril/hydrochlorothiazide therapy. It is more commonly observed in patients who have previously received diuretic therapy resulting in disturbances of water-electrolyte balance. Diuretic therapy should be discontinued 2–3 days before initiating treatment with this drug.

Dosing in Renal Impairment

Creatinine clearance above 30 mL/min

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

Creatinine clearance below 30 mL/min

Use of the drug is contraindicated.

Special Populations

For patients with salt depletion/fluid volume depletion, the initial dose of enalapril should be 5 mg or less, and monotherapy titration is recommended.

Dosing in Elderly Patients

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

There is no time limitation regarding the duration of treatment.

Children

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

Overdose

There is no specific information on the treatment of enalapril/hydrochlorothiazide overdose. Management is symptomatic and supportive. Treatment with enalapril/hydrochlorothiazide should be discontinued, and close monitoring of the patient should be initiated. Recommended measures include induction of emesis and/or gastric lavage, correction of dehydration and electrolyte imbalances, and management of arterial hypotension.

Enalapril Maleate

Symptoms The most common signs of overdose, based on available data, are profound arterial hypotension beginning approximately 6 hours after drug intake, coinciding with blockade of the renin-angiotensin-aldosterone system (RAAS), and stupor. Symptoms associated with ACE inhibitor overdose may include circulatory shock, disturbances in electrolyte balance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Plasma enalaprilat levels up to 100 and 200 times higher than maximum therapeutic concentrations have been recorded after ingestion of 300 mg and 440 mg of enalapril, respectively.

Treatment After ingestion of a large quantity of tablets, discontinuation of the drug, monitoring of vital signs in a hospital setting, gastric lavage, administration of activated charcoal, and a laxative are recommended. Treatment is symptomatic. Arterial hypotension should be corrected by infusion of 0.9% sodium chloride solution. Usually, placing the patient in a horizontal position with slight head-down tilt is sufficient. In more severe cases, infusion of 0.9% sodium chloride solution should be performed, and if necessary, infusion of angiotensin II and/or intravenous administration of catecholamines. Blood pressure, pulse, respiration, serum urea, creatinine and electrolyte concentrations, and diuresis should be monitored.

In more severe cases, toxic amounts of enalapril and/or enalaprilat should be removed from the bloodstream via hemodialysis. Pacemaker therapy is indicated for bradycardia resistant to pharmacological treatment. Vital signs and serum electrolyte and creatinine concentrations should be continuously monitored.

Hydrochlorothiazide
The most common manifestations are symptoms caused by electrolyte deficiency (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. If cardiac glycosides are also being administered, hypokalemia may precipitate cardiac arrhythmias. Other manifestations of overdose may include tachycardia, arterial hypotension, shock, weakness, confusion, dizziness, muscle spasms, paresthesia, exhaustion, disturbances of consciousness, nausea, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, and elevated blood urea nitrogen (primarily due to renal failure).

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

Side effects.

The most common side effects were dizziness and increased fatigue, which usually disappeared when the dose was reduced and rarely required discontinuation of the drug.

Organ systems/disorders	Very common (≥ 1/10)	Common (from ≥ 1/100 to < 1/10)	Uncommon (from ≥ 1/1000 to < 1/100)	Rare (from ≥ 1/10000 to < 1/1000)	Very rare (< 1/10000)	Not known (cannot be estimated from available data)
Benign, malignant and unspecified neoplasms (including cysts and polyps)						Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)1)
Blood and lymphatic system disorders			Anemia (including aplastic and hemolytic anemia)	Neutropenia, decreased hemoglobin levels, decreased hematocrit, thrombocytopenia, granulocytosis, bone marrow suppression, leukopenia, pancytopenia, lymphadenopathy, autoimmune disorders
Immune system disorders		Anaphylactic reaction
Endocrine system disorders						Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolic and nutritional disorders		Hypokalemia, increased cholesterol levels, increased triglyceride levels, hyperuricemia	Hypoglycemia2), hypomagnesemia, gout3), electrolyte imbalance (hyponatremia)	Increased blood glucose levels	Hypercalcemia2)
Nervous system and psychiatric disorders		Headache, depression, syncope, taste disturbances	Confusion, somnolence, insomnia, nervousness, paresthesia, vertigo, decreased libido3), restlessness	Abnormal dreams, sleep disturbances, paresis (due to hypokalemia)
Eye disorders	Blurred vision		Xanthopsia			Choroidal effusion
Ear and labyrinth disorders			Tinnitus
Cardiac disorders	Dizziness	Hypotension, orthostatic hypotension, arrhythmia, angina pectoris, tachycardia	Flushing, palpitations, necrotizing vasculitis (angiitis), myocardial infarction or stroke4), possibly due to excessive hypotension in high-risk patients2)	Raynaud's syndrome
Respiratory, thoracic and mediastinal disorders	Cough	Dyspnea	Rhinorrhea, sore throat and hoarseness, bronchospasm/asthma	Lung infiltrates, respiratory distress (including pneumonitis and pulmonary edema), rhinitis, allergic alveolitis/eosinophilic pneumonia	Acute respiratory distress syndrome (ARDS)2)
Gastrointestinal disorders	Nausea	Diarrhea, abdominal pain	Ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcers, flatulence3)	Stomatitis/aphthous ulcers, glossitis	Angioneurotic edema of the intestine
Hepatobiliary disorders				Liver failure, hepatic necrosis (may be fatal), hepatitis (hepatocellular or cholestatic), jaundice, cholecystitis (particularly in patients with pre-existing gallstone disease)
Skin and subcutaneous tissue disorders		Rash (exanthema), hypersensitivity/angioedema: face, extremities, lips, tongue, glottis and/or larynx2)	Diaphoresis, pruritus, urticaria, alopecia	Multiform erythema, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, purpura, cutaneous lupus erythematosus, erythroderma, pemphigoid		A syndrome that may include: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive antinuclear antibody test, elevated ESR, eosinophilia and leukocytosis. Rash, photosensitivity or other dermatological manifestations
Musculoskeletal and connective tissue disorders		Muscle cramps5)	Arthralgia2)
Renal and urinary disorders			Renal dysfunction, renal failure, proteinuria, glucosuria	Oliguria, interstitial nephritis
Reproductive system and breast disorders			Impotence	Gynecomastia
General disorders and administration site conditions	Asthenia	Chest pain, increased fatigue	Malaise, fever
Investigations		Hyperkalemia, increased serum creatinine levels	Increased blood urea nitrogen, hyponatremia	Elevated liver enzymes, increased serum bilirubin levels

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

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions.

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

Packaging.

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

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and site of operations.

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