Enap-N, tablets 25 mg+10 mg 60 pcs

Heart failure, Hypertension (high blood pressure), Edema

Arterial hypertension (patients who are indicated for combination therapy).

Indications

Arterial hypertension (patients for whom combination therapy is indicated).

Special instructions

Arterial hypotension

Arterial hypotension with all clinical consequences can be observed after the first dose of Enap® N tablets in patients with severe CHF and hyponatremia, severe renal failure or left ventricular dysfunction and, in particular, in patients with hypovolemia as a result of diuretic therapy, a salt-free diet, diarrhea, vomiting or hemodialysis.

If arterial hypotension occurs, it is necessary to place the patient on his back with a low head and, if necessary, adjust the volume of blood volume by infusion of a solution of 0.9% sodium chloride. Arterial hypotension that occurs after taking the first dose is not a contraindication for further treatment.

Caution is required in patients with coronary heart disease, severe cerebrovascular disease, aortic stenosis or idiopathic hypertrophic obstructive subaortic stenosis that obstructs the outflow of blood from the left ventricle, severe atherosclerosis, in elderly patients as a result of the risk of developing arterial hypotension and deterioration of blood supply to the heart, brain and kidneys.

Disturbances of water and electrolyte balance

Regular monitoring of serum electrolyte concentrations during treatment is necessary to identify possible imbalances and promptly take the necessary measures. Determination of serum electrolyte concentrations is mandatory for patients with prolonged diarrhea and vomiting.

In patients taking the drug Enap® N, it is necessary to identify signs of water-electrolyte imbalance, such as dry mouth, thirst, weakness, drowsiness, increased excitability, myalgia and cramps (mainly of the calf muscles), decreased blood pressure, tachycardia, oliguria and gastrointestinal disorders (nausea, vomiting).

Renal dysfunction

The drug Enap® N in patients with renal failure (creatinine clearance 30-75 ml/min) should be used only after preliminary titration of the doses of enalapril and hydrochlorothiazide separately, according to the doses in the combined drug Enap® N.

Liver dysfunction

The drug Enap® N should be used with caution in patients with liver failure or progressive liver diseases, since hydrochlorothiazide can cause hepatic coma even with minimal disturbances in water and electrolyte balance. Several cases of acute liver failure with cholestatic jaundice, fulminant liver necrosis and death (rarely) have been reported during treatment with ACE inhibitors. If jaundice occurs and the activity of liver transaminases increases, treatment with Enap® N should be stopped immediately, and patients should be monitored.

Metabolic and endocrine effects

Caution is necessary in all patients treated with oral hypoglycemic agents or insulin, since hydrochlorothiazide may weaken and enalapril may enhance their effects.

Thiazide diuretics may reduce renal excretion of calcium and cause a slight and transient increase in serum calcium.

Severe hypercalcemia may be a sign of latent hyperparathyroidism. Before testing the function of the parathyroid glands, thiazide diuretics must be discontinued.

During treatment with thiazide diuretics, the concentrations of cholesterol and triglycerides in the blood serum may increase.
Therapy with thiazide diuretics may worsen hyperuricemia and/or aggravate gout in some patients. However, enalapril increases the excretion of uric acid by the kidneys, thereby counteracting the hyperuricemic effect of hydrochlorothiazide.

Allergic reactions/Angioedema

If angioedema of the face occurs, it is usually sufficient to discontinue therapy and prescribe antihistamines to the patient.

Angioedema of the tongue, pharynx or larynx can be fatal. In case of angioedema of the tongue, pharynx or larynx, which can lead to airway obstruction, it is necessary to immediately administer epinephrine (0.3-0.5 ml of epinephrine (adrenaline) solution subcutaneously in a ratio of 1:1000) and maintain airway patency (intubation or tracheostomy).

Among black patients receiving ACE inhibitor therapy, the incidence of angioedema is higher than among patients of other races.

Patients with a history of angioedema not associated with ACE inhibitors are at increased risk of developing angioedema when taking any ACE inhibitor.

In patients taking thiazide diuretics, hypersensitivity reactions can develop both with and without a history of allergic reactions. Worsening of systemic lupus erythematosus has been reported.

Due to the increased risk of anaphylactic reactions, Enap® N should not be prescribed to patients undergoing hemodialysis using high-flow polyacrylonitrile membranes (AN69®), undergoing low-density lipoprotein apheresis with dextran sulfate and immediately before the desensitization procedure to wasp or bee venom.

Surgical interventions/general anesthesia

Before surgery (including dentistry), it is necessary to warn the anesthesiologist about the use of ACE inhibitors.
During surgery or general anesthesia with the use of drugs that cause arterial hypotension, ACE inhibitors may block the formation of angiotensin II in response to compensatory release of renin. If a pronounced decrease in blood pressure develops, explained by a similar mechanism, it can be corrected by increasing the volume of circulating blood.

Cough

Cough has been reported when using ACE inhibitors. The cough is dry and prolonged, which disappears after stopping taking ACE inhibitors. When making a differential diagnosis of cough, cough caused by the use of ACE inhibitors must also be taken into account.

Impact on the ability to drive a vehicle and other mechanical means:

At the beginning of treatment with Enap® N, a pronounced decrease in blood pressure, dizziness and drowsiness may occur, which can reduce the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. Therefore, at the beginning of treatment, it is not recommended to drive vehicles or engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Active ingredient

Hydrochlorothiazide, Enalapril

Composition

For 1 tablet:

Active ingredients:

Hydrochlorothiazide 25.00 mg

Enalapril maleate 10.00 mg

Excipients:

sodium bicarbonate 5.10 mg,

lactose monohydrate 120.02 mg,

corn starch 29.60 mg,

pregelatinized starch 6.00 mg,

talc 6.00 mg,

magnesium stearate 2.00 mg,

quinoline yellow dye, E104 0.06 mg

Contraindications

– hypersensitivity (including to individual components of the drug or sulfonamide derivatives);
– anuria, severe renal dysfunction (creatinine clearance (CC) less than 30 ml/min);
– a history of angioedema associated with previous use of ACE inhibitors, as well as hereditary or idiopathic angioedema;
– bilateral renal artery stenosis, stenosis of the artery of a single kidney;
– pregnancy and lactation period;
– age under 18 years (efficacy and safety have not been established);
– lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Side Effects

Classification of the incidence of side effects of the World Health Organization (WHO):
– very often (> 1/10)
– often (> 1/100 and – infrequently (> 1/1000 and – rarely (> 1/10000 and – very rarely) (On the part of the hematopoietic and lymphatic system:
– rarely: neutropenia, decreased hemoglobin and hematocrit, thrombocytopenia, leukopenia, suppression of bone marrow function;

Metabolic and nutritional disorders
– uncommon: gout;

From the central nervous system:
– very often: dizziness, weakness;
– often: headache, asthenia;
– infrequently: insomnia, drowsiness, paresthesia, increased excitability;

From the senses:
– uncommon: tinnitus;

From the cardiovascular system
– often: orthostatic hypotension;
– uncommon: fainting, marked decrease in blood pressure, palpitations, tachycardia, chest pain;

From the respiratory system:
– often: cough;
– uncommon: shortness of breath;

From the digestive system:
– often: nausea;
– uncommon: diarrhea, vomiting, dyspepsia, abdominal pain, flatulence, constipation, dry mouth;
– rarely: cholestatic jaundice, fulminant necrosis;

Allergic reactions:
– uncommon: Stevens-Johnson syndrome;
– rarely: angioedema;
– very rarely: intestinal angioedema;

From the skin:
– uncommon: skin rash, itching, increased sweating, skin necrosis, alopecia;

From the genitourinary system:
– uncommon: impaired renal function, acute renal failure, impotence, decreased libido;

From the musculoskeletal system:
– often: muscle spasms;
– uncommon: arthralgia;

Laboratory indicators:
– rarely: hyperglycemia, hyperuricemia, hypokalemia, hyperkalemia, hyponatremia, increased concentrations of urea and creatinine in the blood serum, increased activity of liver transaminases and bilirubin;

Other:
– a symptom complex is described that may include fever, myalgia and arthralgia, serositis, vasculitis, increased erythrocyte sedimentation rate, leukocytosis and eosinophilia, skin rash, and a positive test for antinuclear antibodies.

Interaction

Serum potassium

The use of potassium supplements, potassium-sparing agents, or potassium-containing salt substitutes, especially in patients with renal failure, can lead to a significant increase in serum potassium levels. Potassium loss while taking thiazide diuretics is usually reduced by enalapril. Serum potassium levels usually remain within normal limits.

Lithium

When used simultaneously with lithium preparations, the excretion of lithium is slowed down (increased cardiotoxic and neurotoxic effects of lithium).

Non-depolarizing muscle relaxants

Thiazide diuretics may enhance the effect of tubocurarine chloride.

Narcotic analgesics/neuroleptics

Concomitant use of thiazide diuretics, narcotic analgesics or phenothiazine derivatives can lead to orthostatic hypotension.

Other antihypertensive drugs

The combined use of beta-blockers, alpha-blockers, ganglion-blocking agents, methyldopa or slow calcium channel blockers with enalapril can further reduce blood pressure.

Allopurinol, cytostatics and immunosuppressants

Concomitant use with ACE inhibitors may increase the risk of developing leukopenia.

Glucocorticosteroids, calcitonin

Concomitant use of thiazide diuretics can lead to the development of hypokalemia.

Cyclosporine

Concomitant use with ACE inhibitors may increase the risk of developing hyperkalemia.

Non-steroidal anti-inflammatory drugs

Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) (including selective cyclooxygenase-2 inhibitors) may weaken the antihypertensive effect of ACE inhibitors.

NSAIDs and ACE inhibitors have an additive effect on increasing serum potassium, which may lead to a deterioration of renal function, especially in patients with impaired renal function. This effect is reversible.

NSAIDs may reduce the diuretic and antihypertensive effects of diuretics.

Antacids

Antacids may reduce the bioavailability of ACE inhibitors.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Thiazide diuretics may reduce the effect of adrenergic agonists (epinephrine).

Ethanol enhances the hypotensive effect of ACE inhibitors and thiazide diuretics, which can cause orthostatic hypotension.

Oral hypoglycemic agents and insulin

Epidemiological studies suggest that the simultaneous use of ACE inhibitors and hypoglycemic agents may lead to hypoglycemia. More often, hypoglycemia develops in the first weeks of therapy in patients with impaired renal function. Long-term and controlled clinical studies of enalapril do not confirm these data and do not limit the use of enalapril in patients with diabetes mellitus. However, such patients should be under regular medical supervision.

The use of oral hypoglycemic agents and insulin with thiazide diuretics may require adjustment of their doses.

Cholestyramine and colestipol

A single dose of cholestyramine or colestipol reduces the absorption of hydrochlorothiazide in the gastrointestinal tract by 85% and 43%, respectively.

Gold preparations

With the simultaneous use of ACE inhibitors and gold preparations (sodium aurothiomalate) intravenously, a symptom complex has been described, including facial flushing, nausea, vomiting and arterial hypotension.

Overdose

Symptoms: increased diuresis, marked decrease in blood pressure with bradycardia or other heart rhythm disturbances, convulsions, disturbances of consciousness (including coma), acute renal failure, disturbances in the acid-base state and water-electrolyte balance of the blood.

Treatment: the patient is transferred to a horizontal position with raised legs.

In mild cases, gastric lavage and ingestion of activated charcoal are indicated; in more serious cases, measures aimed at stabilizing blood pressure are indicated – intravenous administration of plasma substitutes, infusion of 0.9% sodium chloride solution.

The patient must monitor the level of blood pressure, heart rate, respiratory rate, serum concentration of urea, creatinine, electrolytes and diuresis, if necessary, intravenous administration of angiotensin II, hemodialysis (enalaprilat excretion rate – 62 ml/min).

Clinical pharmacology

A combined drug, the effect of which is determined by the properties of the components included in its composition.

Enalapril, an ACE inhibitor, is a prodrug: as a result of its hydrolysis, enalaprilat is formed, which inhibits ACE.

Hydrochlorothiazide is a thiazide diuretic. Acts at the level of the distal renal tubules, increasing the excretion of sodium and chloride ions.

At the beginning of treatment with hydrochlorothiazide, the volume of fluid in the vessels decreases as a result of increased excretion of sodium and fluid, which leads to a decrease in blood pressure and a decrease in cardiac output.

Due to hyponatremia and decreased fluid in the body, the renin-angiotensin-aldosterone system is activated. A reactive increase in angiotensin II concentration partially limits the decrease in blood pressure. With continued therapy, the hypotensive effect of hydrochlorothiazide is based on a decrease in total peripheral vascular resistance. Activation of the renin-angiotensin-aldosterone system results in metabolic effects on blood electrolyte balance, uric acid, glucose and lipids, which partially counteract the effectiveness of antihypertensive treatment.

Despite their effective reduction in blood pressure, thiazide diuretics do not reduce structural changes in the heart and blood vessels. Enalapril enhances the antihypertensive effect: it inhibits the renin-angiotensin-aldosterone system, i.e. angiotensin II production and its effects. Additionally, it reduces the production of aldosterone and enhances the effect of bradykinin and the release of prostaglandins. Since it often has its own diuretic effect, this may enhance the effect of hydrochlorothiazide.

Enalapril reduces pre- and afterload, which unloads the left ventricle, reduces regression of hypertrophy and collagen proliferation, and prevents damage to myocardial cells. As a result, the heart rate slows down and the load on the heart decreases), coronary blood flow improves and oxygen consumption by cardiomyocytes decreases. Thus, the sensitivity of the heart to ischemia is reduced, and the number of dangerous ventricular arrhythmias is reduced. It has a beneficial effect on cerebral blood flow in patients with arterial hypertension and chronic cardiovascular diseases. Prevents the development of glomerulosclerosis, maintains and improves kidney function and slows down the course of chronic kidney disease, even in those patients who have not yet developed arterial hypertension.

It is known that the antihypertensive effect of ACE inhibitors is greater in patients with hyponatremia, hypovolemia and elevated serum renin levels, while the effect of hydrochlorothiazide is independent of serum renin levels. Therefore, the simultaneous administration of enalapril and hydrochlorothiazide has an additional antihypertensive effect. In addition, enalapril prevents or reduces the metabolic effects of diuretic therapy and has a beneficial effect on structural changes in the heart and blood vessels.

The simultaneous administration of an ACE inhibitor and hydrochlorothiazide is used when each drug alone is not sufficiently effective or monotherapy is carried out using maximum doses of the drug, which increases the incidence of undesirable effects. This combination allows you to obtain a better therapeutic effect with lower doses of enalapril and hydrochlorothiazide and reduce the development of undesirable effects.

The antihypertensive effect of the combination usually lasts for 24 hours.

Storage conditions

In a place protected from light, at a temperature not exceeding 25 °C.

Shelf life

5 years

Manufacturer

KRKA dd Novo Mesto, Slovenia