Enap-H - instructions for use, dose, side effects, contraindications

Enalapril inhibits ACE, promotes conversion of angiotensin I into angiotensin II, reduces the concentration of aldosterone in the blood, increases the release of renin juxtaglomerular cells in the walls of arterioles of glomeruli, improves the functioning of the kallikrein-kinin system, stimulates the release of prostaglandins and endothelium-derived relaxing factor (NO), inhibits the sympathetic nervous system . Together, these effects eliminate spasm and dilate the peripheral arteries, reduce the overall peripheral resistance of blood vessels, systolic and diastolic blood pressure (BP), post- and preload on the myocardium. Expands arteries to a greater extent than veins, with a reflex increase in heart rate (heart rate) is not noted. The hypotensive effect is more pronounced with a high concentration of renin in the blood plasma than with normal or decreased.Reduction of blood pressure within therapeutic limits does not affect cerebral circulation. Improves the blood supply of the ischemic myocardium. Strengthens the renal blood flow, while the glomerular filtration rate does not change. In patients with initially reduced glomerular filtration, its rate usually increases.

The maximum effect of enalapril develops in 6-8 hours and persists up to 24 hours.

Hydrochlorothiazide - Thiazide diuretic with moderate strength of action. Reduces the reabsorption of sodium ions at the level of the cortical segment of the Henle loop, without affecting its area passing through the medulla of the kidney. It blocks carbonic anhydrase in the proximal part of convoluted tubules, increases the excretion of potassium ions, hydrocarbonates and phosphates by the kidneys. Virtually does not affect the acid-base state. Increases the excretion of magnesium ions. Delays in the body calcium ions. The diuretic effect develops after 1-2 hours, reaches a maximum after 4 hours, lasts 10-12 hours. The effect decreases with a decrease in the glomerular filtration rate and stops at a value of less than 30 ml / min. Reduces blood pressure by reducing the volume of circulating blood (BCC), changes in reactivity of the vascular wall.

The use of a combination of enalapril and hydrochlorothiazide leads to a more pronounced decrease in blood pressure in comparison with the monotherapy of each of the drugs alone and allows the anti-hypertensive effect of Enap®H to be maintained for at least 24 hours.

Pharmacokinetics:

Enalapril. After ingestion, absorption is 60%. Eating does not affect absorption. In the liver is metabolized to form an active metabolite of enalaprilat, which is a more effective ACE inhibitor than enalapril. The connection with the proteins of the blood plasma enalaprilata - 50-60%. Time to reach the maximum concentration (TCam) enalapril-1h, enalaprilata - 3-4 hours. Enalaprilat easily passes through the histohematological barriers, excluding the blood-brain barrier, a small amount penetrates through the placenta and into breast milk. Renal clearance of enalapril and enalaprilate is 0.005 ml / s (18 l / h) and 0.00225-0.00264 ml / s (8.1-9.5 l / h), respectively. The half-life of Enalaprilat (T1 / 2) is 11 hours. It is mainly excreted by the kidneys - 60% (20% in the form of enalapril and 40% in the form of enalaprilate), 33% through the intestine (6% in the form of enalapril and 27% in the form of enalaprilate). Removed during hemodialysis (speed 38-62 ml / min) and peritoneal dialysis, serum concentration of enalaprilat after 4-hour hemodialysis decreases by 45-57%.In patients with reduced renal function, excretion slows down, which requires a dose reduction in accordance with renal dysfunction, especially in patients with severe renal failure.

In patients with hepatic insufficiency, metabolism of enalapril can be slowed down without changing its pharmacodynamic effect.

In patients with chronic heart failure (CHF), the absorption and metabolism of enalaprilat slows down, and the volume of distribution also decreases.

Hydrochlorothiazide is absorbed mainly in the duodenum and proximal part of the small intestine. Absorption is 70% and increases by 10% when taken with food. The maximum concentration in the blood serum is achieved after 1.5 - 5 hours. The distribution volume is about 3 l / kg. Connection with blood plasma proteins - 40%. Bioavailability is 70%. In the therapeutic range of doses, the average area under the pharmacokinetic curve increases in direct proportion to the increase in dose, with the appointment of once a day, cumulation is negligible. Penetrates through the hematoplacental barrier and into breast milk. Accumulated in amniotic fluid.The serum concentration of hydrochlorothiazide in the blood of the umbilical vein is almost the same as in the maternal blood. Concentration in the amniotic fluid exceeds that in the blood serum from the umbilical vein (by 19 times). It is not metabolized in the liver, it is excreted primarily by the kidneys: 95% unchanged and about 4% in the form of hydrolyzate-2-amino-4-chloro-m-benzene disulfonamide by glomerular filtration and active tubular secretion in the proximal part of the nephron. The renal clearance of hydrochlorothiazide in healthy volunteers and patients with arterial hypertension is approximately 5.58 ml / s (335 ml / min). Hydrochlorothiazide has a two-phase withdrawal profile. T1 / 2 in the initial phase is 2 hours, in the final phase (10-12 hours after administration) - about 10 hours.

In elderly patients hydrochlorothiazide does not adversely affect the pharmacokinetics of enalapril, but the serum concentration of enalaprilat is higher. When hydrochlorothiazide was prescribed, patients with CHF were found to have a decrease in proportion to the development of CHF by 20-70%. T1 / 2 hydrochlorothiazide increased to 28.9 hours; renal clearance is 0.17-3.12 ml / s (10-187 ml / min) (averages of 1.28 ml / s (77 ml / min).

In patients who underwent intestinal bypass surgery for obesity, hydrochlorothiazide absorption can be reduced by 30%, and serum concentration by 50%, compared to healthy volunteers.

Simultaneous administration of enalapril and hydrochlorothiazide does not affect the pharmacokinetics of each of them.

Indications:Arterial hypertension (patients who are shown combined therapy).

Contraindications:

- hypersensitivity (including to individual components of the drug or sulfonamide derivative);

- Anuria, expressed renal dysfunction (creatinine clearance (CK) less than 30 ml / min);

- angioedema in history, associated with the use of previously ACE inhibitors, as well as hereditary or idiopagic angioedema;

- bilateral stenosis of the renal arteries, stenosis of the artery of a single kidney;

- pregnancy and lactation;

- age under 18 years (effectiveness and safety not established);

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Carefully:

- severe stenosis of the aortic estuary or idiopathic hypertrophic obstructive subaortic stenosis;

- ischemic heart disease and cerebrovascular diseases (including cerebral circulatory insufficiency), because of the lack of cerebral circulation. excessive reduction of blood pressure can lead to the development of myocardial infarction and stroke;

- chronic heart failure; expressed

- Atherosclerosis;

- severe autoimmune systemic diseases of connective tissue (including systemic lupus erythematosus, scleroderma);

- oppression of bone marrow hematopoiesis; diabetes mellitus, because Thiazide diuretics can reduce glucose tolerance;

- hyperkalemia;

- condition after kidney transplantation;

- violations of the liver and / or kidneys (KK 30-75 ml / min);

- conditions, accompanied by a decrease in BCC (as a result of diuretic therapy, while limiting consumption of table salt, diarrhea and vomiting);

- elderly age.

Pregnancy and lactation:

The drug Enap ® N is contraindicated in pregnancy.

The effect of ACE inhibitors on the fetus in the first trimester of pregnancy is not established. The use of ACE inhibitors in the second and third trimesters of pregnancy was accompanied by a negative effect on the fetus and the newborn.Newborns developed arterial hypotension, renal failure, hyperkalemia, and / or hypoplasia of the skull bones. Perhaps the development of oligohydramnion.

apparently due to impaired renal function of the fetus. This can lead to limb contracture, deformation of the skull bones, including its facial part, and lung hypoplasia.

The use of diuretics in pregnancy is not recommended because it can cause jaundice of the fetus and newborn, thrombocytopenia and, possibly, other, unwanted reactions observed in adults.

Enalapril and hydrochlorothiazide penetrate into breast milk. Therefore, when prescribing Enap ® H during lactation, it is necessary to abandon breastfeeding.

Dosing and Administration:

The drug Enap ® N should be taken regularly at the same time, preferably in the morning, during or after a meal, without chewing, squeezed with a small amount of liquid. The recommended dose is 1 tablet per day.

In patients who are on diuretic therapy, it is recommended to cancel treatment or to reduce the dose of diuretics at least 3 days before the start of treatment with Enap®H to prevent the development of symptomatic arterial hypotension. Before the beginning of treatment, the function of the kidneys should be investigated.The duration of treatment is determined by the doctor.

Dose with impaired renal function

In patients with renal insufficiency with a CK of 30-75 ml / min, the Enap ® H preparation should be used only after preliminary titration of the doses of enalapril and hydrochlorothiazide separately, correspondingly to the doses in the combined Enap ® H preparation.

Side effects:

Classification of the frequency of development of side effects of the World Health Organization (WHO):

- very often (> 1/10)

- often (> 1/100 and <1/10)

- infrequently (> 1/1000 and <1/100)

- rarely (> 1/10000 and <1/1000)

- very rarely (<1/10000), including individual messages.

From the hemopoietic system and lymphatic system:

rarely: neutropenia, decreased hemoglobin and hematocrit, thrombocytopenia, leukopenia, oppression of bone marrow function;

Metabolic and nutritional disorders

infrequently: gout;

From the central nervous system:

very often: dizziness, weakness; often: headache, asthenia;

infrequently: insomnia, drowsiness, paresthesia, increased excitability;

From the sense organs:

infrequently: noise in the ears;

From the cardiovascular system:

often: orthostatic hypotension;

infrequently: fainting, marked decrease in blood pressure, palpitations, tachycardia, chest pain;

From the respiratory system:

often: cough; infrequently: dyspnea;

From the digestive system:

often: nausea;

infrequently: diarrhea, vomiting, indigestion, abdominal pain, flatulence, constipation, dry mouth;

rarely: cholestatic jaundice, fulminant necrosis;

Allergic reactions:

infrequently: Stevens-Johnson syndrome;

rarely: angioedema;

very rarely: intestinal angioedema;

From the skin:

infrequent: skin rash, itching, increased sweating, skin necrosis, alopecia;

From the genitourinary system:

infrequently: impaired renal function, acute renal failure, impotence, decreased libido;

From the musculoskeletal system:

often: muscle spasms; infrequently: arthralgia;

Laboratory indicators:

rarely: hyperglycemia, hyperuricemia, hypokalemia, hyperkalemia, hyponatremia, increased urea and creatinine levels in the serum, increased activity of "liver" transaminases and bilirubin;

Other:

describes a symptom complex that may include fever,myalgia and arthralgia, serositis, vasculitis, increased erythrocyte sedimentation rate, leukocytosis and eosinophilia, skin rash, positive antinuclear antibody test.

Overdose:

Symptoms: increased diuresis, marked decrease in blood pressure with bradycardia or other cardiac arrhythmias, convulsions, impaired consciousness (including coma), acute renal insufficiency, violation of the acid-base state and water-electrolyte balance of blood.

Treatment: the patient is transferred to a horizontal position with raised legs. In mild cases, gastric lavage and ingestion of activated charcoal are shown, in more serious cases - measures aimed at stabilizing blood pressure - intravenous administration of plasma substitutes, infusion of 0.9% sodium chloride solution. The patient should monitor blood pressure, heart rate, respiratory rate, serum urea concentration, creatinine, electrolytes and diuresis, if necessary, intravenous angiotensin II, hemodialysis (enalaprilate removal rate -62 ml / min).

Interaction:

Potassium of blood serum

The use of potassium supplements,potassium-sparing agents or preparations containing potassium salt substitutes, especially in patients with renal insufficiency, can lead to a significant increase in potassium in the serum. The loss of potassium on the background of taking thiazide diuretics, as a rule, decreases under the action of enalapril. The potassium content in the serum usually remains within the normal range.

Lithium

At simultaneous application with preparations of lithium - delay of deducing of lithium (strengthening of cardiotoxic and neurotoxic action of lithium).

Nondepolarizing muscle relaxants

Thiazide diuretics can enhance the effect of tubocurarine chloride.

Harkotic analgesics / antipsychotics

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

Other antihypertensive agents

Combined with enalapril, the use of beta-blockers, alpha-blockers, ganglion blocking agents, methyldopa, or blockers of "slow" calcium channels can further reduce blood pressure.

Allopurinol, cytostatics and immunosuppressants

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

Glucocorticosteroids. calcitonin

The simultaneous administration of thiazide diuretics can lead to the development of

hypokalemia.

Cyclosporin

Simultaneous administration with ACE inhibitors may increase the risk of hyperkalemia.

Nonsteroidal anti-inflammatory drugs

Simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs) (including selective cyclokigen-2 inhibitors) can weaken the antihypertensive effect of ACE inhibitors.

NSAIDs and ACE inhibitors have an additive effect on potassium levels in the blood serum, which can lead to impaired renal function, especially in patients with impaired renal function. This effect is reversible. NSAIDs can reduce the diuretic and antihypertensive effects of diuretics.

Antacids

Antacids can reduce the bioavailability of ACE inhibitors.

Sympathomimetics can reduce the antihypertensive effect of ACE inhibitors. Thiazide diuretics can reduce the effect of adrenomimetics (epinephrine).

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

Hypoglycemic agents for oral administration and insulin

Epidemiological studies suggest that simultaneous use of ACE inhibitors and hypoglycemic agents can 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 findings 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 hypoglycemic agents for oral administration and insulin with thiazide diuretics may require correction of their doses.

Kolestyramine and colestipol

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

Preparations of gold

With simultaneous use of ACE inhibitors and preparations of gold (sodium aurotomy malate) intravenously, a symptom complex is described, which includes facial flushing, nausea, vomiting and arterial hypotension.

Special instructions:

Arterial hypotension

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

In case of arterial hypotension, it is necessary to place the patient on the back with a low headboard and, if necessary, adjust the volume of BCC by infusing a solution of 0.9% sodium chloride. Arterial hypotension, which occurred after taking the first dose, is not a contraindication for further treatment. Caution is required in patients with coronary heart disease, expressed cerebrovascular diseases, aortic stenosis or idiopathic hypertrophic obstructive subaortal stenosis, which prevents the outflow of blood from the left ventricle, marked atherosclerosis, in elderly patients as a result of the risk of arterial hypotension and impaired blood flow to the heart, brain and kidney.

Violations of the water-electrolyte balance

Regular monitoring of serum electrolyte concentration during the treatment period is necessary to identify possible imbalances and timely adoption of the necessary measures. Determination of the serum concentration of electrolytes is mandatory for patients with prolonged diarrhea, vomiting.

In patients taking Enap®H, it is necessary to detect signs of disturbance of the water-electrolyte balance, such as dry mouth, thirst, weakness, drowsiness, increased excitability, myalgia and convulsions (mainly the calf muscles), lowering blood pressure, tachycardia, oliguria and gastrointestinal disorders (nausea, vomiting).

Impaired renal function

The drug Enap ® N in patients with renal insufficiency (CK 30-75 ml / min) should be used only after preliminary titration of doses of enalapril and hydrochlorothiazide separately, correspondingly to the doses in the combined Enap ® H preparation.

Impaired liver function

The drug Enap®H must be used with caution in patients with hepatic insufficiency or progressive liver disease, since hydrochlorothiazide can cause hepatic coma even with minimal disturbances of water-electrolyte balance. Several cases of development of acute hepatic insufficiency with cholestatic jaundice, fulminant liver necrosis and lethal outcome (rarely) during treatment with ACE inhibitors have been reported. When jaundice occurs and the activity of "liver" transaminases is increased, treatment with Enap ® H should be stopped immediately, patients should be monitored.

Metabolic and endocrine effects

Caution is needed in all patients receiving treatment with hypoglycemic agents for ingestion or insulin, since hydrochlorothiazide can weaken, and enalapril strengthen their action.

Thiazide diuretics can reduce the excretion of calcium by the kidneys and cause a slight and transient increase in serum calcium. Pronounced hypercalcaemia may be a sign of latent hyperparathyroidism. Before the study of the function of parathyroid glands, thiazide diuretics must be discontinued.

Against the background of treatment with thiazide diuretics, the concentrations of cholesterol and triglycerides in serum can increase.

Therapy with thiazide diuretics in some patients may exacerbate hyperuricemia and / or aggravate the course of gout. but enalapril enhances the excretion of uric acid by the kidneys, thereby counteracting the hyperuricemic effect of hydrochlorothiazide

Allergic reactions / Angioedema

When an angioedema develops in the face, it is usually sufficient to discontinue therapy and prescribe antihistamines to the patient.

Angioedema, edema of the tongue, throat or larynx can be lethal. With angioedema, swelling of the tongue, throat or larynx, which can lead to airway obstruction, you must immediately enter epinephrine (0.3-0.5 ml epinephrine (adrenaline) solution subcutaneously in a ratio of 1: 1000) and maintain airway patency (intubation or tracheostomy).

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

Patients with a history of angioedema not associated with ACE inhibitors have an increased risk of developing angioedema due to the administration of any ACE inhibitor.

In patients taking thiazide diuretics, hypersensitivity reactions can develop both in the presence and in the absence of an anamnesis of allergic reactions. Reported worsening of the course of systemic lupus erythematosus.

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

Surgical interventions / general anesthesia

Before surgery (including dentistry), an anesthesiologist should be warned about the use of ACE inhibitors. During surgical interventions or general anesthesia with the use of drugs that cause arterial hypotension, ACE inhibitors can block the formation of angiotensin II in response to compensatory release of renin. If this results in a pronounced decrease in blood pressure, explained by such a mechanism, it can be corrected by increasing the volume of circulating blood.

Cough

Cough was used in the use of ACE inhibitors. Cough is dry, prolonged, which disappears after discontinuation of ACE inhibitors. With a differential diagnosis of cough, one must also consider the cough caused by the use of ACE inhibitors.

Effect on the ability to drive transp. cf. and fur:At the beginning of treatment with Enap ® H, there may be a marked decrease in blood pressure, dizziness and drowsiness, which can reduce the ability to drive vehicles, 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 and engage in other potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:Tablets 25 mg + 10 mg.

Packaging:10 tablets per blister. Two blisters are placed in a pack of cardboard together with instructions for use.

Storage conditions:

In a dry place, at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

3 years. Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N012098 / 01

Date of registration:27.07.2010

The owner of the registration certificate:KRKA-PHARMA, doo, Zagreb, CroatiaKRKA-PHARMA, doo, Zagreb, Croatia Croatia

Manufacturer: & nbsp

KRKA, d.d. Slovenia

Representation: & nbspKRKA KRKA Slovenia

Information update date: & nbsp01.01.2016

Illustrated instructions

Instructions

Enap®-H (Enap®-H)