Expiration date: 05/2025

The composition and form of issue:

Tablets. 1 tablet contains:

enalapril maleate 10 or 20 mg

hydrochlorothiazide 12, 5 mg

Excipients: sodium hydrogen carbonate lactose monohydrate calcium hydrogen phosphate anhydrous maize starch talc magnesium stearate 

Description of dosage form:

Round, flat white tablets, with beveled edge and notch on one side.

Pharmacokinetics:

Enalapril is rapidly absorbed from the gastrointestinal tract. The amount of suction at 60%. Food does not affect the absorption of enalapril. Cmax is achieved after 1 h. in the liver, enalapril is hydrolyzed to the active metabolite — enalaprilat, which is the carrier of the pharmacological effect.

Cmax enalaprilat in serum is achieved after 3-6 hours.

Enalapril is excreted in urine (60%) and feces (33%) mainly in the form of enalaprilat.

Enalaprilat penetrates into most tissues of the body, mainly in the lungs, kidneys and blood vessels. Binding to plasma proteins-50-60%. Enalaprilat not subjected to further metabolism and 100% excreted in the urine. Excretion is a combination of glomerular filtration and tubular secretion. Renal Cl of enalapril and enalaprilat is 0, 005 ml/s (18 l/h) and 0 00225-0, 00264 ml/s (8, 1-9, 5 l/h), respectively. Displayed in several stages. When assigning multiple doses of enalapril T1/2 englaprilata of blood serum is approximately 11 h. Enalapril and enalaprilat penetrate the placental barrier and are excreted in breast milk.

Enalaprilat is removed from the bloodstream by hemodialysis and peritoneal dialysis.

Hemodialysis Cl enalaprilata-0, 63-1, 03 ml/s (38-62 ml/min) serum concentration of enalaprilat after 4-hour hemodialysis decreases by 45-57%.

In patients with reduced renal function, excretion slows down, which requires a change in dosage in accordance with renal function, especially in patients with severe renal failure.

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

In patients with heart failure, the absorption and metabolism of enalaprilat are slowed down, and the volume of distribution is reduced. Since these patients may have renal failure, they may slow down the excretion of enalapril.

The pharmacokinetics of enalapril may also change in elderly patients, more due to comorbidities than in the elderly.

Hydrochlorothiazide is absorbed mainly in the duodenum and proximal small intestine. Absorption is 70% and increases by 10% when taken with food. The level of maximum serum concentration is reached through 1, 5-5 h. the Volume of distribution is about 3 l/kg. Linking blood plasma proteins — 40%. The drug accumulates in red blood cells, the mechanism of cumulation is unknown. Not metabolized in liver, excreted mainly by the kidneys: 95% — in unchanged form and about 4% in the form hydroxypropane - 2-amino-4-chloro-m - benzolsulfonat. Renal Cl of hydrochlorothiazide in healthy volunteers and patients with arterial hypertension — about 5, 58 ml/s (335 ml/min). Hydrochlorothiazide has a two-phase excretion profile. T1 / 2 in the initial phase — 2 h, in the final phase (10-12 h after administration) — about 10 h.Penetrates the placental barrier and accumulates in the amniotic fluid. Serum concentration of hydrochlorothiazide in the blood of the umbilical vein is almost the same as in the maternal blood. The concentration in the amniotic fluid exceeds that in the serum of the umbilical vein (19 times). The level of hydrochlorothiazide in breast milk is very low. Hydrochlorothiazide was not found in serum in infants whose mothers were taking hydrochlorothiazide during breastfeeding.

In elderly patients, hydrochlorothiazide does not adversely affect the pharmacokinetics of enalapril, but the serum concentration of enalaprilat is higher. In the appointment of hydrochlorothiazide to patients with heart failure found that its absorption is reduced in proportion to the degree of disease — 20-70%. T1 / 2 hydrochlorothiazide increases to 28, 9 h renal Cl-0, 17-3, 12 ml/s (10-187 ml/min) (average values 1, 28 ml/s (77 ml / min).

In patients who underwent intestinal bypass surgery for obesity, hydrochlorothiazide absorption may be less than 30%, and serum concentrations by 50%, than in healthy volunteers.

Simultaneous administration of enalapril and hydrochlorothiazide has no effect on the pharmacokinetics of each of them.

Description of pharmacological action:

Combined preparation, the effect of which is due to the properties of the components included in its composition.

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

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

Effect of combination of

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

Due to hyponatremia and fluid reduction in the body, the renin-angiotensin-aldosterone system is activated. Reactive increase in the concentration of angiotensin II partially limits the decrease in blood PRESSURE. With the continuation of therapy, the hypotensive effect of hydrochlorothiazide is based on a decrease in OPSS. The result of the activation of renin-angiotensin-aldosterone system are metabolic effects on the electrolyte balance of blood, uric acid, glucose and lipids, which partially neutralizes the effectiveness of antihypertensive treatment. Despite the effective decrease in blood PRESSURE, thiazide diuretics do not reduce structural changes in the heart and blood vessels. Enalapril enhances the antihypertensive effect-inhibits the renin-angiotensin-aldosterone system, i.e. the production of angiotensin II and its effects. Additionally reduces the production of aldosterone and increases the effect of bradykinin and the release of PG. Since it often has its own diuretic effect, it can enhance the action of hydrochlorothiazide.

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

It is known that the antihypertensive effect of ACE inhibitors is greater in patients with hyponatremia, hypovolemia and increased renin levels in serum, whereas the effect of hydrochlorothiazide is not dependent on the level of renin in the serum. Therefore, the simultaneous administration of enalapril and hydrochlorothiazide has an additional antihypertensive effect. In addition, enalapril prevents or weakens the metabolic effects of diuretic therapy and has a beneficial effect on structural changes in the heart and blood vessels.

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

The antihypertensive effect of the combination is usually maintained for 24 hours.

Indications:

• Arterial hypertension (in patients, which shows the combined therapy).
  

Contraindications:

• hypersensitivity (including to individual components of the drug or sulfonamides)
  
• anuria, severe renal dysfunction (creatinine Cl <30 ml / min)
  
• an anamnesis of angioedema associated with the use of ACE inhibitors earlier, as well as hereditary or idiopathic angioedema
  
• primary hyperaldosteronism
  
• addison
  
• porphyria
  
• the age of 18 years (efficacy and safety not established).
  

With caution:

• bilateral renal artery stenosis or single kidney artery stenosis, renal dysfunction (creatinine Cl-30-75 ml / min)
  
• severe aortic stenosis or idiopathic hypertrophic subaortic stenosis
  
• IHD and cerebrovascular diseases (including cerebrovascular insufficiency)
  
• chronic heart failure
  
• severe autoimmune systemic diseases of connective tissue (including systemic lupus erythematosus, scleroderma)
  
• oppression of bone marrow hematopoiesis
  
• diabetes
  
• hyperkalemia
  
• condition after kidney transplantation
  
• severe hepatic and/or renal impairment
  
• conditions accompanied by a decrease in BCC (as a result of diuretic therapy, with limited salt intake, diarrhea and vomiting)
  
• old age
  
• gout.
  

Use during pregnancy and breast-feeding:

The drug is contraindicated in pregnancy. When pregnancy occurs, the drug should be stopped immediately. If necessary, the appointment of the drug during lactation nursing mothers should give up breastfeeding.

Side effect:

General: weakness, hypersensitivity reactions (angioedema, thrombocytopenic purpura, urticaria, itching), necrotizing angiitis, fever, respiratory distress syndrome, including pneumonitis and pulmonary edema, anaphylactic reactions.

From the cardiovascular system: heartbeat, various cardiac arrhythmias, marked decrease in blood PRESSURE, orthostatic hypotension, cardiac arrest, myocardial infarction, cerebrovascular stroke, angina, Raynaud's syndrome.

From the digestive tract: dry mouth, glossitis, stomatitis, inflammation of the salivary glands, anorexia, nausea, vomiting, diarrhea, constipation, flatulence, epigastric pain, intestinal colic, ileus, pancreatitis, liver failure, hepatitis, jaundice, melanoma.

Respiratory system: rhinitis, sinusitis, pharyngitis, hoarseness, bronchospasm, pneumonia, pulmonary infiltrates, eosinophilic pneumonia, pulmonary embolism, pulmonary infarction, pulmonary edema, unproductive "dry" cough.

From the genitourinary system: oliguria, gynecomastia, decreased potency, renal failure, impaired renal function, interstitial nephritis.

With the skin: sweating, rash, exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, tinea, alopecia, photosensitivity.

From the senses: blurred vision, taste disturbance, violation of smell, tinnitus, conjunctivitis, dryness of the conjunctiva, lacrimation.

CNS: depression, ataxia, drowsiness, insomnia, anxiety, nervousness, peripheral neuropathy (paresthesia, dysesthesia).

Laboratory findings: hypokalemia, hyperkalemia, hypomagnesemia, hypercalcemia, hyponatremia, hypochloremic alkalosis, hyperglycemia, glucosuria, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, increased activity of liver enzymes, hyperbilirubinemia, leukocytosis, eosinophilia, neutropenia, leukopenia, agranulocytosis, anemia, pancytopenia.

Other: lupus-like syndrome (fever, myalgia and arthralgia, serositis, vasculitis, increased erythrocyte sedimentation rate, leukocytosis and eosinophilia, skin rash, positive test for antinuclear antibodies).

Drug interaction:

Simultaneous administration of other antihypertensive drugs, barbiturates, tricyclic antidepressants, phenothiazines and drugs, as well as alcohol intake, enhances the antihypertensive effect of Enap-NL.

Analgesics and NSAIDs, a large amount of salt in the diet, while taking colestyramine or colestipol reduce the effect of Enap-NL. Simultaneous use of Enap® - NL and NSAIDs and analgesics (due to inhibition of PG synthesis) may reduce the effectiveness of enalapril and increase the risk of deterioration of renal function and/or heart failure. In some patients, with simultaneous treatment, the antihypertensive effect of enalapril may also decrease, so patients should be carefully observed.

Simultaneous use of Enap-NL and lithium preparations can lead to lithium intoxication, as enalapril and hydrochlorothiazide reduce the excretion of lithium. It is necessary to control the concentration of lithium in the blood serum and adjust the dosage accordingly. If possible, simultaneous treatment with Enap-NL and lithium drugs should be avoided.

Concomitant treatment with potassium-sparing diuretics (spironolactone, amiloride, triamterene) or potassium supplementation can lead to hyperkalemia.

Simultaneous administration with allopurinol, cytostatics, immunosuppressants or systemic corticosteroids can cause leukopenia, anemia or pancytopenia, therefore, periodic monitoring of the hemogram is required.

Acute renal failure has been reported in two patients after kidney transplantation who received both enalapril and cyclosporine. It is assumed that acute renal failure was the result of a decrease in renal blood flow caused by cyclosporine, and a decrease in glomerular filtration caused by enalapril. Therefore, caution is necessary while using enalapril and cyclosporine.

Co-administration of sulphonamides and oral hypoglycemic agents from the group of sulfonylureas may cause hypersensitivity reactions (possible cross sensitivity).

Care should be taken while using with cardiac glycosides. Possible hydrochlorothiazide-induced hypovolemia, hypokalemia and hypomagnesemia may increase glycoside toxicity.

Co-administration with corticosteroids increases the risk of hypokalemia.

With simultaneous use of Enap-NL and theophylline, enalapril can reduce the half-life of theophylline.

With simultaneous use of Enap-NL and cimetidine, the half-life of enalapril may increase. The risk of arterial hypotension, increased during General anesthesia or the use of non-depolarizing muscle relaxants (e.g. tubocurarine).

Method of application and doses:

Inside, whole, during or after a meal, with a small amount of liquid.

Treatment of hypertension never start with a combination of drugs. Must initially be determined by an adequate dose of the individual components. The dosage should always be selected individually for each patient.

The usual dose - 1 table. per day. Patients should become accustomed to taking the drug regularly at the same time, preferably in the morning.

In case of missing the next dose of the drug, it should be taken as soon as possible, if before taking the next dose there is a sufficiently large amount of time. If you have a few hours before taking the next dose, you should wait and take only this dose. You should never double the dose.

If a satisfactory therapeutic effect is not achieved, it is recommended to add another drug or change therapy.

In patients on diuretic therapy, it is recommended to cancel treatment or reduce the dose of diuretics at least 3 days before the start of treatment with Enap-NL to prevent the development of symptomatic hypotension. Before treatment should be investigated renal function.

The duration of treatment is not limited.

Dosage for impaired renal function

Patients with Cl creatinine >0. 5 ml/s or serum creatinine <265 mol/l (3 mg/100 ml) should be administered the usual dose of the drug Enap-NL.

Overdose:

If the patient has taken too many tablets in 1 dose, call a doctor immediately.

Symptoms: increased diuresis, marked decrease in blood PRESSURE with bradycardia or other cardiac arrhythmias, convulsions, paresis, paralytic ileus, impaired consciousness (including coma), renal failure, violation of CSC, electrolyte balance of blood.

Treatment: the patient is transferred to a horizontal position with a low headboard. In mild cases, gastric lavage and ingestion of saline solution are indicated, in more serious cases — measures aimed at stabilizing blood pressure: in/in the introduction of saline solution, plasma substitutes. In the patient, it is necessary to control the level of blood PRESSURE, heart rate, respiratory rate, serum concentration of urea, creatinine, electrolytes and diuresis, if necessary — in/in the introduction of angiotensin II, hemodialysis (rate of excretion of enalaprilat — 62 ml/min).

Special instruction:

A marked decrease in blood PRESSURE with all clinical consequences can be observed after the first administration of Enap-NL tablets in patients with severe heart failure and hyponatremia, severe renal failure, hypertension or left ventricular dysfunction and, in particular, in patients in a state of hypovolemia, as a result of diuretic therapy, a salt-free diet, diarrhea, vomiting or hemodialysis. Arterial hypotension after the first dose and its more serious consequences are rare and passing phenomena. One way to avoid them is to cancel diuretics (if possible) before treatment with Enap-NL.

In the case of hypotension, it is necessary to put the patient on the back with a low headboard and, if necessary, adjust the plasma volume by infusion of saline solution. Transient hypotension is not a contraindication to continue treatment. After normalization of blood PRESSURE and replenishment of BCC patients are usually well tolerated subsequent doses. Caution is needed when used in patients with impaired renal function (Cl creatinine — from 0, 5 to 1, 3 ml/s). Patients with impaired renal function may show signs of drug accumulation. If necessary, combination therapy with enalapril and hydrochlorothiazide should be abolished.

It is necessary to avoid the appointment of Enapa-NL in patients with bilateral renal artery stenosis or renal artery stenosis of the single kidney, because it can lead to deterioration of renal function or even acute renal failure (enalapril effect). Therefore, it is necessary to control renal function before and during treatment with the drug.

Caution is required in patients with coronary artery disease, severe cerebrovascular disease, aortic stenosis or other stenosis, preventing the outflow of blood from the left ventricle, severe atherosclerosis, in elderly patients due to the risk of hypotension and deterioration of perfusion of the heart, brain and kidneys.

Requires regular monitoring of serum concentration of electrolytes during treatment to detect possible imbalance and the timely adoption of the necessary measures. Determination of serum electrolyte concentration is mandatory for patients with prolonged diarrhea, vomiting and receiving/infusion.

In patients taking Enap-NL, it is necessary to actively identify signs of electrolyte imbalance, such as dry mouth, thirst, weakness, drowsiness, lethargy, arousal, muscle pain and cramps (mainly calf muscles), decreased blood PRESSURE, tachycardia, oliguria and gastrointestinal disorders (nausea, vomiting).

Enap-NL should be used with caution in patients with liver failure or progressive liver disease, as hydrochlorothiazide can cause hepatic coma even with minimal electrolyte disturbances.

During the treatment of Enap-NL, hypomagnesemia and sometimes hypercalcemia may occur as a result of increased magnesium excretion and slowing the excretion of calcium in the urine under the influence of hydrochlorothiazide. A significant increase in serum calcium levels may be a sign of latent hyperparathyroidism. In some patients, as a result of the action of hydrochlorothiazide, hyperuricemia or worsening of the course of gout may occur. If there is an increase in the concentration of uric acid in the blood serum, treatment should be discontinued. It can be renewed after normalization of laboratory parameters and further carried out under their control. Caution is necessary in all patients, receiving treatment oral gipoglikemicakimi means or insulin, since hydrochlorothiazide may weaken and children to strengthen their action. Patients with diabetes should be observed more often, and if necessary, some change in the dose of hypoglycemic agents may be required. In the event of angioedema of the face or neck, it is usually sufficient to discontinue therapy and prescribe antihistamines to the patient. In more severe cases (swelling of the tongue, pharynx and larynx) angioedema is treated with adrenaline, it is necessary to maintain airway patency (intubation or laryngotomy). The antihypertensive effect Anapa-NL can increase after sympathectomy. Due to the increased risk of anaphylactic reactions, Enap-NL should not be prescribed to patients on hemodialysis using polyacrylonitrile membranes undergoing apheresis with dextran sulfate and immediately before the desensitization procedure to aspen or bee venom. During treatment with Enap-NL, hypersensitivity reactions may occur in patients without prior Allergy or bronchial asthma. Deterioration of systemic lupus erythematosus was reported.

Several cases of acute liver failure with cholestatic jaundice, liver necrosis and fatal outcome (rarely) during treatment with ACE inhibitors have been reported. The cause of these syndromes is not entirely clear. In the event of jaundice and increased activity of liver enzymes, treatment should be immediately discontinued, patients should be monitored.

Caution is also necessary in patients taking sulfonamides or oral hypoglycemic agents from the sulfonylurea group (possible cross-sensitivity).

During treatment requires periodic monitoring of the number of white blood cells, especially in patients with connective tissue or kidney disease.

In patients after extensive surgery, receiving drugs, causing hypotension, during General anesthesia, enalapril can block the formation of angiotensin II with compensatory release of renin. If a doctor suggests this mechanism of arterial hypotension, treatment can be carried out by increasing the BCC.

During treatment, periodic monitoring of serum concentrations of electrolytes, glucose, urea, creatinine and liver enzyme activity, as well as protein in the urine is required. Treatment of Enap-NL should be discontinued before the study of the function of the parathyroid glands.

Enap-NL does not affect the ability to drive a car or operate machinery, however some patients, mainly at the beginning of treatment may experience hypotension and dizziness, mediated and passing reduce the ability to driving and working with machinery. Therefore, at the beginning of treatment, it is not recommended to drive a car, work with mechanisms and perform other work that requires concentration, until a response to treatment is established.