ENAP-NL

Active material: Enalapril, Gidroxlorotiazid
When ATH: C09BA02
CCF: Antihypertensive drugs
ICD-10 codes (testimony): I10
When CSF: 01.09.16.03
Manufacturer: KRKA d.d. (Slovenia)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills white, round, flat, with a beveled edge and a notch on one side.

Excipients: natriya carbonate, lactose monohydrate, calcium hydrogen phosphate (anhydrous), corn starch, talc, magnesium stearate.

10 PC. – blisters (2) – packs cardboard.

Pharmacological action

Combined preparation, action is due to the properties of the components, its constituent.

Enalapril – ACE inhibitor, It is a prodrug: as a result of hydrolysis is formed enalaprilat, and which inhibits ACE.

Gidroxlorotiazid – tiazidnый diuretic. It acts at the level of the distal tubule, increasing the excretion of sodium and chloride ions.

Early treatment hydrochlorothiazide volume of liquid in the vessels, reduced by increasing excretion of sodium and fluid, resulting in reduced blood pressure and reduced cardiac output.

Due hyponatremia and reduce body fluid, aktiviruetsya renin-angiotensin system alydosteronovaya. Reactive increase in the concentration of angiotensin II partially restricts blood pressure reduction. With continued therapy, the hypotensive effect of hydrochlorothiazide is based on the decrease in systemic vascular resistance. The result of the activation of the renin-angiotensin-aldosterone system are metabolic effects on blood electrolyte balance, uric acid, glucose and lipids, partially neutralize the effectiveness of antihypertensive treatment.

Although effective BP reduction thiazide diuretics do not reduce the structural changes in the heart and blood vessels. It enhances the antihypertensive effect of enalapril: ingibiruet renin-angiotensin-alydosteronovuyu sistemu, ie. production of angiotensin II and its effects. In addition, it reduces the production of aldosterone, and enhances the action of bradykinin, and prostaglandins release. Unnecessarily. he often has its own diuretic effect, this can increase the effects of hydrochlorothiazide.

Enalapril reduces sight- and afterload, that unloads the left ventricle, regression of hypertrophy and reduce the growth of collagen, It prevents damage to myocardial cells. As a result, the heart rate slows down and reduces the load on the heart (in chronic heart failure), improved coronary blood flow and oxygen consumption decreases cardiomyocytes. Thus, reduced sensitivity of the heart to ischemia, and also reduced the number of dangerous ventricular arrhythmias. It has a beneficial effect on cerebral blood flow in patients with hypertension and chronic heart disease. It prevents the development of glomerulosclerosis, support and improve kidney function and slow the course of chronic kidney disease, even in those patients, who have not yet developed hypertension.

Known, that the antihypertensive effect of ACE inhibitors in patients with higher hyponatremia, hypovolemia, and elevated levels of renin in the blood serum, whereas the effect of hydrochlorothiazide is not dependent on the level of renin in serum. Therefore, co-administration of enalapril and hydrochlorothiazide has additional antihypertensive effect. Besides, enalapril prevents or reduces the metabolic effects of diuretic therapy, and has a favorable effect on the structural changes in the heart and blood vessels.

Co-administration of an ACE inhibitor and hydrochlorothiazide when used, when each drug alone is insufficiently effective or monotherapy conducted using maximum doses, which increases the frequency of adverse effects. This combination provides a better therapeutic effect with lower doses of enalapril and hydrochlorothiazide and reduce the development of adverse effects.

The antihypertensive effect of the combination usually persists for 24 no.

Pharmacokinetics

Enalapril

Absorption

Enalapril is rapidly absorbed from the gastrointestinal tract. The amount of absorption is 60%. Food does not affect the absorption of enalapril. T_max is 1 no. T_max enalaprilat serum is 3-6 no.

Distribution

Enalaprilat penetrates into most tissues of the body, mainly in the lungs, kidney and blood vessels. The binding to plasma proteins 50-60%.

Enalapril and enalaprilat cross the placental barrier, excreted in breast milk.

Metabolism

In baked эnalapril gidrolizuetsya to aktivnogo metabolite – эnalaprilata, which is the carrier of the pharmacological effect and is not subject to further metabolism.

Deduction

Excretion – a combination of glomerular filtration and tubular secretion. The renal clearance of enalapril and enalaprilat up 0.005 ml / s (18 l /) and 0.00225-0.00264 ml / s (8.1-9.5 l /) respectively. Is displayed in several stages.

When you assign multiple doses of enalapril T_1/2 enalaprilat from serum is approximately 11 no. Enalapril is displayed in the urine – 60% and feces – 33% predominantly in the form of enalaprilate. Enalaprilate in 100% excreted in the urine.

Enalaprilat is removed from the blood by hemodialysis or peritoneal dialysis. Hemodialysis clearance enalaprilate 0.63-1.03 ml / s (38-62 ml / min). Serum enalaprilat after a 4-hour hemodialysis reduced by 45-57%.

Pharmacokinetics in special clinical situations

In patients with reduced kidney function is slowing down, that it requires changing the dosage according to the function of kidneys, especially in patients with severe renal insufficiency.

In patients with hepatic impairment the metabolism of enalapril can be slowed down without damaging the pharmacodynamic effect.

Patients with heart failure absorption and metabolism slows enalaprilat, also reduced V_d. Since these possible renal failure patients, they can slow down the excretion of enalapril.

In elderly patients, the pharmacokinetics of enalapril can vary largely due to comorbidities, older than.

Gidroxlorotiazid

Absorption

Hydrochlorothiazide is absorbed, mainly, in the duodenum and proximal small intestine. Absorption sostavlyaet 70% and increased by 10% when taken with food. T_max is 1.5-5 no.

Distribution

V_d about 3 l / kg. The binding to plasma proteins – 40%. Drug accumulates in erythrocytes, unknown mechanism of accumulation.

It penetrates through the placental barrier and accumulates in the amniotic fluid. Serum concentrations of hydrochlorothiazide in the blood of the umbilical vein is essentially the same, as in maternal blood. The concentration in the amniotic fluid exceeds that in serum from umbilical vein 19 time. The level of hydrochlorothiazide in breast milk is very low. Hydrochlorothiazide was not detected in the serum of infants, whose mothers have taken hydrochlorothiazide during breastfeeding.

Metabolism

Hydrochlorothiazide is not metabolized in the liver.

Deduction

Hydrochlorothiazide is excreted mainly in the urine – 95% as unchanged and about 4% a hydrolyzate of 2-amino-4-chloro-m-benzenedisulfonamida.

Renal clearance of hydrochlorothiazide in healthy volunteers and patients with hypertension is approximately 5.58 ml / s (335 ml / min). Hydrochlorothiazide is a biphasic elimination profile. T1 / 2 is in the initial phase 2 no, in the final phase (through 10-12 h after administration) – about 10 no.

Pharmacokinetics in special clinical situations

Elderly patients hydrochlorothiazide has no negative effect on the pharmacokinetics of enalapril, but the serum concentration of enalaprilat thus higher.

In patients with heart failure in the application of hydrochlorothiazide found, that its absorption is reduced in proportion to the extent of the disease 20-70%. T_1/2 hydrochlorothiazide increases to 28.9 no. Renal clearance is 0.17-3.12 ml / s (10-187 ml / min), averages 1.28 ml / s (77 ml / min).

Patients, undergoing surgery intestinal bypass surgery for obesity, absorption of hydrochlorothiazide may be reduced by 30%, and serum concentration on 50%, than in healthy volunteers.

The simultaneous use of enalapril and hydrochlorothiazide does not affect the pharmacokinetics of each.

Testimony

- Arterial hypertension (patients, which shows the combination therapy).

Dosage regimen

Treatment of hypertension should not start with a combination of drugs. Originally it should be determined appropriate doses of the individual components. The dose should always be individualized for each patient.

Taking medication regularly at the same time (preferably in the morning). Swallow whole tablets during or after a meal, drinking a small amount of liquid.

The usual dose is 1 tab. / day.

In the case of missing reception the next dose, it must be taken as soon as possible, if before the next dose is left quite a lot of time. If prior to receiving subsequent doses of a few hours left, you should wait and take only her. Do not double the dose.

If not reached a satisfactory therapeutic effect, we recommend adding another drug or change therapy.

Patients, are on diuretic therapy, Treatment is recommended to cancel or reduce the dose of diuretics at least 3 days before the start of treatment Enap^®-NL for the prevention of symptomatic hypotension. Before treatment should be investigated renal function.

Duration of treatment is not limited to.

Patients with CC > 30 ml / min or serum creatinine <265 mmol / l (3 mg / dL) It can be assigned to the usual dose Enap^®-NL.

Side effect

Cardio-vascular system: palpitations, various heart rhythm disturbances, marked reduction in blood pressure, orthostatic hypotension, cardiac arrest, myocardial infarction, cerebrovascular stroke, angina, Raynaud's syndrome, necrotizing vasculitis.

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

The respiratory system: rhinitis, sinusitis, pharyngitis, hoarseness, bronchospasm, asthma, pneumonia, pulmonary infiltrates, eosinophilic pneumonia, pulmonary embolism, pulmonary infarction, respiratory distress (including pneumonitis and pulmonary edema).

From the central and peripheral nervous system: depression, ataxia, drowsiness, insomnia, anxiety, nervousness, perifericheskaya neuropathy (paresthesia, dysesthesia).

From the urinary system: oligurija, renal failure, impairment of renal function, interstitial nephritis.

Reproductive system: gynecomastia, reduced potency.

From the senses: blurred vision, damage to taste, violation of smell, noise in ears, conjunctivitis, dryness of the conjunctiva, lacrimation.

From the hematopoietic system: leukocytosis, eozinofilija, neutropenia, leukopenia, agranulocytosis, anemia, gipoglobinemiâ, pancytopenia.

Metabolism: kaliopenia, hyperkalemia, gipomagniemiya, hypercalcemia, giponatriemiya, hypochloraemic alkalosis, giperglikemiâ, glycosuria, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, increase in liver enzymes, giperʙilliruʙinemija.

Dermatological reactions: Sweating, rash, shingles, alopecia.

Allergic reactions: hives, itch, skin rash, exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, photosensitivity, hypersensitivity reactions (angioedema, trombotsitopenicheskaya purpura), anaphylactic reactions.

Other: weakness, fever, lupus-like syndrome, described in the literature (fever, myalgia and arthralgia, serositis, vasculitis, skin rash, increased erythrocyte sedimentation rate, leukocytosis, eozinofilija, a positive test for antinuclear antibodies).

Contraindications

- Anurija;

- Expressed by the human kidney (CC<30 ml / min);

- Hereditary or idiopathic angioedema;

- Angioedema, associated with the use of ACE inhibitors (history);

- Primary hyperaldosteronism;

- Addison's disease;

- Porphyria;

- Childhood and adolescence up 18 years (efficacy and safety have not been established);

- Hypersensitivity to the drug;

- Hypersensitivity to sulfonamides.

FROM caution use in patients with bilateral renal artery stenosis, artery stenosis sole kidney, renal impairment (CC 30-75 ml / min), marked aortic stenosis, idiopathic hypertrophic subaortic stenosis, CHD, cerebrovascular diseases (incl. when cerebrovascular insufficiency), chronic heart failure, severe autoimmune systemic diseases of connective tissue (incl. SLE, scleroderma), suppression of bone marrow hematopoiesis, diabetes, hyperkalemia, condition after kidney transplantation, severe hepatic dysfunction and / or kidney, states, accompanied by a decrease in the bcc (as a result of diuretic therapy, while limiting intake of salt, diarrhea and vomiting), podagre, in elderly patients.

Pregnancy and lactation

The drug is contraindicated in pregnancy. In the event of pregnancy, the drug should be discontinued immediately.

If necessary, use during lactation should decide the issue of termination of breastfeeding.

Cautions

Hypotension with all the clinical consequences may occur after the first dose of pills Enap^®-NL in patients with severe heart failure and hyponatremia, severe renal insufficiency, hypertension or left ventricular dysfunction and, especially, patients, in a state gilovolemii, as a result of diuretic therapy, salt-free diet, diarrhea, vomiting or hemodialysis.

Hypotension after the first dose and its more serious consequences – rare and transient phenomenon. To avoid hypotension prior to treatment preparation Enap^®-NL possible repeal diuretics.

In the case of hypotension patients must be placed on the back with a low headboard and if necessary adjusted plasma volume infusion of saline. Transient hypotension is not a contraindication to further treatment. After normalization of blood pressure and volume replacement patients usually tolerate subsequent doses.

Care should be taken when using the drug in patients with impaired renal function (CC 0.5-1.3 ml / s), because they may show signs of accumulation of the drug. If necessary, it can be used a combination of enalapril with a lower number of hydrochlorothiazide or a combination therapy with enalapril and hydrochlorothiazide should be abolished.

Patients, taking hydrochlorothiazide, may develop azotemia.

It should be avoided Enap^®-NL patients with bilateral renal artery stenosis or renal artery stenosis sole kidney, as this may lead to deterioration of renal function, or even acute renal failure (the effect of enalapril). Requires monitoring of renal function before and during treatment with.

Caution is required when using the drug 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 older patients as a result of the risk of hypotension and deterioration of cardiac perfusion, brain and kidney.

You should regularly monitor the serum concentration of electrolytes during treatment to detect possible imbalance, and the timely adoption of the necessary measures. Determination of serum electrolytes is necessary for patients with prolonged diarrhea, vomiting and getting in / Infusion.

Patients, taking Enap^®-NL, you must actively identify signs of electrolyte imbalance: dry mouth, thirst, weakness, drowsiness, slackness, excitation, muscle pain or cramps (mainly calf muscle), tachycardia, blood pressure reduction, oliguria and gastrointestinal disturbances (nausea, vomiting).

Enap^®-NL should be used with caution in patients with hepatic insufficiency or progressive liver disease, as hydrochlorothiazide may cause hepatic coma even at minimum electrolyte disturbances.

During treatment, Enap^®-The IO may be gipomagniemia and sometimes hypercalcemia, resulting increase excretion of magnesium and slow urinary excretion of calcium under the influence of hydrochlorothiazide.

A significant increase in serum calcium levels may be a sign of hidden hyperparathyroidism.

In some patients as a result of hydrochlorothiazide may experience worsening of hyperuricemia or gout. If marked rise uric acid concentrations in blood serum, treatment should be discontinued. It can be resumed after the normalization of laboratory parameters and thereafter, carried out under their control.

Caution is needed when using the drug in all patients, treated with oral hypoglycemic agents or insulin, as hydrochlorothiazide may weaken, enalapril and strengthen their action. Patients with diabetes should be more frequently observed, It may require some variation in dosage gipoglikemicheskih.

If you experience angioedema face or neck is usually sufficient treatment discontinuation and administering to the patient antihistamines. In more severe cases, (swelling of the tongue, pharynx and larynx) angioneurotic edema treated with epinephrine, airway intubation or supported thyroidotomy.

The antihypertensive effect of Enap^®-The IO may be exacerbated after simpatèktomii.

Due to the increased risk of anaphylactic reactions should not be prescribed Enap^®-NL patients, hemodialysis with polyacrylonitrile membranes, undergoing apheresis with dextran sulfate and immediately before desensitization to wasp or bee venom.

During treatment, Enap^®-NL hypersensitivity reactions may occur in patients with no previous allergies or asthma.

Reported worsening of SLE therapy with ACE inhibitors.

A few cases of acute liver failure with cholestatic jaundice, liver necrosis and death (rarely) during treatment with an ACE inhibitor. The cause of these syndromes is unknown. If you have jaundice and elevated liver enzymes the treatment should be discontinued, the patient must be supervised.

Caution is also required in patients, taking sulfonamides or oral hypoglycemic agents of the sulfonylureas in connection with a possible cross-hypersensitivity.

During treatment requires periodic monitoring of white blood cell count, especially in patients with connective tissue disease or renal.

Patients, receiving during general anesthesia or after major surgery drugs, causing hypotension, enalapril may block the formation of angiotensin II, secondary to compensatory renin release. If your doctor suggests this mechanism of arterial hypotension, treatment may be increasing bcc.

During treatment requires periodic monitoring of serum electrolytes, Glucose, urea, creatinine and liver enzymes, and urinary protein. Treatment Enap^®-NL should be discontinued prior to the research function of the parathyroid glands.

Effects on ability to drive vehicles and management mechanisms

Enap^®-NL does not affect driving or working with machinery, However, some patients (preferably at the beginning of treatment) there may be hypotension and dizziness, that reduce the ability to driving and operating machinery. So at the beginning of treatment is recommended to avoid driving, using machinery and other work, requiring concentration, until, until the preferred treatment response.

Overdose

With single patient receiving too many tablets, should immediately call a doctor.

Symptoms: increased diuresis, marked reduction in blood pressure with bradycardia or other cardiac arrhythmias, convulsions, paresis, paralytic ileus, disturbances of consciousness (including who), renal failure, violation of AAR, blood electrolyte imbalance.

Treatment: the patient is transferred to a horizontal position with a low headboard. In mild cases showing a gastric lavage and ingestion of saline. In more serious cases, the event shows, to stabilize blood pressure: in / in a saline solution, plasma expanders. It is necessary to control blood pressure, Heart Rate, respiratory rate, serum concentration of urea, creatinine, electrolytes and urine output of the patient. If necessary, – in / with the introduction of angiotensin II, hemodialysis (rate of excretion enalaprilate – 62 ml / min).

Drug Interactions

The simultaneous use of Enap^®-NL with other antigipertenzivei means, ʙarʙituratami, tricyclic antidepressants, phenothiazine and Drug, as well as with ethanol, enhances antihypertensive effect Enap^®-NL.

Analgesics and NSAIDs, a large amount of salt in the diet, concomitant use of cholestyramine or colestipol reduce the effect of Enap^®-NL.

If possible, avoid simultaneous use of Enap^®-NL and drugs lithium, since it is possible the development of lithium intoxication due to decreased excretion of lithium. Necessary to control the concentration of lithium in blood serum; the dose is corrected accordingly.

The simultaneous use of Enap^®-NL and NSAIDS, analgesics (due to inhibition of prostaglandin synthesis) Enalapril may reduce the effectiveness and increase the risk of worsening renal function and / or current heart failure. In some patients, while treatment can also decrease the antihypertensive effect of enalapril, therefore patients should be carefully monitored.

The simultaneous use of Enap^®-NL with kalisberegatmi dioretikami (incl. spironolactone, amilorid, triamterene) or addition of potassium can cause hyperkalemia.

The simultaneous use of Enap^®-NL with allopourinolom, cytostatics, immunosuppressants or systemic corticosteroids may cause leukopenia, anemia or pancytopenia, therefore, requires periodic monitoring of hemogram.

Reported acute renal failure in 2 patients after renal transplantation, simultaneously receiving enalapril and cyclosporine. Expected, that acute renal failure was the result of decreased renal blood flow, cyclosporin induced, and reduction of glomerular filtration, caused by enalapril. Therefore, care should be taken while using enalapril and cyclosporine.

The simultaneous use of Enap^®-NL with sul′fonamidami and oral gipoglikemicakimi means of group sulfonylureas may cause hypersensitivity reactions (possible cross-hypersensitivity).

Care should be taken while applying Enap^®-NL with cardiac glycosides. Possible gidrohlorotiazidindutsirovannaya hypovolemia, gipokaliemia and gipomagniemia may increase toxicity glycosides.

The simultaneous use of Enap^®-NL with MCS increases the risk of hypokalemia.

In an application Enap^®-NL and theophylline, Enalapril may reduce T_1/2 teofillina.

In an application Enap^®-NL and cimetidine, may increase T_1/2 Enalapril.

The risk of hypotension is increased during general anesthesia or muscle relaxants application nedepolyariziruyuschih (eg, tuʙokurarina).

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children, dry place at temperatures no higher than 25 ° C. Shelf life – 2 year.