Enafarm-N - instructions for use, dose, side effects, contraindications

Description:Tablets of white or almost white color are flat-cylindrical with a facet and a cross-shaped risk. A slight unevenness of the surface is permissible.

Pharmacotherapeutic group:Hypotensive combined agent (angiotensin-converting enzyme inhibitor (ACE) + diuretic).

ATX: & nbsp

C.09.B.A.02 Enalapril in combination with diuretics

Pharmacodynamics:

Enafarm® H is a combined preparation containing active substances: enalapril and hydrochlorothiazide, the effect of which is due to the properties of the components that make up its composition.

Enalapril-ACE inhibitor, is a "prodrug": as a result of its hydrolysis, a enalaprilate, 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.

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

Due to hyponatremia and a decrease in fluid in the body, the renin-angiotensin-aldosterone system is activated. The reactive increase in angiotensin II concentration partially limits the decrease in blood pressure. With the continuation of therapy, the hypotensive effect of hydrochlorothiazide is based on a decrease in the total peripheral vascular resistance.The result of activation of the 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 reduction of 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. production of angiotensin II and its effects. In addition, 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, it can enhance the action of hydrochlorothiazide.

Enalapril reduces pre- and postnagruzku that unloads the left ventricle, reduces regression of hypertrophy and proliferation of collagen, prevents damage to myocardial cells. As a result, the heart rate slows down and the heart load decreases (with chronic heart failure), coronary blood flow improves and oxygen consumption of cardiomyocytes decreases. Thus, the sensitivity of the heart to ischemia decreases.It has a beneficial effect on cerebral blood flow in patients with arterial hypertension and chronic cardiovascular diseases. Prevents the development of glomerulosclerosis, supports and improves kidney function and slows 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 higher in patients with hyponatremia, hypovolemia and elevated serum renin level, whereas the effect of hydrochlorothiazide does not depend on the level of renin in serum. Therefore, the simultaneous administration of enalapril and hydrochlorothiazide has an additional antihypertensive effect. Besides, 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 applied when each drug is not sufficiently effective alone or monotherapy is performed using the maximum doses of the drug, which increases the incidence of unwanted effects.The antihypertensive effect of the combination is usually maintained for 24 hours.

Pharmacokinetics:

Enalapril quickly absorbed from the gastrointestinal tract. The suction volume is 60%. Food does not affect the absorption of enalapril. The maximum concentration in the blood plasma is reached after 1 hour. In the liver enalapril hydrolyzed to an active metabolite - enalaprilata, which is the carrier of the pharmacological effect. The maximum concentration of enalaprilat in the blood serum is achieved in 3-6 hours. Displayed enalapril with urine (60%) and feces (33%), mainly in the form of enalaprilate. Enalaprilat penetrates into most tissues of the body, mainly in the lungs, kidneys and blood vessels. Communication with blood plasma proteins - 50 - 60%. Enalaprilat does not undergo further metabolism and is 100% excreted in the urine. Excretion is a combination of glomerular filtration and tubular secretion. 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. It is displayed in several stages. When appointing multiple doses of enalapril, the half-life of enalaprilate from serum is approximately 11 hours. Enalapril and enalaprilate penetrate the placental barrier and are excreted in breast milk.

Enalaprilat is removed from the bloodstream during hemodialysis or peritoneal dialysis. Hemodialysis clearance enalaprilat 0.63 - 1.03 ml / s (38 - 62 ml / min); serum concentration of enalaprilat after 4-hour hemodialysis is reduced 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, metabolism of enalapril can be slowed down without damaging its pharmacodynamic effect.

In patients with heart failure, the absorption and metabolism of enalaprilat slows down, and the volume of distribution also decreases. Since these patients may have renal failure, they can slow the excretion of enalapril. The pharmacokinetics of enalapril may also change in elderly patients, mostly due to concomitant diseases, than the elderly.

Hydrochlorothiazide absorbed, mainly in the duodenum and proximal part of the small intestine.Absorption is 70% and increases by 10% when taken with food. The level of maximum serum concentration is reached after 1.5-5 hours. The volume of distribution is about 3 l / kg. Connection with blood plasma proteins - 40%. The drug accumulates in erythrocytes, the mechanism of accumulation is not known. It is not metabolized in the liver, is excreted mainly by the kidneys: 95% unchanged and about 4% in the form of hydrolyzate-2-amino-4-chloro-t-benzene disulfonamide. 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. The half-life period (T1 / 2) in the initial phase is 2 hours, in the final phase (10-12 hours after administration) - about 10 hours. It penetrates the placental barrier and accumulates in the 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). The level of hydrochlorothiazide in breast milk is very low.

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 heart failure were found to have a decrease in proportion to the degree of disease, by 20 -70%. T1 / 2 hydrochlorothiazide increased to 28.9 hours; renal clearance of 0.17 - 3.12 ml / s (10 - 187 ml / min) (mean values of 1.28 ml / s (77 ml / min)).

In patients undergoing surgery of the intestinal bypass surgery for obesity, hydrochlorothiazide absorption can be reduced by 30% and the serum concentration of 50%, than in 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 sulfonamides)

- anuria, marked renal impairment (creatinine clearance less than 30 ml / min)

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

- primary hyperaldosteronism

- Addison's disease

- porphyria

- age to 18 years (effectiveness and safety not established)

Carefully:

- bilateral stenosis of the renal arteries or stenosis of the arteries of the single kidney, impaired renal function (creatinine clearance 30-75 ml / min)

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

- ischemic heart disease and cerebrovascular diseases (including cerebral circulatory 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 impairment of liver or kidney function

- states, accompanied by a decrease in the volume of circulating blood (as a result of therapy with diuretics, while limiting consumption of table salt, diarrhea and vomiting)

- elderly age

- gout.

Pregnancy and lactation:The drug is contraindicated in pregnancy. At the onset of pregnancy, the drug should be stopped immediately.If it is necessary to prescribe the drug during lactation, lactating mothers should refuse breastfeeding.

Dosing and Administration:

Treatment of hypertension does not begin with a combination of drugs. Initially, adequate doses of individual components should be determined. Dosage should always be selected individually for each patient.

The usual dose is 1 tablet per day. Patients should take the pill completely during or after a meal, with a small amount of liquid, preferably in the morning. In case of missed intake of the next dose of the drug, it must be taken as soon as possible, if a sufficiently large amount of time remains before the next dose. If several hours are left before taking the next dose, you should wait and accept only it. Never double the dose.

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

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 Enampharm®-H treatment to prevent the development of symptomatic hypotension.Before the beginning of treatment, the function of the kidneys should be investigated.

Dosage with impaired renal function

Patients with creatinine clearance greater than 0.5 mL / s or serum creatinine less than 265 mol / L (3 mg / 100 mL) may be given a normal dose of Enafarm-N.

Side effects:

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

From the cardiovascular system: heart beat, various heart rhythm disturbances, marked decrease in blood pressure, orthostatic hypotension, cardiac arrest, myocardial infarction, cerebrovascular stroke, angina pectoris, Raynaud's syndrome.

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

From the 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 insufficiency, impaired renal function, interstitial nephritis.

From the skin: sweating, rash, exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, Stephen-Johnson syndrome, alopecia, photosensitivity.

From the sense organs: impaired vision, impaired taste, impaired sense of smell, tinnitus, conjunctivitis, dry conjunctiva, lachrymation.

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

Laboratory indicators: hypokalemia, hyperkalemia, hypomagnesemia, hypercalcemia, hyponatremia, hypochloraemic alkalosis, hyperglycemia, glucosuria, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, increased activity of "hepatic" enzymes, hyperbilirubinemia, leukocytosis, eosinophilia, neutropenia, leukopenia, agranulocytosis, anemia, pancytopenia.

Other: lupus-like syndrome, described in the literature (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 heart rhythm disturbances, convulsions, paresis, paralytic ileus, impaired consciousness (including coma), renal insufficiency, acid-base balance disturbance, electrolyte balance disturbance.

Treatment: the patient is transferred to a horizontal position with a low headboard. In mild cases, gastric lavage and ingestion of saline are indicated, in more serious cases, measures aimed at stabilizing blood pressure in / in the administration of physiological solution, plasma substitutes. The patient needs to monitor blood pressure, heart rate, respiration rate, serum urea concentration, creatinine, electrolytes and diuresis, if necessary - intravenous angiotensin II, hemodialysis (enalaprilate removal rate - 62 ml / min).

Interaction:

Simultaneous reception of other antihypertensive agents, barbiturates, tricyclic antidepressants, phenothiazines and narcotics, as well as alcohol intake, enhances the antihypertensive effect of Enafarm-N.

Analgesics and non-steroidal anti-inflammatory drugs, a large amount of salt in the diet, simultaneous reception of colestyramine or colestipol reduce the effect of Enafarm-H. Simultaneous use with lithium preparations can lead to lithium intoxication, since enalapril and hydrochlorothiazide reduce the excretion of lithium. It is necessary to control the concentration of lithium in the blood serum and its dosage is accordingly adjusted. If possible, simultaneous treatment of Enafarm-H and lithium preparations should be avoided. Simultaneous use of Enafarm-H and non-steroidal anti-inflammatory drugs and analgesics (due to inhibition of prostaglandin synthesis) can reduce the efficacy of enalapril and increase the risk of impaired 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 treatment with potassium-sparing diuretics (spironolactone, amiloride, triamterene) or the addition of potassium can lead to hyperkalemia.

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

There was reported acute renal failure in 2 patients after kidney transplantation, simultaneously receiving enalapril and ciclosporin. It is suggested 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 needed when concomitantly using enalapril and cyclosporine. Simultaneous administration of sulfonamides and oral hypoglycemic agents from the sulfonylurea group can cause reactions of increased sensitivity (cross-sensitivity is possible).

Caution is necessary when used concomitantly with cardiac glycosides. Possible hydrochlorothiazidine-induced hypovolemia, hypokalemia and hypomagnesemia can increase the toxicity of glycosides.

Simultaneous administration with corticosteroids increases the risk of hypokalemia.

When used concomitantly with theophylline, enalapril can reduce the half-life of theophylline.

With simultaneous application with cimetidine, the half-life of enalapril may increase. The risk of arterial hypotension increases during general anesthesia or the use of nondepolarizing muscle relaxants (eg, tubocurarine).

Special instructions:

A marked decrease in blood pressure with all clinical consequences can be observed after the first administration of Enafarm-N tablets in patients with severe heart failure and hyponatremia, severe renal failure, hypertension or left ventricular dysfunction, and especially in patients in a state of hypovolemia as a result diuretic therapy, salt-free diets, diarrhea, vomiting or hemodialysis. Arterial hypotension after taking the first dose and its more serious consequences is a rare and ongoing phenomenon. It can be avoided by the elimination of diuretics, if possible, before the beginning of treatment with Enafarm-N.

In the 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 plasma by infusing saline. Transient arterial hypotension is not a contraindication for continuing treatment. After normalizing blood pressure and replenishing the volume of circulating blood, patients usually tolerate subsequent doses well. Caution is necessary when used in patients with impaired renal function (creatinine clearance from 0.5 to 1.3 ml / s). In patients receiving hydrochlorothiazide, can develop azotemia. Patients with impaired renal function may show signs of accumulation of the drug. If necessary, a combination of enalapril with a lower amount of hydrochlorothiazide or a combination therapy with enalapril and hydrochlorothiazide should be eliminated.

It is necessary to avoid the appointment of Enafarm-H to patients with bilateral stenosis of the renal arteries or stenosis of the renal artery of a single kidney, as this can lead to impaired renal function or even to acute renal failure (enalapril effect).Therefore, it is necessary to monitor the function of the kidneys before and during treatment with the drug.

Caution is required in patients with coronary heart disease, expressed cerebrovascular diseases, aortic stenosis or other stenosis, which prevents the outflow of blood from the left ventricle, expressed atherosclerosis, in elderly patients as a result of the risk of hypotension and deterioration of perfusion of the heart, brain and kidneys.

A regular monitoring of the serum concentration of electrolytes during the treatment period is necessary to identify possible imbalances. Determination of the serum concentration of electrolytes is mandatory for patients with prolonged diarrhea, vomiting and receiving intravenous infusions.

In patients taking Enafarm-N, signs of electrolyte imbalance, such as dry mouth, thirst, weakness, drowsiness, lethargy, agitation, muscle pain and cramps (mainly the calf muscles), lowering blood pressure, tachycardia, oliguria and gastrointestinal tract, intestinal disorders (nausea, vomiting).

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

During treatment with Enafarm-H, hypomagnesemia and sometimes hypercalcemia may occur, resulting from an increase in the excretion of magnesium and a delay in 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, the action of hydrochlorothiazide may indicate hyperuricemia or worsening of gout. If there is an increase in the concentration of uric acid in the serum, treatment should be discontinued. It can be resumed after the normalization of laboratory indicators and in the future, under their control. Caution is necessary in all patients receiving oral hypoglycemic agents or insulin, since hydrochlorothiazide can weaken, and enalapril strengthen their action. Patients with diabetes should be more frequently observed, and if necessary, some change in the dose of hypoglycemic agents may be required.When an angioedema develops in the face or neck, it is usually sufficient to discontinue therapy and prescribe antihistamines to the patient. In more severe cases (swelling tongue, pharynx and larynx) angioedema is treated adrenaline, it is necessary maintain airway patency (intubation or laryngotomy). The antihypertensive effect of Enapharma-H can be enhanced after sympathectomy. Due to the increased risk of anaphylactic reactions, Enafarm-H 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 Enafarm-H, hypersensitivity reactions can occur in patients without previous allergies or bronchial asthma. Reported worsening of the course of systemic lupus erythematosus.

It was reported several cases of acute hepatic impairment with cholestatic jaundice, liver necrosis and death (rarely) during treatment with ACE inhibitors. The reason for these syndromes is not completely clear.When jaundice occurs and the activity of "liver" enzymes increases, treatment should be stopped immediately, patients should be monitored.

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

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

Patients After extensive surgical operations, which received medicines, causing arterial hypotension, during general anesthesia, enalapril can block the formation of angiotensin II, secondary to the compensatory release of renin. If the doctor assumes this mechanism of arterial hypotension, treatment can be carried out by increasing the volume of circulating blood.

During treatment, periodic monitoring of the serum concentration of electrolytes, glucose, urea, creatinine and the activity of "liver" enzymes, as well as urine protein, is necessary. Treatment with Enafarm-H should be discontinued before the study of parathyroid function.

Effect on the ability to drive transp. cf. and fur:Enafarm-N does not affect the management of the car or the work with the mechanisms, however, in some patients, primarily at the beginning of treatment, arterial hypotension and dizziness may occur, which may reduce the ability to drive and operate machinery. Therefore, at the beginning of treatment, it is recommended to avoid driving a car, work with mechanisms and perform other work that requires concentration of attention, until an answer to treatment is established.

Form release / dosage:

Tablets 25 mg + 10 mg.

Packaging:

By 7, 10 or 14 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

1,2 or 4 contour squares with instructions for use in a pack of cardboard. For 100 or 200 tablets per bottle of high-density polyethylene. 72 bottles with instructions for use in a cardboard box (for hospitals).

Storage conditions:In a dry place protected from light. Keep out of the reach of children.

Shelf life:

3 years.

After the expiration date indicated on the package, do not use the drug.

Terms of leave from pharmacies:On prescription

Registration number:LS-001681

Date of registration:20.01.2012

The owner of the registration certificate:FARMAKOR PRODUCTION, LTD. FARMAKOR PRODUCTION, LTD. Russia

Manufacturer: & nbsp

FARMAKOR PRODUCTION, LTD. Russia

Information update date: & nbsp24.12.2015

Illustrated instructions

Instructions

Enafarm®-H (Enafarm®-N)