Enzix

Active material: Enalapril, Indapamid
When ATH: C09BA02
CCF: Antihypertensive drugs
ICD-10 codes (testimony): I10
When CSF: 01.09.16.03
Manufacturer: HEMOFARM A.D. (Serbia)

DOSAGE FORM, COMPOSITION AND PACKAGING

Tablets set.

Enalapril Tablets, white, round, lenticular, with Valium on one side (5 PC. in blister).

Excipients: lactose monohydrate, magnesium carbonate, gelatin, krospovydon, magnesium stearate.

Tablets indapamide, Film-coated in white, round, lenticular (5 PC. in blister).

Excipients: lactose monohydrate, povidone K30, krospovydon, magnesium stearate, sodium lauryl, talc.

Cover structure indapamide tablets: gipromelloza, macrogol 6000, Titanium dioxide (E171).

10 PC. – blisters (3) – packs cardboard.

Enzix duo

Tablets set.

Tablets enalapril white, round, lenticular, with Valium on one side (10 PC. in blister).

Excipients: lactose monohydrate, magnesium carbonate, gelatin, krospovydon, magnesium stearate.

Tablets indapamide, Film-coated in white, round, lenticular (5 PC. in blister).

Excipients: lactose monohydrate, povidone K30, krospovydon, magnesium stearate, sodium lauryl, talc.

The composition of the film coating of tablets indapamide: gipromelloza, macrogol 6000, Titanium dioxide (E171).

15 PC. – blisters (3) – packs cardboard.

Enzix duo forte

Tablets set.

Enalapril Tablets, white, round, lenticular, with Valium on one side (10 PC. in blister).

Excipients: lactose monohydrate, magnesium carbonate, gelatin, krospovydon, magnesium stearate.

Tablets indapamide, Film-coated in white, round, lenticular (5 PC. in blister).

Excipients: lactose monohydrate, povidone K30, krospovydon, magnesium stearate, sodium lauryl, talc.

The composition of the film coating of tablets indapamide: gipromelloza, macrogol 6000, talc, Titanium dioxide (E171).

15 PC. – blisters (3) – packs cardboard.

Pharmacological action

Antihypertensive drugs, containing the two drugs in the same package: ACE inhibitor – эnalapril diuretic – indapamid.

Enalapril – ACE inhibitor. It is a prodrug: pharmacologically active metabolite of enalapril has – Enalaprilat. Inhibits the formation of angiotensin II from angiotensin I, resulting in decreased aldosterone. This decreases systemic vascular resistance, systolic and diastolic blood pressure, office- and preload on the myocardium. Enalapril artery expands to a greater extent, than veins (with the reflex increase in heart rate were observed), reduces the degradation of bradykinin, increases the synthesis of prostaglandin.

The antihypertensive effect is more pronounced at high plasma renin, than the normal or reduced its level.

Enalapril increases coronary and renal blood flow. Reduction of blood pressure is not within a therapeutic effect on cerebral blood flow, blood vessels in the brain are maintained at a sufficient level and against the background of reduced pressure.

With long-term use of enalapril reduces myocardial hypertrophy of the left ventricle myocytes and the walls of your arteries resistive type, that prevents the progression of heart failure and slows the development of left ventricular dilatation. Enalapril improves myocardial išemizirovannogo.

Impact agregatia platelets. It has some diuretic effect.

The action comes after enalapril 1 no, reaches through 4-6 hours and lasts up 24 no.

Indapamid – thiazide diuretic with moderate strength and duration of action. It has a mild diuretic effect and salureticheskim, are associated with the blockade of sodium ion reabsorption, Chlorine, hydrogen, and to a lesser extent potassium ions in the proximal tubule and cortical segment distal tubule of the nephron.

It reduces the tone of smooth muscles of arteries, reduces round by reducing the reactivity of the vascular wall to norepinephrine and angiotensin II; increase in prostaglandin synthesis, having vasodilating activity; inhibition of calcium current in vascular smooth muscle cells. It helps to reduce left ventricular hypertrophy.

At therapeutic doses has no effect on the lipid and carbohydrate metabolism (incl. in patients with concomitant diabetes).

The antihypertensive effect of indapamide is developing in the late first / early second week of taking the drug at a constant. After a single dose antihypertensive effect persists for 24 no.

The simultaneous use of enalapril and indapamide leads to increased antihypertensive effect of enalapril.

Pharmacokinetics

Enalapril

Absorption

After oral administration about 60% absorbed in the digestive tract. Simultaneous food intake does not affect absorption of enalapril. C_max enalapril plasma levels achieved after 1-2 no, эnalaprilata – through 3-4 no. Bioavailability – 40%.

Distribution

Binding to plasma proteins is to enalaprilate 50-60%.

Enalaprilate easily passes through the blood-tissue barriers, excluding GEB, a small amount crosses the placental barrier and is excreted in breast milk.

Metabolism

Enalapril is rapidly and completely hydrolyzed in the liver to the active metabolite – эnalaprilata, which is a more potent inhibitor of ACE, enalapril.

Deduction

T_1/2 эnalaprilata – about 11 no. Displayed c urine 60% (20% – as enalapril and 40% – as enalaprilat), with feces – 33% (6% – as enalapril and 27% – as enalaprilat).

Pharmacokinetics in special clinical situations

In chronic renal failure occurs accumulation of enalapril in reducing filtration less 10 ml / min.

Enalapril is removed by hemodialysis (speed 62 ml / min) and peritoneal dialysis.

Indapamid

Absorption

Once inside quickly and completely absorbed from the gastrointestinal tract. Eating slows down the absorption rate, but does not affect its fullness. C_max achieved through 1-2 hours after ingestion. High Bioavailability (93%).

Distribution

C_ss established through 7 regular admission days.

Binding to plasma proteins is 79%. Associated with elastin and smooth muscle of the vascular wall. He has extensive V_d, It penetrates the blood-tissue barriers (incl. placental) and breast milk.

Metabolism

It is metabolized in the liver.

Deduction

T_1/2 averages 14-18 no. With urine output 60-80% as metabolites (unchanged output of about 5%), with feces – 20%. Not accumulates.

Pharmacokinetics in special clinical situations

In patients with renal insufficiency pharmacokinetics unchanged.

Testimony

- Arterial hypertension.

Dosage regimen

Enzix and Enzix Duo

1 tab. Enalapril (10 mg) and 1 tab. indapamida (2.5 mg) taken orally morning at the same time. Depending on the dynamics of indicators of blood pressure enalapril dose may be increased to receipt 2 times / day.

Enzix Duo Forte

1 tab. Enalapril (20 mg) and 1 tab. indapamida (2.5 mg) taken orally morning at the same time. Depending on the dynamics of indicators of blood pressure enalapril dose may be increased to receipt 2 times / day.

The maximum daily dose of enalapril 40 mg, indapamida – 2.5 mg.

At renal insufficiency of mild to moderate severity (CC 30-80 ml / min) enalapril dose should be 5-10 mg / day.

Side effect

Enalapril

From the central and peripheral nervous system: headache, dizziness, weakness, insomnia, alarm, confusion, fatiguability, drowsiness (2-3%); in some cases when used in high doses – nervousness, depression, paresthesia.

The respiratory system: nonproductive cough, interstitial pneumonitis, bronchospasm / asthma, breathlessness, rhinorrhea, pharyngitis.

From the senses: vestibular disorders, hearing and visual impairment, noise in ears.

From the digestive system: dry mouth, anorexia, dyspeptic symptoms (nausea, diarrhea or constipation, vomiting, stomach ache), ileus, pancreatitis, liver and biliary excretion, hepatitis (hepatocellular or cholestatic), jaundice, increase in liver transaminases, giperʙiliruʙinemija.

Cardio-vascular system: excessive reduction of blood pressure, Orthostatic hypotension; rarely – chest pain, angina, myocardial infarction (usually associated with a marked decrease in blood pressure), Arrhythmia (predserdnaya beards- or tachycardia, auricular fibrillation), heartbeat, thromboembolism pulmonary artery branches, precordialgia, fainting.

Metabolism: hyperkalemia, giponatriemiya, gipoglikemiâ (in patients with diabetes mellitus).

From the hematopoietic system: rarely – decrease in hematocrit and hemoglobin concentration, thrombocytopenia, neutropenia, agranulocytosis (patients with autoimmune diseases), eozinofilija, increased erythrocyte sedimentation rate.

From the urinary system: impairment of renal function, proteinuria, giperkreatininemiя, increase of urea.

On the part of the reproductive system: decreased libido, tides, reduced potency.

Dermatological reactions: alopecia, photosensitivity.

Allergic reactions: skin rash, angioneurotic edema of the face, limbs, lips, language, glottis and / or larynx, disfonija, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, pemphigus, itch, hives, serositis, vasculitis, myositis, arthralgia, arthritis, stomatitis, glossitis; rarely – intestinal angioedema.

Indapamid

From the central and peripheral nervous system: asthenia, nervousness, headache, dizziness, drowsiness, vertigo, insomnia, depression, paresthesia; rarely – fatigue, generalized weakness, malaise, muscle spasm, tension, irritability, alarm.

From the digestive system: nausea, anorexia, dry mouth, gastralgia, vomiting, diarrhea or constipation, discomfort in the abdomen, pancreatitis.

From the senses: conjunctivitis, blurred vision.

The respiratory system: cough, pharyngitis, sinusitis, rhinorrhea; rarely – rhinitis.

Cardio-vascular system: orthostatic hypotension, hypokalemia characteristic ECG changes, Arrhythmia, heartbeat.

From the urinary system: increase in the frequency of infections, nocturia, polyuria, increase of urea nitrogen in the blood plasma, giperkreatininemiя.

Metabolism: kaliopenia, giponatriemiya, hypochloraemic alkalosis, hypercalcemia, glycosuria, Sweating, weight loss.

On the part of the reproductive system: reduced potency, decreased libido.

Allergic reactions: skin rash, hives, itch, gemorragicheskiy vasculitis.

Other: flu-like symptoms, chest pain, backache, infection, exacerbation of SLE.

Contraindications

Enalapril

- A history of angioedema, associated with treatment with ACE inhibitors;

- Porphyria;

- Pregnancy;

- Lactation;

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

- Hypersensitivity to enalapril and other ACE inhibitors.

FROM caution Enalapril should be used with primary hyperaldosteronism, bilateral renal artery stenosis, stenosis of the artery to a solitary kidney, hyperkalemia, condition after kidney transplantation, states, accompanied by a decrease in the bcc (incl. vomiting, diarrhea), when aortic stenosis, mitral stenosis (violations of hemodynamics), idiopathic hypertrophic subaortic stenosis, systemic connective tissue diseases, CHD, cerebrovascular diseases, diabetes, in renal failure (proteinuria – more 1 g / day), hepatic failure, patients, a diet with salt restriction, or on hemodialysis, while admission to immunosuppressants and saluretikami, in elderly patients (senior 65 years).

Indapamid

- Anurija;

- Hypokalemia;

- Severe hepatic impairment (incl. encephalopathy);

- Severe renal insufficiency;

- Pregnancy;

- Lactation;

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

- Concomitant use of drugs, prolonging the QT interval;

- Hypersensitivity to the drug, other derivatives of the sulfonamide or other components of the preparation.

FROM caution indapamide should be used for patients with diabetes decompensated, hyperuricemia (especially, accompanied by gout and urate nephrolithiasis).

Pregnancy and lactation

The drug is contraindicated during pregnancy and lactation.

For newborns and babies, who were in utero effects of ACE inhibitors, should be closely monitored for early detection of significant decrease in blood pressure, oligurii, hyperkalemia and neurological disorders, development is possible due to the decrease in renal and cerebral blood flow while reducing blood pressure, called ACE inhibitors. If oliguria need to maintain blood pressure and renal perfusion through the introduction of appropriate fluids and vasoconstrictor.

Cautions

Enalapril

Patients should be under medical surveillance for 2 hours after receiving the initial dose, and further 1 h to stabilize blood pressure.

In patients with a decrease in CBV (as a result of diuretic therapy, while limiting intake of salt, hemodialysis, diarrhea, rvote) when applying enalapril (as well as other ACE inhibitors) even at an initial dose increases the risk of a sudden and significant decrease in blood pressure.

Transient hypertension is not a contraindication for continuation of treatment after stabilization of blood pressure. In case of repeated significant decrease in blood pressure should reduce the dose or stop the drug.

The use of high-dialysis membranes increases the risk of an anaphylactic reaction. In days, free dialysis dosing regimen should be adjusted depending on the level of blood pressure.

You should carefully monitor the condition of patients with severe heart failure, Coronary heart disease and cerebral vascular disease. In these patients, the sharp decrease in blood pressure can lead to myocardial infarction, stroke or renal dysfunction.

Sudden withdrawal of the drug does not lead to a sharp increase in blood pressure.

Before examining the function of the parathyroid glands enalapril should be discontinued.

In case of side effects, or angioedema drug should be discontinued and appropriate treatment.

Before surgery (including dentistry) the patient should notify the surgeon / anesthesiologist on the use of ACE inhibitors.

Before and during treatment with ACE inhibitors need periodic monitoring of blood pressure, blood parameters (Hemoglobin, Potassium, creatinine, urea, liver transaminases), Protein in the urine.

Indapamid

In the appointment of indapamide to patients, receiving cardiac glycosides, laxatives, against the backdrop of hyperaldosteronism, as well as elderly patients shows regular monitoring of potassium and creatinine.

In patients receiving indapamide should systematically monitor the concentration of potassium, sodium, magnesium plasma, pH, glucose, uric acid and residual nitrogen. The most careful control is shown in liver cirrhosis (especially with edema or ascites – the risk of metabolic alkalosis, increase the expression of hepatic encephalopathy), CHD, Heart Failure, as well as in elderly patients. For high-risk patients also include an increased QT interval on an electrocardiogram (congenital or develop on the background of a pathological process). The first determination of the concentration of potassium in the blood should be held during the first week of treatment.

Hypercalcemia in patients receiving indapamide may be due to previously undiagnosed hyperparathyroidism.

Diabetic patients are extremely important to control the level of glucose in the blood, especially in the presence of hypokalemia.

Considerable dehydration may lead to acute renal failure (reduction in glomerular filtration rate). Patients need to compensate for the loss of water at the beginning of treatment carefully monitor renal function.

Indapamide may give a positive result in doping control.

Patients with hypertension and hyponatremia (due to diuretics) necessary for 3 the day before you start taking ACE inhibitors stop taking diuretics (if necessary, diuretics can be resumed later), in such cases, either the initial prescribed low doses of ACE inhibitors.

In the appointment of indapamide should be considered, derivatives of sulfonamides can exacerbate during SLE.

Use in Pediatrics

Efficacy and safety of enalapril and indapamide in children and adolescents under the age of 18 years not set.

Effects on ability to drive vehicles and management mechanisms

Early treatment, before the end of the period of adjustment of the dosage the patient should refrain from driving vehicles and Occupation potentially hazardous activities, require high concentration and speed of psychomotor reactions, tk. dizziness, especially after receiving the initial dose.

Overdose

Enalapril

Symptoms: marked reduction in blood pressure up to the development of collapse, myocardial infarction, acute stroke and thromboembolic complications, convulsions, stupor.

Treatment: the patient is transferred to a horizontal position with a low headboard. Displaying gastric lavage and ingestion of laxatives.

If necessary, carry out activities, to stabilize blood pressure: in / in a saline solution, plasma expanders, angiotensin II, possible hemodialysis.

Indapamid

Symptoms: nausea, vomiting, weakness, dysfunction of the gastrointestinal tract, water and electrolyte disturbances; in some cases – excessive reduction of blood pressure, dizziness, drowsiness, confusion, respiratory depression. Patients with cirrhosis may develop hepatic coma.

Treatment: gastric lavage and / or administration of activated charcoal, Correction fluid and electrolyte balance, simptomaticheskaya therapy. No specific antidote.

Drug Interactions

Enalapril

The simultaneous use of enalapril and indapamide leads to increased antihypertensive effect of enalapril.

In an application with enalapril NPVC, including selective COX-2 inhibitors, analgesics, antipyretics may reduce the hypotensive effect of enalapril.

In some cases, in patients with impaired renal function, receiving NSAIDs, including selective COX-2 inhibitors, ACE inhibitors may result in further deterioration of renal function. These changes are reversible.

The antihypertensive effect of enalapril increase diuretics, beta-blockers, methyldopa, nitrates, blockers of slow calcium channel dihydropyridine, gidralazin, prazosin.

Enalapril in conjunction with potassium-sparing diuretics (spironolactone, triamterene, amilorid), as well as the potassium-containing drugs increase the risk of hyperkalemia.

Enalapril reduces the effect of drugs, containing theophylline.

Immunosuppressive, allopurinol, cytostatics reinforce haematotoxicity enalapril. Preparations, causing bone marrow suppression, increase the risk of neutropenia and / or agranulocytosis.

Enalapril slows excretion of lithium (while the use of enalapril with lithium salts is shown to control the concentration of lithium in the blood plasma).

The combined use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic drugs) can enhance the hypoglycemic effect of the latter with risk of hypoglycaemia. This occurs most frequently during the first 3 weeks of joint application, and in patients with renal insufficiency. In patients with diabetes mellitus, hypoglycemic agents receiving oral insulin, requires monitoring of blood glucose, especially during the first month of combined use of ACE inhibitors.

Simptomokompleks, including facial flushing, nausea, vomiting, and hypotension, described in rare cases, joint use of drugs for parenteral use gold (sodium aurothiomalate) and ACE inhibitors (Enalapril).

Ethanol enhances the hypotensive effect of enalapril.

Indapamid

With simultaneous use of indapamide with saluretikami, cardiac glycosides, glitches- and mineralocorticoid, tetrakozaktidom, amphotericin B (I /), laxatives increase the risk of hypokalemia.

At the same time taking indapamide with cardiac glycosides increases the likelihood of glycoside intoxication; with calcium – hypercalcemia; metformin – vozmozhno usugublenie molochnokislogo acidosis.

Indapamide slows elimination of lithium and thereby increase its concentration in blood plasma.

Astemizol, Erythromycin (I /), pentamidine, sultopryd, terfenadine, vynkamyn, antiarrhythmics class IA (quinidine, disopyramide) and class III (Amiodarone, bretylium, sotalol) upon receipt on the background idapamida may cause arrhythmia type “pirouette”.

NSAIDs, GCS, tetracosactide, sympathomimetic reduce the antihypertensive effect of indapamide; ʙaklofen – increases.

Indapamide combination with potassium-sparing diuretics can be effective in a certain category of patients, but it is not completely ruled out the possibility of a hypo- or hyperkalemia, especially in patients with diabetes and renal insufficiency.

ACE inhibitors during the simultaneous use of indapamide increases the risk of hypotension and / or acute renal failure (especially when existing renal artery stenosis).

Indapamide increases the risk of renal dysfunction while the use of iodinated contrast agents in high doses (dehydration). Before use of iodine-containing contrast agents in patients, taking indapamide, you need to restore lost fluids.

Tricyclic antidepressants and antipsychotic drugs increase the hypotensive effect of indapamide and increase the risk of orthostatic hypotension.

With simultaneous use of indapamide with cyclosporine increases the risk of hypercreatininemia.

Indapamide reduces the effect of indirect anticoagulants (coumarin derivatives or indandiona) due to higher concentration of clotting factors by reducing the BCC and increase their production by the liver (may require dose adjustment).

Indapamide enhances the action of non-depolarizing muscle relaxants.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be protected from moisture, inaccessible to children at temperature from 15 ° to 25 ° C. Shelf life – 3 year.