Enzix (Tablets) Instructions for Use

Marketing Authorization Holder

Nizhpharm JSC (Russia)

Manufactured By

Chemopharm, LLC (Russia)

Or

Hemofarm, A.D. (Serbia)

Contact Information

NIZHPHARM group of companies (Russia)

ATC Code

C09BA02 (Enalapril and diuretics)

Active Substances

Indapamide (Rec.INN registered by WHO)

Enalapril (Rec.INN registered by WHO)

Dosage Forms

	Enzix Duo Forte	Tablets kit: 15 pcs. in a blister, 3 blisters in a pack, incl.: indapamide tab., film-coated, 2.5 mg: 5 pcs.; enalapril tab. 20 mg: 10 pcs.
	Enzix Duo	Tablets kit: 15 pcs. in a blister, 3 blisters in a pack, incl.: indapamide tab., film-coated, 2.5 mg: 5 pcs.; enalapril tab. 10 mg: 10 pcs.

Dosage Form, Packaging, and Composition

Enzix

Tablets kit.

Indapamide tablets, film-coated, white, round, biconvex (5 pcs. in a blister).

Excipients: lactose monohydrate – 76.96 mg, povidone K30 – 2.82 mg, crospovidone – 0.88 mg, magnesium stearate – 0.88 mg, sodium lauryl sulfate – 0.44 mg, talc – 3.52 mg.

Composition of the indapamide tablet coating: hypromellose – 1.7222 mg, macrogol 6000 – 0.3445 mg, talc – 1.903 mg, titanium dioxide (E171) – 0.4303 mg.

Enalapril tablets, white, round, biconvex, with a score on one side (5 pcs. in a blister).

Excipients: lactose monohydrate – 125 mg, magnesium carbonate 84.6 mg, gelatin – 9.2 mg, crospovidone – 9.2 mg, magnesium stearate – 2 mg.

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

Enzix Duo

Tablets kit.

Indapamide tablets, film-coated, white, round, biconvex (5 pcs. in a blister).

Excipients: lactose monohydrate – 76.96 mg, povidone K30 – 2.82 mg, crospovidone – 0.88 mg, magnesium stearate – 0.88 mg, sodium lauryl sulfate – 0.44 mg, talc – 3.52 mg.

Composition of the indapamide tablet film coating: hypromellose – 1.7222 mg, macrogol 6000 – 0.3445 mg, talc – 1.9030 mg, titanium dioxide (E171) – 0.4303 mg.

Enalapril tablets, white, round, biconvex, with a score on one side (10 pcs. in a blister).

Excipients: lactose monohydrate – 125 mg, magnesium carbonate – 84.6 mg, gelatin – 9.2 mg, crospovidone – 9.2 mg, magnesium stearate – 2 mg.

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

Enzix Duo Forte

Tablets kit.

Indapamide tablets, film-coated, white, round, biconvex (5 pcs. in a blister).

Excipients: lactose monohydrate – 76.96 mg, povidone K30 – 2.82 mg, crospovidone – 0.88 mg, magnesium stearate – 0.88 mg, sodium lauryl sulfate – 0.44 mg, talc – 3.52 mg.

Composition of the indapamide tablet film coating: hypromellose – 1.7222 mg, macrogol 6000 – 0.3445 mg, talc – 1.9030 mg, titanium dioxide (E171) – 0.4303 mg.

Enalapril tablets, white, round, biconvex, with a score on one side (10 pcs. in a blister).

Excipients: lactose monohydrate – 116.7 mg, magnesium carbonate – 120.6 mg, gelatin – 10.7 mg, crospovidone – 10.7 mg, magnesium stearate – 2.2 mg.

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

Clinical-Pharmacological Group

Antihypertensive combination drug

Pharmacotherapeutic Group

Antihypertensive agent, combination (diuretic + ACE inhibitor)

Pharmacological Action

Antihypertensive drug containing two medicinal products in one package: ACE inhibitor – enalapril and diuretic – Indapamide.

Enalapril is an ACE inhibitor. It is a prodrug: the pharmacological activity is possessed by the metabolite of enalapril – enalaprilat. It suppresses the formation of angiotensin II from angiotensin I, which leads to a decrease in aldosterone content. This reduces total peripheral vascular resistance, systolic and diastolic blood pressure, and post- and preload on the myocardium. Enalapril dilates arteries to a greater extent than veins (with no reflex increase in heart rate noted), reduces the degradation of bradykinin, and increases the synthesis of prostaglandin.

The antihypertensive effect is more pronounced with high plasma renin levels than with normal or reduced levels.

Enalapril enhances coronary and renal blood flow. A decrease in blood pressure within therapeutic limits does not affect cerebral circulation; blood flow in cerebral vessels is maintained at a sufficient level even against the background of reduced pressure.

With long-term use of enalapril, hypertrophy of the left ventricular myocardium and myocytes of the walls of resistive-type arteries decreases, which prevents the progression of heart failure and slows the development of left ventricular dilation. Enalapril improves blood supply to the ischemic myocardium.

It reduces platelet aggregation. It has a certain diuretic effect.

The action of enalapril begins within 1 hour, reaches a maximum in 4-6 hours, and lasts up to 24 hours.

Indapamide is a thiazide-like diuretic with moderate strength and long-lasting action. It has moderate saluretic and diuretic effects, which are associated with the blockade of reabsorption of sodium, chloride, hydrogen ions, and to a lesser extent potassium ions in the proximal tubules and the cortical segment of the distal tubule of the nephron.

It reduces the tone of arterial smooth muscles, reduces total peripheral vascular resistance by reducing the reactivity of the vascular wall to norepinephrine and angiotensin II; increasing the synthesis of prostaglandins with vasodilating activity; inhibiting calcium influx into vascular smooth muscle cells. It contributes to the reduction of left ventricular hypertrophy.

In therapeutic doses, it does not affect lipid and carbohydrate metabolism (including in patients with concomitant diabetes mellitus).

The antihypertensive effect of indapamide develops at the end of the first/beginning of the second week with continuous use of the drug. After a single dose, the antihypertensive effect persists for 24 hours.

Simultaneous use of enalapril and indapamide leads to an enhancement of the antihypertensive effect of enalapril.

Pharmacokinetics

Enalapril

Absorption

After oral administration, about 60% is absorbed from the gastrointestinal tract. Simultaneous food intake does not affect the absorption of enalapril. C_max of enalapril in blood plasma is reached in 1-2 hours, of enalaprilat – in 3-4 hours. The bioavailability of the drug is 40%.

Distribution

Plasma protein binding for enalaprilat is 50-60%.

Enalaprilat easily passes through histohematic barriers, excluding the blood-brain barrier; a small amount penetrates the placental barrier and is excreted in breast milk.

Metabolism

Enalapril is rapidly and completely hydrolyzed in the liver to form an active metabolite – enalaprilat, which is a more potent ACE inhibitor than enalapril.

Elimination

T_1/2 of enalaprilat is about 11 hours. It is excreted in urine 60% (20% as enalapril and 40% as enalaprilat), in feces – 33% (6% as enalapril and 27% as enalaprilat).

Pharmacokinetics in special clinical situations

In chronic renal failure, accumulation of enalapril occurs when filtration is less than 10 ml/min.

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

Indapamide

Absorption

After oral administration, it is rapidly and completely absorbed from the gastrointestinal tract. Food intake somewhat slows the rate of absorption but does not affect its completeness. C_max is reached 1-2 hours after oral administration. Bioavailability is high (93%).

Distribution

C_ss is established after 7 days of regular use.

Plasma protein binding is 79%. It also binds to elastin of the vascular wall smooth muscles. It has a significant V_d, penetrates histohematic barriers (including the placental barrier) and into breast milk.

Metabolism

It is metabolized in the liver.

Elimination

T_1/2 averages 14-18 hours. 60-80% is excreted in urine as metabolites (about 5% is excreted unchanged), 20% in feces. It does not accumulate.

Pharmacokinetics in special clinical situations

In patients with renal failure, the pharmacokinetics do not change.

Indications

• Arterial hypertension.

ICD codes

Dosage Regimen

Enzix and Enzix Duo

1 tab. of enalapril (10 mg) and 1 tab. of indapamide (2.5 mg) are taken orally in the morning simultaneously. Depending on the dynamics of blood pressure indicators, the dose of enalapril can be increased to 2 times/day.

Enzix Duo Forte

1 tab. of enalapril (20 mg) and 1 tab. of indapamide (2.5 mg) are taken orally in the morning simultaneously. Depending on the dynamics of blood pressure indicators, the dose of enalapril can be increased to 2 times/day.

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

In mild to moderate renal impairment (creatinine clearance 30-80 ml/min) the dose of enalapril should be 5-10 mg/day.

Adverse Reactions

Enalapril

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

From the respiratory system: non-productive dry cough, interstitial pneumonitis, bronchospasm/bronchial asthma, dyspnea, rhinorrhea, pharyngitis.

From the senses: vestibular disorders, hearing and vision disorders, tinnitus.

From the digestive system: dry mouth, anorexia, dyspeptic symptoms (nausea, diarrhea or constipation, vomiting, abdominal pain), intestinal obstruction, pancreatitis, impaired liver and bile secretion function, hepatitis (hepatocellular or cholestatic), jaundice, increased activity of liver transaminases, hyperbilirubinemia.

From the cardiovascular system: excessive decrease in blood pressure, orthostatic collapse; rarely – retrosternal pain, angina pectoris, myocardial infarction (usually associated with a pronounced decrease in blood pressure), arrhythmias (atrial brady- or tachycardia, atrial fibrillation), palpitations, pulmonary artery branch thromboembolism, heart area pain, syncope.

From metabolism: hyperkalemia, hyponatremia, hypoglycemia (in patients with diabetes mellitus).

From the hematopoietic system: rarely – decreased hematocrit and hemoglobin concentration, thrombocytopenia, neutropenia, agranulocytosis (in patients with autoimmune diseases), eosinophilia, increased ESR.

From the urinary system: impaired renal function, proteinuria, hypercreatininemia, increased urea content.

From the reproductive system: decreased libido, hot flashes, decreased potency.

Dermatological reactions: alopecia, photosensitivity.

Allergic reactions: skin rash, angioedema of the face, extremities, lips, tongue, glottis and/or larynx, dysphonia, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, pemphigus, itching, urticaria, serositis, vasculitis, myositis, arthralgia, arthritis, stomatitis, glossitis; very rarely – intestinal angioedema.

Indapamide

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

From the digestive system: nausea, anorexia, dry mouth, gastralgia, vomiting, diarrhea or constipation, abdominal discomfort, pancreatitis may occur.

From the senses: conjunctivitis, visual impairment.

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

From the cardiovascular system: orthostatic hypotension, ECG changes characteristic of hypokalemia, arrhythmias, palpitations.

From the urinary system: increased frequency of infections, nocturia, polyuria, increased plasma urea nitrogen, hypercreatininemia.

From metabolism: hypokalemia, hyponatremia, hypochloremic alkalosis, hypercalcemia, glucosuria, sweating, weight loss.

From the reproductive system: decreased potency, decreased libido.

Allergic reactions: skin rash, urticaria, itching, hemorrhagic vasculitis.

Other: flu-like syndrome, chest pain, back pain, infections, exacerbation of SLE.

Contraindications

Enalapril

• History of angioedema associated with ACE inhibitor treatment;
• Porphyria;
• Pregnancy;
• Lactation period;
• Children and adolescents under 18 years of age (efficacy and safety not established);
• Hypersensitivity to enalapril and other ACE inhibitors.

Use with caution in primary hyperaldosteronism, bilateral renal artery stenosis, stenosis of the artery of a solitary kidney, hyperkalemia, condition after kidney transplantation, conditions accompanied by a decrease in circulating blood volume (including vomiting, diarrhea), with aortic stenosis, mitral stenosis (with hemodynamic impairments), idiopathic hypertrophic subaortic stenosis, systemic connective tissue diseases, coronary artery disease, cerebrovascular diseases, diabetes mellitus, in renal failure (proteinuria – more than 1 g/day), in hepatic failure, in patients on a salt-restricted diet or on hemodialysis, with simultaneous use with immunosuppressants and saluretics, in elderly patients (over 65 years of age).

Indapamide

• Anuria;
• Hypokalemia;
• Severe hepatic failure (including with encephalopathy);
• Severe renal failure;
• Pregnancy;
• Lactation period;
• Children and adolescents under 18 years of age (efficacy and safety not established);
• Concomitant use of drugs that prolong the QT interval;
• Hypersensitivity to the drug, other sulfonamide derivatives or other components of the drug.

Use with caution in decompensated diabetes mellitus, hyperuricemia (especially accompanied by gout and urate nephrolithiasis).

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and lactation. If it is necessary to use the drug Enzix during lactation, breastfeeding should be discontinued.

Newborns and infants who have been exposed to ACE inhibitors in utero should be closely monitored for timely detection of marked hypotension, oliguria, hyperkalemia, and neurological disorders, the development of which is possible due to decreased renal and cerebral blood flow with the decrease in blood pressure caused by ACE inhibitors. In case of oliguria, it is necessary to maintain blood pressure and renal perfusion by administering appropriate fluids and vasoconstrictors.

Use in Hepatic Impairment

Contraindicated in hepatic failure.

Use in Renal Impairment

In mild to moderate renal impairment (creatinine clearance from 30 to 80 ml/min) the dose of enalapril should be 5-10 mg/day.

The drug is contraindicated in anuria, severe renal impairment (creatinine clearance less than 30 ml/min).

Pediatric Use

The efficacy and safety of enalapril and indapamide in children and adolescents under 18 years of age have not been established.

Geriatric Use

Use with caution in elderly patients (over 65 years of age).

Special Precautions

Enalapril

Patients require medical supervision for 2 hours after taking the initial dose of the drug and additionally for 1 hour until blood pressure stabilizes.

In patients with reduced circulating blood volume (as a result of diuretic therapy, salt restriction, hemodialysis, diarrhea, vomiting) when using enalapril (like other ACE inhibitors) even in the initial dose, the risk of sudden and marked decrease in blood pressure increases.

Transient arterial hypertension is not a contraindication for continuing treatment with the drug after blood pressure stabilization. In case of repeated marked decrease in blood pressure, the dose should be reduced or the drug discontinued.

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

The condition of patients with severe heart failure, coronary artery disease, and cerebrovascular diseases should be carefully monitored. In such patients, a sharp decrease in blood pressure can lead to myocardial infarction, stroke, or impaired renal function.

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

Before examining parathyroid gland function, enalapril should be discontinued.

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

Before surgical intervention (including dental surgery), the patient should inform the surgeon/anesthesiologist about the use of ACE inhibitors.

Before and during treatment with ACE inhibitors, periodic monitoring of blood pressure, blood parameters (hemoglobin, potassium, creatinine, urea, liver transaminase activity), and urine protein is necessary.

Indapamide

When prescribing indapamide to patients taking cardiac glycosides, laxatives, in the presence of hyperaldosteronism, as well as to elderly patients, regular monitoring of potassium and creatinine levels is indicated.

During indapamide administration, plasma concentrations of potassium, sodium, magnesium, pH, glucose, uric acid, and residual nitrogen should be systematically monitored. The most thorough monitoring is indicated in cases of liver cirrhosis (especially with edema or ascites – risk of metabolic alkalosis, which enhances the manifestations of hepatic encephalopathy), coronary artery disease, heart failure, as well as in elderly patients. The high-risk group also includes patients with an increased QT interval on the ECG (congenital or developed due to any pathological process). The first determination of blood potassium concentration should be performed within the first week of treatment.

Hypercalcemia during indapamide administration may be a consequence of previously undiagnosed hyperparathyroidism.

In patients with diabetes mellitus, it is extremely important to control blood glucose levels, especially in the presence of hypokalemia.

Significant dehydration can lead to the development of acute renal failure (decreased glomerular filtration). Patients need to compensate for water loss and carefully monitor kidney function at the beginning of treatment.

Indapamide may give a positive result in doping control.

Patients with arterial hypertension and hyponatremia (due to diuretic use) must stop taking diuretics 3 days before starting ACE inhibitors (if necessary, diuretic intake can be resumed later), or in such cases, initial low doses of ACE inhibitors are prescribed.

When prescribing indapamide, it should be taken into account that sulfonamide derivatives can exacerbate the course of systemic lupus erythematosus.

Use in Pediatrics

The efficacy and safety of enalapril and indapamide in children and adolescents under 18 years of age have not been established.

Effect on the Ability to Drive Vehicles and Operate Machinery

At the beginning of treatment, until the dose titration period is completed, the patient should refrain from driving vehicles and engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions, as dizziness is possible, especially after taking the initial dose of the drug.

Overdose

Enalapril

Symptoms pronounced decrease in blood pressure up to the development of collapse, myocardial infarction, acute cerebrovascular accident or thromboembolic complications, convulsions, stupor.

Treatment the patient is placed in a horizontal position with a low headboard. In mild cases, gastric lavage and oral administration of a saline laxative are indicated. In more severe cases, measures aimed at stabilizing blood pressure are carried out: intravenous administration of saline, plasma substitutes, angiotensin II; hemodialysis is possible.

Indapamide

Symptoms nausea, vomiting, weakness, gastrointestinal dysfunction, water-electrolyte imbalances; in some cases – excessive decrease in blood pressure, dizziness, drowsiness, confusion, respiratory depression. In patients with liver cirrhosis, hepatic coma may develop.

Treatment gastric lavage and/or administration of activated charcoal, correction of water-electrolyte balance, symptomatic therapy. There is no specific antidote.

Drug Interactions

Enalapril

Concomitant use of enalapril and indapamide leads to an enhancement of the antihypertensive effect of enalapril.

When enalapril is used concomitantly with NSAIDs, including selective COX-2 inhibitors, and analgesic-antipyretics, a reduction in the hypotensive effect of enalapril is possible.

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

The antihypertensive effect of enalapril is enhanced by diuretics, beta-blockers, methyldopa, nitrates, dihydropyridine slow calcium channel blockers, hydralazine, prazosin.

Concomitant use of enalapril with potassium-sparing diuretics (spironolactone, triamterene, amiloride), as well as with potassium-containing preparations, increases the risk of hyperkalemia.

Enalapril reduces the effect of medicines containing theophylline.

Immunosuppressants, allopurinol, and cytostatics enhance the hematotoxicity of enalapril. Drugs that cause bone marrow suppression increase the risk of neutropenia and/or agranulocytosis.

Enalapril contributes to a slowdown in lithium excretion (with concomitant use of enalapril with lithium salts, monitoring of plasma lithium concentration is indicated).

Concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic drugs) may enhance the hypoglycemic effect of the latter with a risk of hypoglycemia. This occurs most frequently during the first 3 weeks of combined use and in patients with renal failure. In diabetic patients receiving oral hypoglycemic drugs and insulin, blood glucose monitoring is necessary, especially during the first month of combined use with ACE inhibitors.

A symptom complex including facial flushing, nausea, vomiting, and arterial hypotension has been described in rare cases with concomitant use of parenteral gold preparations (sodium aurothiomalate) and ACE inhibitors (enalapril).

Ethanol enhances the hypotensive effect of enalapril.

Indapamide

Concomitant use of indapamide with saluretics, cardiac glycosides, gluco- and mineralocorticoids, tetracosactide, amphotericin B (intravenous), and laxatives increases the risk of hypokalemia.

Concomitant use of indapamide with cardiac glycosides increases the likelihood of glycoside intoxication; with calcium preparations – hypercalcemia; with metformin – possible worsening of lactic acidosis.

Indapamide contributes to a slowdown in lithium excretion and thereby an increase in its plasma concentration.

Astemizole, erythromycin (intravenous), pentamidine, sultopride, terfenadine, vincamine, class I A antiarrhythmic drugs (quinidine, disopyramide) and class III antiarrhythmic drugs (amiodarone, bretylium, sotalol) when taken against the background of indapamide may lead to the development of torsades de pointes arrhythmia.

NSAIDs, corticosteroids, tetracosactide, and sympathomimetics reduce the hypotensive effect of indapamide; baclofen enhances it.

The combination of indapamide with potassium-sparing diuretics may be effective in some categories of patients; however, the possibility of developing hypo- or hyperkalemia is not completely excluded, especially in patients with diabetes mellitus and renal failure.

ACE inhibitors, when used concomitantly with indapamide, increase the risk of arterial hypotension and/or acute renal failure (especially with existing renal artery stenosis).

Indapamide increases the risk of renal function impairment when used concomitantly with high doses of iodine-containing contrast agents (dehydration of the body). Before using iodine-containing contrast agents in patients taking Indapamide, fluid loss must be restored.

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

Concomitant use of indapamide with cyclosporine increases the risk of hypercreatininemia.

Indapamide reduces the effect of indirect anticoagulants (coumarin or indandione derivatives) due to an increase in the concentration of clotting factors as a result of a decrease in blood volume and increased production by the liver (dose adjustment may be required).

Indapamide enhances the effect of non-depolarizing muscle relaxants.

Storage Conditions

The drug should be stored in a dry place, protected from moisture, out of the reach of children, at a temperature between 15°C (59°F) and 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.