Iruzid^® (Tablets) Instructions for Use

ATC Code

C09BA03 (Lisinopril and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Lisinopril (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (ACE inhibitor + diuretic)

Pharmacological Action

A combined antihypertensive drug that contains the ACE inhibitor Lisinopril and the thiazide diuretic Hydrochlorothiazide. It has antihypertensive and diuretic effects. The hypotensive effect of both components is additive.

Lisinopril is an ACE inhibitor that reduces the formation of angiotensin II from angiotensin I. The decrease in angiotensin II content leads to a direct reduction in aldosterone secretion. It reduces the degradation of bradykinin and increases the synthesis of prostaglandins. It reduces systemic vascular resistance, blood pressure, preload, pulmonary capillary pressure, causes an increase in cardiac output and improves exercise tolerance in patients with chronic heart failure. It dilates arteries to a greater extent than veins. Some effects are explained by the impact on tissue renin-angiotensin systems. With long-term use, it reduces the severity of myocardial hypertrophy and hypertrophy of the walls of resistive-type arteries. It improves blood supply to the ischemic myocardium.

The antihypertensive effect begins approximately after 6 hours and persists for 24 hours. The duration of the effect also depends on the dose magnitude. The onset of action is within 1 hour. The maximum effect is determined after 6-7 hours. In arterial hypertension, the effect is noted in the first days after the start of treatment, a stable effect develops after 1-2 months.

No marked increase in blood pressure is observed upon abrupt withdrawal of the drug.

In addition to lowering blood pressure, Lisinopril reduces albuminuria. In patients with hyperglycemia, it promotes the normalization of the function of damaged glomerular endothelium.

Lisinopril does not affect blood glucose concentration in patients with diabetes mellitus and does not lead to an increased incidence of hypoglycemia.

Hydrochlorothiazide is a thiazide diuretic, whose diuretic effect is associated with impaired reabsorption of sodium, chloride, potassium, magnesium ions, and water in the distal part of the nephron; it delays the excretion of calcium ions and uric acid. It has antihypertensive properties; the hypotensive action develops due to the dilation of arterioles. It has practically no effect on normal blood pressure levels.

The diuretic effect develops within 1-2 hours, reaches a maximum after 4 hours, and persists for 6-12 hours. The antihypertensive action occurs after 3-4 days, but 3-4 weeks may be required to achieve the optimal therapeutic effect.

Pharmacokinetics

Lisinopril

After oral administration of lisinopril, C_max in blood serum is reached after 7 hours. It is weakly bound to plasma proteins. The average absorption of lisinopril is about 25%, with significant interindividual variability (6-60%). Food does not affect the absorption of lisinopril. Lisinopril is not metabolized and is excreted unchanged exclusively by the kidneys. After multiple administration, the effective T_1/2 of lisinopril is 12 hours. Impaired renal function slows the excretion of lisinopril, but this slowing becomes clinically significant only when the glomerular filtration rate decreases below 30 ml/min. In elderly patients, the maximum plasma concentration and AUC of the drug are on average 2 times higher compared to younger patients. Lisinopril is removed from the body by hemodialysis. It penetrates the blood-brain barrier to a small extent.

Hydrochlorothiazide

After oral administration, C_max of hydrochlorothiazide is achieved within 1-3 hours. The absolute bioavailability, estimated by cumulative renal excretion of hydrochlorothiazide, is about 60%. Binding to plasma proteins is 40-70%. V_d is 0.8±0.3 L/kg. It is not metabolized in the human body and is excreted in the urine almost unchanged. About 60% of the orally administered dose is excreted within 48 hours. Renal clearance is about 250-300 ml/min. T_1/2 is 10-15 hours. A difference in plasma concentrations between men and women is observed. Women tend to have a clinically significant increase in plasma concentration of hydrochlorothiazide. In patients with impaired renal function, the excretion rate of hydrochlorothiazide is reduced. Studies involving patients with a CrCl of 90 ml/min showed that the T_1/2 of hydrochlorothiazide increases. In patients with reduced renal function, T_1/2 is about 34 hours.

Indications

Arterial hypertension (in patients for whom combined therapy with lisinopril and hydrochlorothiazide is indicated).

ICD codes

Dosage Regimen

Tablets

The fixed combination Lisinopril+Hydrochlorothiazide is taken orally at an initial dose of 10 mg/12.5 mg once daily.

If necessary, the dose can be increased to 20 mg+12.5 mg once daily.

In patients with CrCl greater than 30 and less than 80 ml/min, this combination can be used only after titration of the dose of individual components. The recommended initial dose of lisinopril in uncomplicated renal failure is 5-10 mg.

Adverse Reactions

From the cardiovascular system: marked decrease in blood pressure, chest pain; rarely – orthostatic hypotension, tachycardia, bradycardia, appearance of symptoms of heart failure, impaired AV conduction, myocardial infarction.

From the digestive system: nausea, vomiting, abdominal pain, dry mouth, diarrhea, dyspepsia, anorexia, taste disturbance, pancreatitis, hepatitis (hepatocellular and cholestatic), jaundice, hyperbilirubinemia; increased activity of hepatic transaminases (especially in patients with a history of kidney disease, diabetes mellitus, and renovascular hypertension).

From the skin: urticaria, increased sweating, photosensitivity, skin itching, hair loss.

From the nervous system: mood lability, impaired concentration, paresthesia, increased fatigue, drowsiness, convulsive twitching of limb and lip muscles; rarely – asthenic syndrome, confusion.

From the respiratory system: dyspnea, dry cough, bronchospasm, apnea.

From the hematopoietic system: leukopenia, thrombocytopenia, neutropenia, agranulocytosis, anemia (decreased hemoglobin concentration, hematocrit, erythrocytopenia).

Allergic reactions: angioedema of the face, extremities, lips, tongue, glottis and/or larynx, skin rash, itching, fever, vasculitis, positive reactions to antinuclear antibodies, increased ESR, eosinophilia.

From the urinary system: increased levels of urea and creatinine in blood plasma, uremia, oliguria/anuria, impaired renal function, acute renal failure.

From metabolism: hyperkalemia and/or hypokalemia, hyponatremia, hypomagnesemia, hypochloremia, hypercalcemia, hyperuricemia, hyperglycemia, hypercholesterolemia, hypertriglyceridemia, decreased glucose tolerance, exacerbation of gout.

From the musculoskeletal system: arthralgia, arthritis, myalgia, decreased potency.

General reactions: fever.

Contraindications

Angioedema (including history of Quincke’s edema associated with the use of ACE inhibitors); anuria; severe renal failure (CrCl less than 30 ml/min); hemodialysis using high-flux membranes; hypercalcemia; hyponatremia; porphyria; precoma; hepatic coma; severe forms of diabetes mellitus; age under 18 years (efficacy and safety not established); hypersensitivity to lisinopril, other ACE inhibitors or hydrochlorothiazide and excipients of the drug used.

With caution: aortic stenosis/hypertrophic cardiomyopathy; bilateral renal artery stenosis, stenosis of the artery of a single kidney with progressive azotemia, condition after kidney transplantation, moderate and mild renal failure (CrCl greater than 30 ml/min); primary hyperaldosteronism; arterial hypotension; bone marrow hypoplasia; hyponatremia (increased risk of arterial hypotension in patients on a salt-restricted diet); hypovolemic conditions (including diarrhea, vomiting); connective tissue diseases (including systemic lupus erythematosus, scleroderma); diabetes mellitus; gout; bone marrow depression; hyperuricemia; hyperkalemia; coronary artery disease; cerebrovascular diseases (including cerebral circulatory insufficiency); severe chronic heart failure; hepatic insufficiency; elderly age.

Use in Pregnancy and Lactation

The use of lisinopril during pregnancy is contraindicated.

If pregnancy is established, the drug should be discontinued immediately. The use of ACE inhibitors in the II and III trimesters of pregnancy has an adverse effect on the fetus (possible marked decrease in blood pressure, renal failure, hyperkalemia, skull hypoplasia, intrauterine death). There are no data on negative effects of the drug on the fetus in case of use in the I trimester. Newborns and infants who have been exposed to ACE inhibitors in utero should be closely observed for timely detection of marked hypotension, oliguria, hyperkalemia.

If it is necessary to use during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

With caution: hepatic insufficiency.

Use in Renal Impairment

Contraindication: severe renal failure (CrCl less than 30 ml/min); hemodialysis using high-flux membranes.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Symptomatic hypotension may occur after taking the initial dose of the drug. Such cases are more common in patients who have had fluid and electrolyte loss due to previous treatment with diuretics. Therefore, it is necessary to discontinue diuretics 2-3 days before starting treatment with this combination.

Marked decrease in blood pressure most often occurs with a decrease in circulating blood volume caused by diuretic therapy, reduced salt intake, dialysis, diarrhea, or vomiting.

In patients with chronic heart failure with or without concomitant renal impairment, marked hypotension may occur. It is more often detected in patients with severe chronic heart failure, as a result of the use of high doses of diuretics, hyponatremia, or impaired renal function. Such patients require strict medical supervision at the beginning of treatment. The same approach is necessary when prescribing the drug to patients with coronary artery disease, cerebrovascular insufficiency, in whom a sharp decrease in blood pressure can lead to myocardial infarction or stroke.

Before starting treatment, if possible, the sodium concentration should be normalized and/or the reduced circulating blood volume should be replenished, and the effect of the initial dose of the drug on the patient should be carefully monitored.

In chronic heart failure, marked hypotension after starting treatment with ACE inhibitors can lead to further deterioration of renal function. Cases of acute renal failure have been noted.

In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney receiving ACE inhibitors, an increase in serum urea and creatinine was noted, usually reversible after discontinuation of treatment. This was more often observed in patients with renal failure.

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been rarely observed in patients treated with ACE inhibitors, including Lisinopril, which can occur at any time during treatment. In such a case, treatment with lisinopril should be discontinued as soon as possible and the patient should be observed until the symptoms completely regress. In cases where edema involves only the face and lips, the condition most often resolves without treatment, however, antihistamines may be prescribed. Angioedema with laryngeal edema can be fatal. When the tongue, glottis, or larynx is involved, airway obstruction may occur, so appropriate therapy (0.3-0.5 ml of epinephrine (adrenaline) solution 1:1000 subcutaneously) and/or measures to ensure airway patency should be immediately carried out.

In patients with a history of angioedema not associated with previous ACE inhibitor treatment, the risk of its development during ACE inhibitor treatment may be increased.

A cough has been observed with the use of ACE inhibitors. The cough is dry, persistent, and disappears after discontinuation of ACE inhibitor treatment. In the differential diagnosis of cough, cough caused by the use of an ACE inhibitor should be considered.

An anaphylactic reaction has also been noted in patients undergoing hemodialysis using high-permeability dialysis membranes (AN69^®) who are simultaneously taking ACE inhibitors. In such cases, the possibility of using another type of dialysis membrane or another antihypertensive agent should be considered.

When using blood pressure-lowering drugs in patients undergoing major surgery or during general anesthesia, Lisinopril may block the formation of angiotensin II.

Marked hypotension, which is considered a consequence of this mechanism, can be corrected by increasing the circulating blood volume.

Before surgery (including dentistry), the anesthesiologist must be informed about the use of ACE inhibitors.

In some cases, hyperkalemia has been observed. Risk factors for the development of hyperkalemia include renal failure, diabetes mellitus, the use of potassium preparations or drugs that cause an increase in blood potassium concentration (e.g., heparin), especially in patients with impaired renal function.

In patients at risk of symptomatic hypotension (on a salt-restricted diet) with or without hyponatremia, as well as in patients who have received high doses of diuretics, fluid and salt loss should be compensated before starting treatment.

Thiazide diuretics can affect glucose tolerance, so doses of oral hypoglycemic agents should be adjusted.

Thiazide diuretics can reduce the renal excretion of calcium and cause hypercalcemia. Marked hypercalcemia may be a symptom of latent hyperparathyroidism. It is recommended to discontinue treatment with thiazide diuretics before performing a test to assess parathyroid function.

During treatment with the drug, regular monitoring of potassium, glucose, urea, and lipids in blood plasma is necessary.

During treatment, it is not recommended to consume alcoholic beverages, as ethanol enhances the hypotensive effect of the drug.

Caution should be exercised during physical exercise, in hot weather (risk of dehydration and excessive decrease in blood pressure due to reduced circulating blood volume).

Effect on ability to drive vehicles and mechanisms

During treatment, one should refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions, as dizziness is possible, especially at the beginning of the course of treatment.

Drug Interactions

Potassium-sparing diuretics (spironolactone, triamterene, amiloride), potassium preparations, salt substitutes containing potassium – increased risk of hyperkalemia, especially in patients with impaired renal function.

Vasodilators, barbiturates, phenothiazines, tricyclic antidepressants, ethanol – enhancement of the hypotensive action.

NSAIDs, estrogens – reduction of the antihypertensive effect of lisinopril.

Lithium preparations – slowing of lithium excretion from the body (enhancement of the cardiotoxic and neurotoxic effects of lithium).

Antacids, cholestyramine – reduced absorption from the gastrointestinal tract.

Enhancement of neurotoxicity of salicylates.

Reduction of the action of oral hypoglycemic drugs, norepinephrine, epinephrine, and anti-gout drugs.

Enhancement of effects (including side effects) of cardiac glycosides, action of peripheral muscle relaxants, reduction of excretion of quinidine.

Reduces the effectiveness of oral contraceptives.

With simultaneous use of methyldopa, the risk of hemolysis increases.

Ethanol enhances the hypotensive effect of this combination.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.