Zoniksem (Tablets) Instructions for Use

ATC Code

C09AA03 (Lisinopril)

Active Substance

Lisinopril (Rec.INN registered by WHO)

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

ACE blocker

Pharmacological Action

ACE inhibitor. The mechanism of the antihypertensive action is associated with the inhibition of ACE activity, which leads to a decrease in the rate of conversion of angiotensin I to angiotensin II (which has a pronounced vasoconstrictive effect and stimulates the secretion of aldosterone in the adrenal cortex). As a result of the reduced formation of angiotensin II, a secondary increase in plasma renin activity occurs due to the elimination of the negative feedback during renin release and a direct decrease in aldosterone secretion. The decrease in aldosterone secretion may contribute to an increase in potassium concentration.

Lisinopril reduces total peripheral vascular resistance, lowers blood pressure, preload, pulmonary capillary wedge pressure, causes an increase in cardiac output and improves myocardial tolerance to stress in patients with chronic heart failure (CHF). It dilates arteries to a greater extent than veins. Some effects are explained by the impact on tissue RAAS. With long-term use, this leads to the regression of myocardial hypertrophy and pathological remodeling in the cardiovascular system. It improves endothelial function and blood supply to the ischemic myocardium.

ACE inhibitors prolong the life expectancy of patients with CHF and slow the progression of left ventricular dysfunction in patients who have had myocardial infarction without clinical manifestations of heart failure.

Lisinopril reduces albuminuria. In patients with hyperglycemia, it promotes the normalization of the function of damaged glomerular endothelium. It does not affect blood glucose concentration in patients with diabetes mellitus and does not lead to an increased incidence of hypoglycemia.

Pharmacokinetics

After oral administration, Lisinopril is slowly and incompletely absorbed from the gastrointestinal tract. Absorption averages 25% and is highly variable – 6-60%. Bioavailability is 29%. C_max in plasma is reached in approximately 7 hours. Plasma protein binding is insignificant. It is excreted unchanged in the urine. In patients with normal renal function, T_1/2 is 12 hours.

Lisinopril is removed from the body by hemodialysis.

Indications

Essential and renovascular arterial hypertension (as monotherapy or in combination with other antihypertensive drugs).

Chronic heart failure (as part of combination therapy).

Acute myocardial infarction (within the first 24 hours with stable hemodynamic parameters to maintain these parameters and prevent left ventricular dysfunction and heart failure).

Diabetic nephropathy (to reduce albuminuria in patients with insulin-dependent diabetes mellitus with normal blood pressure and in patients with non-insulin-dependent diabetes mellitus with arterial hypertension).

ICD codes

Dosage Regimen

Determine the dose individually based on indication, therapeutic regimen, and renal function.

For essential hypertension, initiate therapy at 2.5 mg once daily. Titrate the dose gradually. The usual maintenance dose is 5 mg to 20 mg administered once daily. The maximum daily dose is 40 mg.

For chronic heart failure, start with 2.5 mg once daily under close medical supervision due to the risk of symptomatic hypotension. Increase the dose to a target maintenance dose of 5 mg to 20 mg once daily, as tolerated by the patient.

In patients with acute myocardial infarction, administer 5 mg within the first 24 hours, followed by 5 mg after 24 hours, then 10 mg after 48 hours, and then 10 mg once daily. Continue therapy for at least 6 weeks. Do not initiate therapy if systolic blood pressure is below 100 mm Hg.

For diabetic nephropathy, the recommended dose is 10 mg once daily. Titrate the dose up to 20 mg once daily if necessary to achieve a reduction in albuminuria.

Adjust the dosage in patients with renal impairment according to creatinine clearance (CrCl). For CrCl 30-70 ml/min, initiate at 2.5-5 mg daily. For CrCl 10-30 ml/min, initiate at 2.5 mg daily. For CrCl less than 10 ml/min (including patients on dialysis), initiate at 2.5 mg daily, with the dose titrated based on blood pressure response. Lisinopril is removed by hemodialysis.

In elderly patients, initiate therapy at the lower end of the dosage range. Use caution during dose titration due to a potentially greater sensitivity to the drug’s effects.

Take the tablet once daily, with or without food. Monitor blood pressure and renal function regularly during therapy.

Adverse Reactions

From the hematopoietic system rarely – decrease in hemoglobin, decrease in hematocrit; very rarely – bone marrow function depression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, hemolytic anemia, lymphadenopathy.

From the immune system infrequently – angioedema (face, lips, tongue, larynx or epiglottis, upper and lower extremities); rarely – syndrome including increased ESR, arthralgia and appearance of antinuclear antibodies, urticaria; very rarely – autoimmune diseases, intestinal angioedema.

From the endocrine system rarely – syndrome of inappropriate ADH secretion.

From the psyche infrequently – mood lability; rarely – anorexia; frequency unknown – depression, confusion.

From the nervous system often – dizziness, headache; infrequently – paresthesia, sleep disorder (drowsiness/insomnia); rarely – confusion, frequency unknown – convulsive twitching of limb and lip muscles.

From the organ of vision rarely – visual impairment.

From the organ of hearing and labyrinthine disorders infrequently – vertigo.

From the cardiovascular system often – orthostatic hypotension; infrequently – marked decrease in blood pressure, acute myocardial infarction, tachycardia, palpitation sensation; rarely – worsening of the severity of symptoms and course of CHF, AV conduction disorder, chest pain, cerebrovascular accident in “high-risk” patients due to a marked decrease in blood pressure, Raynaud’s syndrome, vasculitis.

From the respiratory system often – dry cough; infrequently – rhinitis; very rarely – sinusitis, dyspnea, bronchospasm, allergic alveolitis/eosinophilic pneumonia.

From the digestive system often – nausea, vomiting, diarrhea; rarely – dry mouth, dyspepsia, abdominal pain, taste changes; very rarely – pancreatitis.

From the liver and biliary tract rarely – hepatocellular or cholestatic jaundice, hepatitis.

From the urinary system: often – impaired renal function; rarely – uremia, acute renal failure; very rarely – oliguria, anuria; frequency unknown – proteinuria.

From the skin and subcutaneous tissues infrequently – skin itching, rash; rarely – psoriasis; very rarely – pemphigus, toxic epidermal necrolysis (Lyell’s syndrome), erythema multiforme, Stevens-Johnson syndrome, cutaneous pseudolymphoma.

From the musculoskeletal system rarely – myalgia, arthralgia/arthritis.

From the reproductive system and mammary gland infrequently – sexual dysfunction; rarely – gynecomastia.

From laboratory parameters infrequently – increased plasma urea concentration, hypercreatininemia, hyperkalemia, increased activity of liver transaminases; rarely – hyperbilirubinemia, hyponatremia; very rarely – increased ESR, increased titer of antinuclear antibodies, decreased glucose concentration.

General reactions rarely – fever, asthenia, increased fatigue, alopecia, impaired fetal development; very rarely – increased sweating.

Contraindications

Hypersensitivity to lisinopril, other ACE inhibitors; history of angioedema, including while using ACE inhibitors; hereditary angioedema or idiopathic angioedema; pregnancy; breastfeeding period; age under 18 years (efficacy and safety not established); hemodialysis or hemofiltration using high-flux, high-permeability dialysis membranes (e.g., AN69); low-density lipoprotein apheresis using dextran sulfate; desensitizing therapy to hymenoptera venom (bees, wasps); simultaneous use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (creatinine clearance less than 60 ml/min); simultaneous use with angiotensin II receptor antagonists (ARA II) in patients with diabetic nephropathy; simultaneous use with neutral endopeptidase inhibitors (e.g., drugs containing sacubitril) due to the high risk of developing angioedema.

With caution impaired renal function; bilateral renal artery stenosis or stenosis of the artery of a single kidney; condition after kidney transplantation; azotemia; hyperkalemia; aortic stenosis, mitral stenosis; hypertrophic obstructive cardiomyopathy; primary hyperaldosteronism; arterial hypotension; cerebrovascular diseases (including cerebral circulation insufficiency); ischemic heart disease; coronary insufficiency, autoimmune systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma); bone marrow hematopoiesis depression; hypovolemic conditions (including as a result of diarrhea, vomiting); diet with restricted salt intake; elderly age (over 65 years); use in patients of the Black race; simultaneous use with drugs containing aliskiren, or angiotensin II receptor antagonists (with dual blockade of the RAAS there is an increased risk of arterial hypotension, hyperkalemia and renal failure); diabetes mellitus.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during lactation (breastfeeding). If it is necessary to use during lactation, the issue of discontinuing breastfeeding should be decided.

Use in Renal Impairment

Use with particular caution in patients with impaired renal function, with bilateral renal artery stenosis or stenosis of the artery of a single kidney; condition after kidney transplantation.

Renal function should be monitored before starting treatment and during therapy.

Pediatric Use

Use in children and adolescents under 18 years of age is contraindicated (efficacy and safety have not been established).

Geriatric Use

Should be used with caution in elderly patients (over 65 years of age).

Special Precautions

A 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 CHF with or without concurrent renal failure, a marked decrease in blood pressure is possible.

In patients with ischemic heart disease, cerebrovascular insufficiency, in whom a sharp decrease in blood pressure can lead to myocardial infarction or stroke, Lisinopril should be prescribed only under strict medical supervision. Transient arterial hypotension is not a contraindication for taking the next dose of lisinopril.

When using lisinopril in some patients with CHF but with normal or low blood pressure, a decrease in blood pressure may be noted, which is usually not a reason to discontinue treatment.

In CHF, severe arterial hypotension that occurs can lead to deterioration of renal function. In some cases, in the presence of CHF with normal or low blood pressure, Lisinopril may also cause an additional decrease in blood pressure. This effect is not a contraindication for further use of lisinopril.

In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, during treatment with ACE inhibitors, an increase in plasma urea nitrogen and serum creatinine has been observed in some cases. These changes were almost always reversible and disappeared after discontinuation of the ACE inhibitor. These complications are especially characteristic of patients with pre-existing renal impairment. If a patient has renovascular hypertension, the risk of developing severe arterial hypotension and renal failure increases. In this category of patients, treatment should be started with lower doses of lisinopril under medical supervision.

Since the simultaneous use of diuretics is an additional risk factor for the development of arterial hypotension, they should be discontinued and renal function should be monitored during the first week.

An increase in plasma urea nitrogen and serum creatinine has also been observed in patients with arterial hypertension without concomitant renal impairment, especially with the simultaneous use of lisinopril and diuretics. These changes were mild, and the indicators returned to normal after discontinuation of lisinopril or the diuretic.

In patients with acute myocardial infarction, lisinopril therapy should not be started if there are signs of renal impairment, expressed as an increase in plasma creatinine above 177 µmol/l and/or proteinuria above 500 mg/day. If renal impairment develops during lisinopril use (plasma creatinine above 265 µmol/l or doubles compared to values before the start of therapy), then the possibility of discontinuing lisinopril should be considered. Lisinopril treatment for acute myocardial infarction is carried out against the background of standard therapy (thrombolytics, acetylsalicylic acid (as an antiplatelet agent), beta-blockers). Lisinopril can be used with an intravenous nitroglycerin solution or with sublingual nitroglycerin use.

The use of lisinopril is not recommended in patients who have had an acute myocardial infarction if systolic blood pressure does not exceed 100 mm Hg.

When using drugs that lower blood pressure in patients during major surgery or during general anesthesia, Lisinopril can block the formation of angiotensin II, secondary to compensatory renin release. Before surgery (including dental surgery), lisinopril should be discontinued 24 hours in advance and the surgeon/anesthesiologist should be informed about the use of an ACE inhibitor.

It is assumed that the simultaneous use of ACE inhibitors and insulin, as well as oral hypoglycemic drugs, can lead to the development of hypoglycemia. The greatest risk of development is observed during the first weeks of combination therapy, as well as in patients with impaired renal function. In patients with diabetes mellitus, careful glycemic control is required, especially during the first month of ACE inhibitor therapy.

Before starting treatment, fluid and salt loss must be compensated. In patients with risk factors for the development of symptomatic arterial hypotension (patients on a diet with limited salt intake with or without hyponatremia, patients with hypovolemia or receiving diuretic therapy), these conditions should be corrected, if possible, before starting treatment with lisinopril. Risk factors for the development of hyperkalemia include chronic renal failure, diabetes mellitus and the simultaneous use of potassium-sparing diuretics (spironolactone, eplerenone, triamterene, or amiloride), potassium preparations or salt substitutes containing potassium ions, as well as the use of drugs whose action is associated with an increase in plasma potassium (e.g., heparin). Periodic monitoring of plasma potassium levels is recommended.

Angioedema of the face, extremities, lips, tongue, mucous membranes, epiglottis and/or larynx has been observed with the use of ACE inhibitors, including drugs containing Lisinopril. This adverse reaction can occur at any stage of therapy. In such cases, it is necessary to urgently discontinue the use of lisinopril and prescribe adequate therapy. The patient should be under medical supervision until the symptoms of edema completely regress. It should be taken into account that even in cases where only tongue swelling is noted, the patient should be under medical supervision, as therapy with antihistamines and corticosteroids may be insufficient.

Patients who have previously undergone respiratory tract surgery have a higher risk of developing angioedema of the larynx or tongue.

Patients who have had angioedema not associated with the use of ACE inhibitors are at greater risk of developing such a complication when taking ACE inhibitors. It should be taken into account that the use of ACE inhibitors in patients of the Black race entails a higher risk of developing angioedema. The effectiveness of ACE inhibitors in reducing blood pressure in patients of the Black race is lower than in representatives of other races. This effect is possibly associated with a pronounced predominance of low-renin status in Black patients with arterial hypertension.

In patients taking ACE inhibitors during desensitization procedures with hymenoptera venom, life-threatening anaphylactoid reactions can very rarely develop. This can be avoided by temporarily discontinuing ACE inhibitor treatment before each desensitization procedure.

A dry cough that appears with the use of ACE inhibitors is non-productive, persistent and disappears after discontinuation of treatment. When conducting a differential diagnosis of cough, its possible connection with ACE inhibitors should be taken into account.

Very rarely, cases of a syndrome that began with the development of cholestatic jaundice, progressed to fulminant necrosis and in some cases led to death have been noted. The mechanism of development of this syndrome is unclear. The use of lisinopril in patients with signs of jaundice or a significant increase in the activity of liver transaminases should be discontinued and appropriate monitoring of laboratory parameters and the patient’s condition should be carried out.

Cases of neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported during the use of ACE inhibitors. Such cases are quite rare in patients with normal renal function. Neutropenia and agranulocytosis disappear after discontinuation of ACE inhibitors. Lisinopril should be used with particular caution in patients with systemic connective tissue diseases receiving immunosuppressive therapy, treatment with allopurinol or procainamide, or if these risk factors are present simultaneously, especially in patients with impaired renal function. In such patients, infectious diseases resistant to antibacterial therapy may develop in some cases. If the drug is used in such patients, regular monitoring of blood leukocytes should be carried out.

If any symptoms of infection appear (e.g., sore throat, fever), the patient should immediately consult a doctor, as they may be a manifestation of neutropenia.

In rare cases, intestinal angioedema develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding facial angioedema and with a normal level of C1-esterase. The diagnosis is established using computed tomography of the abdomen, ultrasound, or during surgery. The symptoms disappeared after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered when conducting a differential diagnosis.

Effect on the ability to drive vehicles and mechanisms

During the treatment period, one should refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions, as weakness or dizziness may develop, especially at the beginning of the course of treatment.

Drug Interactions

Concomitant use with antihypertensive agents may result in an additive antihypertensive effect.

Concomitant use with potassium-sparing diuretics (spironolactone, triamterene, amiloride), potassium preparations, potassium-containing salt substitutes increases the risk of hyperkalemia, especially in patients with impaired renal function.

Concomitant use of ACE inhibitors and NSAIDs increases the risk of impaired renal function; hyperkalemia is rarely observed.

Concomitant use with “loop” diuretics, thiazide diuretics enhances the antihypertensive effect. The occurrence of marked arterial hypotension, especially after taking the first dose of a diuretic, appears to be due to hypovolemia, which leads to a transient increase in the hypotensive effect of lisinopril. The risk of impaired renal function increases.

Concomitant use with indomethacin reduces the antihypertensive effect of lisinopril, apparently due to inhibition of prostaglandin synthesis by NSAIDs (which are believed to play a role in the development of the hypotensive effect of ACE inhibitors).

Concomitant use with insulin, sulfonylurea-derived hypoglycemic agents may lead to hypoglycemia due to increased glucose tolerance.

Concomitant use with clozapine increases the plasma concentration of clozapine.

Concomitant use with lithium carbonate increases the serum lithium concentration, accompanied by symptoms of lithium intoxication.

Lisinopril slows the excretion of lithium preparations, which may increase the risk of adverse effects. Therefore, with concomitant use, it is necessary to regularly monitor the lithium content in the blood plasma.

A case of severe hyperkalemia has been described in a patient with diabetes mellitus with concomitant use with lovastatin.

Concomitant use of lisinopril with beta-blockers, slow calcium channel blockers, diuretics, tricyclic antidepressants/antipsychotics and other antihypertensive drugs increases the severity of the hypotensive effect.

Antacids and cholestyramine reduce the absorption of lisinopril in the gastrointestinal tract.

With concomitant use with insulin and oral hypoglycemic agents, the risk of hypoglycemia increases.

Concomitant use with NSAIDs, COX-2 inhibitors and acetylsalicylic acid (in a dose of more than 3 g/day), estrogens, sympathomimetics reduces the hypotensive effect of lisinopril. NSAIDs and ACE inhibitors increase plasma potassium levels and may impair renal function. This effect is usually reversible.

The use of lisinopril in combination with acetylsalicylic acid as an antiplatelet agent, thrombolytics and/or nitrates is not contraindicated.

Concomitant use of ethanol enhances the effect of lisinopril.

With the simultaneous use of ACE inhibitors and intravenous gold preparations (sodium aurothiomalate), a symptom complex has been described, including facial flushing, nausea, vomiting, and decreased blood pressure.

Concomitant use with selective serotonin reuptake inhibitors may lead to severe hyponatremia.

Concomitant use with allopurinol, procainamide, cytostatics may increase the risk of leukopenia.

Concomitant use with aliskiren and aliskiren-containing preparations in patients with diabetes mellitus and patients with moderate and/or severe renal impairment (creatinine clearance less than 60 ml/min) increases the risk of hyperkalemia, worsening renal function and increasing the frequency of cardiovascular morbidity and mortality.

In elderly patients and patients with impaired renal function, the simultaneous use of ACE inhibitors with sulfamethoxazole/trimethoprim was accompanied by severe hyperkalemia, which is thought to have been caused by trimethoprim; therefore, the drug should be used with caution with preparations containing trimethoprim, regularly monitoring the potassium content in the blood plasma.

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.