Lisinopril (Tablets) Instructions for Use

ATC Code

C09BA03 (Lisinopril and diuretics)

Active Substances

Hydrochlorothiazide

Lisinopril

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (ACE inhibitor + diuretic)

Pharmacological Action

The drug Zoniksem ND is a combination of fixed doses of lisinopril (an ACE inhibitor) and hydrochlorothiazide (a thiazide diuretic), which have a complementary action and enhance each other’s antihypertensive effect.

Lisinopril

An ACE inhibitor, it reduces the formation of angiotensin II from angiotensin I. A decrease in the content of angiotensin II leads to a direct reduction in aldosterone secretion. It reduces the degradation of bradykinin and increases the synthesis of prostaglandins. It reduces total peripheral vascular resistance (TPVR), blood pressure (BP), preload on the myocardium, pressure in the pulmonary capillaries, and causes an increase in cardiac output and improved exercise tolerance in patients with chronic heart failure (CHF). It dilates arteries to a greater extent than veins. Some effects are explained by the impact on the renin-angiotensin-aldosterone system (RAAS). With long-term use, it reduces the severity of myocardial hypertrophy and the walls of resistive-type arteries. It improves blood supply to the ischemic myocardium.

ACE inhibitors increase the life expectancy of patients with CHF and slow the progression of left ventricular dysfunction in patients who have had a myocardial infarction without clinical manifestations of heart failure. The antihypertensive effect begins approximately 6 hours after administration and persists for 24 hours. The duration of the effect also depends on the dose. The onset of action is within 1 hour. The maximum effect is reached in 6-7 hours. In arterial hypertension, the effect is noted in the first days after the start of treatment, and a stable effect develops after 1-2 months.

No marked increase in BP is observed upon abrupt withdrawal of lisinopril.

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

Hydrochlorothiazide

A thiazide diuretic, its 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 antihypertensive action develops due to the dilation of arterioles. It has practically no effect on normal BP levels.

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

Lisinopril and Hydrochlorothiazide, when used simultaneously, have an additive antihypertensive effect.

Pharmacokinetics

The simultaneous use of lisinopril and hydrochlorothiazide does not affect the bioavailability and pharmacokinetics of each of the active components of the drug.

Lisinopril

After oral administration of lisinopril, C_max in blood serum is reached in 7 hours. It is weakly bound to blood 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 administrations, the 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 of lisinopril and AUC (area under the concentration-time curve) 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

It is not metabolized but undergoes rapid excretion through the kidneys. The T_1/2 of hydrochlorothiazide ranges from 5.6 to 14.8 hours. At least 61% of the orally administered hydrochlorothiazide is excreted unchanged within 24 hours. Hydrochlorothiazide crosses the placental barrier but does not cross the blood-brain barrier.

Indications

• Arterial hypertension (in patients for whom combination therapy is indicated).

ICD codes

Dosage Regimen

Tablets

Orally, 1 tablet of the drug Zoniksem NL once a day.

If necessary, the daily dose can be increased to 2 tablets (it is possible to use Zoniksem NL 20 or Zoniksem ND drugs in other dosages). Symptomatic arterial hypotension may occur after taking the initial dose of the drug. Such cases are more common in patients with reduced circulating blood volume (CBV) and reduced electrolyte content due to previous treatment with diuretics. Therefore, diuretic intake should be discontinued 2-3 days before starting treatment with Zoniksem NL.

Renal Impairment

The drug Zoniksem NL is contraindicated in severe renal impairment (creatinine clearance 30 ml/min and less).

With creatinine clearance of 30-80 ml/min, the use of the drug Zoniksem NL is possible only after selecting the dose of each of the active components of the drug separately.

Elderly patients: dose adjustment is not required.

Adverse Reactions

Classification of the frequency of adverse effects (WHO)

In each group, adverse effects are presented in order of decreasing severity.

From the digestive system

Rare: dry oral mucosa, nausea, vomiting, diarrhea, constipation, pancreatitis;

Very rare: intestinal angioedema, abdominal pain, anorexia, gastritis, hepatitis, hepatic failure, cholestatic jaundice.

From the cardiovascular system

Common: marked decrease in blood pressure (including orthostatic hypotension), chest pain;

Rare: tachycardia, bradycardia, worsening of chronic heart failure symptoms, atrioventricular (AV) conduction disturbance, myocardial infarction or cerebrovascular accident due to excessive arterial hypotension.

From the nervous system

Common: dizziness, headache;

Uncommon: mood lability, impaired concentration, increased fatigue, drowsiness, sleep disturbance, convulsive twitching of the muscles of the limbs and lips;

Rare: paresthesia, asthenic syndrome, confusion, depression.

From the respiratory system

Common: “dry” cough;

Rare: bronchospasm, rhinitis, sinusitis, dyspnea, apnea, allergic alveolitis/eosinophilic pneumonia.

From the genitourinary system

Rare: decreased potency;

Very rare: uremia, oliguria/anuria, glucosuria, renal function disorders, acute renal failure, interstitial nephritis.

From the skin

Uncommon: skin rash, photosensitivity, alopecia, skin itching, urticaria;

Very rare: increased sweating, pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, vasculitis, psoriasis.

From the immune system

Very rare: angioedema of the face, lips, tongue, pharynx and/or larynx, extremities, hypersensitivity reactions*.

From the musculoskeletal system

Rare: muscle weakness, arthralgia/arthritis.

From the sensory organs

Very rare: transient visual acuity impairment, photophobia, xanthopsia.

From the hematopoietic organs

Neutropenia/agranulocytosis, leukopenia, thrombocytopenia, bone marrow depression.

Other

Rare: general weakness, asthenia, Raynaud’s syndrome, gynecomastia, exacerbation of gout, impaired fetal kidney development, hypoglycemia;

Very rare: sialadenitis.

Laboratory parameters

Rare: hyperglycemia, hyperuricemia and hyperkalemia or hypokalemia, increased concentration of urea and creatinine, decreased hematocrit and hemoglobin, increased activity of “liver” enzymes and/or bilirubin, hypercholesterolemia, hypertriglyceridemia;

Very rare: hyponatremia, hypomagnesemia, hypochloremia, hypercalcemia, hemolytic anemia, aplastic anemia.

*There are reports of a symptom complex that may include fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibodies, increased ESR, eosinophilia, leukocytosis.

Contraindications

• Anuria;
• Angioedema (including history from the use of ACE inhibitors);
• Hemodialysis using high-flux membranes;
• Hypercalcemia;
• Porphyria;
• Precoma;
• Hepatic coma;
• Severe chronic renal failure (creatinine clearance less than 30 ml/min);
• Exacerbation of gout;
• Diabetes mellitus (severe forms);
• Pregnancy, breastfeeding period;
• Hereditary angioedema and idiopathic angioedema;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to the active substances or any other components of the drug (including to other ACE inhibitors and sulfonamide derivatives).

With caution aortic and/or mitral stenosis, hypertrophic obstructive cardiomyopathy (HOCM), bilateral renal artery stenosis, stenosis of the artery of a single kidney with progressive azotemia, condition after kidney transplantation, moderate chronic renal failure (creatinine clearance more than 30 ml/min), primary hyperaldosteronism, arterial hypotension, bone marrow hypoplasia, hyponatremia (increased risk of arterial hypotension in patients on a low-salt or salt-free diet), conditions accompanied by a decrease in circulating blood volume (including diarrhea, vomiting), connective tissue diseases (SLE, scleroderma), diabetes mellitus, gout, hyperuricemia, hyperkalemia, hepatic failure, cerebrovascular insufficiency, severe chronic heart failure, old age.

Use in Pregnancy and Lactation

Pregnancy

The use of the drug Zoniksem ND during pregnancy is contraindicated. ACE inhibitors in the II and III trimesters of pregnancy have an adverse effect on the fetus (marked decrease in BP, renal failure, hyperkalemia, skull bone hypoplasia, intrauterine fetal death). Newborns and infants who have been exposed to ACE inhibitors in utero should be monitored for the timely detection of marked hypotension, oliguria, hyperkalemia. The use of hydrochlorothiazide is contraindicated in the first trimester of pregnancy. In case of planned or diagnosed pregnancy, the use of the drug Zoniksem ND should be discontinued immediately.

Breastfeeding

If it is necessary to use the drug Zoniksem ND during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Dose adjustment is not required.

Use in Renal Impairment

With creatinine clearance of 30-80 ml/min, the use of the drug Zoniksem ND is possible only after selecting the dose of each of the active components of the drug separately.

The drug Zoniksem ND is contraindicated in severe renal impairment (creatinine clearance 30 ml/min and less).

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

Dose adjustment is not required.

Special Precautions

Symptomatic arterial hypotension

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

In liver cirrhosis accompanied by edema and ascites, arterial hypotension, CHF, significant activation of the RAAS may be noted, especially with marked hypovolemia and reduced plasma electrolyte content (against the background of a salt-free diet or long-term diuretic use).

The use of an ACE inhibitor causes blockade of the RAAS, therefore a sharp decrease in BP and/or an increase in plasma creatinine concentration, indicating the development of acute renal failure, is possible, which is more likely during the initial use of the drug Zoniksem ND or during the first two weeks of therapy.

Thus, in patients with fluid volume depletion due to diuretic therapy, dialysis, diarrhea, vomiting, treatment should be started under strict medical supervision, and dose selection should be carried out with caution.

Renal impairment

Thiazide diuretics should not be used in patients with renal impairment; they are not effective at a creatinine clearance of 30 ml/min or less (i.e., with moderate or severe renal impairment).

The drug Zoniksem ND should not be used in patients with renal failure (creatinine clearance less than 80 ml/min) until doses of each component separately, corresponding to the doses in the combination drug, have been selected.

If patients with arterial hypertension without obvious signs of pre-existing kidney disease show an increase in serum urea and creatinine concentrations while using the drug Zoniksem ND, further use should be discontinued. Resumption of therapy is possible either with lower doses or with monotherapy with the active components of the drug.

In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney taking ACE inhibitors, an increase in serum urea and creatinine concentrations is possible, usually reversible after discontinuation of therapy.

Hepatic impairment

Thiazide diuretics should be used with caution in patients with hepatic impairment or progressive liver disease, as even minimal changes in electrolyte balance can provoke the development of hepatic coma in such patients. The use of ACE inhibitors by patients with liver diseases can lead to the development of fulminant liver necrosis.

Patients with diabetes mellitus and other endocrine pathologies

When using the drug Zoniksem ND in patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentration should be regularly monitored during the first month of therapy. Thiazide diuretics can reduce the renal excretion of calcium and cause a temporary moderate increase in serum calcium levels. Marked hypercalcemia may be a manifestation of undiagnosed hyperparathyroidism. Thiazide diuretics should be discontinued before testing parathyroid function.

Therapy with thiazide diuretics may increase cholesterol and triglyceride concentrations.

In some patients, therapy with thiazide diuretics may exacerbate hyperuricemia and/or aggravate the course of gout. However, Lisinopril enhances the renal excretion of uric acid, thereby counteracting the hyperuricemic effect of hydrochlorothiazide.

During treatment, regular monitoring of plasma calcium, potassium, glucose, urea, lipids, and creatinine levels is necessary.

Hypersensitivity/Angioedema (Quincke’s edema)

When using ACE inhibitors, including lisinopril, in rare cases, the development of angioedema of the face, lips, tongue, pharynx and/or larynx may be observed. If these symptoms appear, the use of the drug should be discontinued immediately, and the patient should be observed until the signs of edema completely disappear.

If angioedema involves only the face and lips, its manifestations usually resolve on their own, or antihistamines may be used to treat its symptoms. Angioedema accompanied by swelling of the tongue or larynx can lead to airway obstruction and be fatal.

If such symptoms appear, epinephrine (adrenaline) should be administered subcutaneously immediately (in a 1:1000 dilution (0.3 or 0.5 ml) and/or airway patency should be ensured.

In patients with a history of angioedema not associated with ACE inhibitor use, the risk of its development when using drugs of this group may be increased.

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 normal C1-esterase levels. The diagnosis is established using computed tomography of the abdomen, ultrasound, or at the time of surgery. Symptoms disappear after discontinuation of ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

Anaphylactoid reactions during desensitization procedures

There are isolated reports of the development of prolonged, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenoptera venom (bees, wasps).

ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. The appointment of an ACE inhibitor should be avoided in patients receiving immunotherapy with hymenoptera venom. However, the development of anaphylactoid reactions can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before the start of the desensitization procedure.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis

In rare cases, life-threatening anaphylactoid reactions may develop in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be discontinued before each LDL apheresis procedure using high-flux membranes.

Hemodialysis

In patients receiving ACE inhibitors, anaphylactoid reactions have been observed during hemodialysis using high-flux membranes (e.g., AN69^®). Therefore, it is advisable to use a different type of membrane or to use an antihypertensive drug from a different pharmacotherapeutic group.

Cough

During therapy with ACE inhibitors, a cough may occur. It is persistent and non-productive in nature and resolves after discontinuation of the drug. An ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgical Interventions/General Anesthesia

The use of ACE inhibitors in patients undergoing surgery with general anesthesia may lead to a marked decrease in BP, especially when using general anesthetic agents that have an antihypertensive effect.

It is recommended to discontinue the use of ACE inhibitors, including lisinopril, 12 hours before surgery, informing the surgeon/anesthesiologist about the use of ACE inhibitors.

Hyperkalemia

The development of hyperkalemia is possible. Risk factors for the development of hyperkalemia include renal failure, diabetes mellitus, the use of potassium preparations or drugs that cause an increase in serum potassium concentration (including heparin), especially in patients with impaired renal function.

In patients at risk of symptomatic arterial hypotension, fluid and salt losses must be compensated prior to initiation of therapy.

Elderly Patients

Before starting treatment with Zoniksem ND, renal function and plasma potassium levels should be assessed. The initial dose should be selected depending on the degree of BP reduction, especially in cases of reduced blood volume and CHF (NYHA functional class IV). Such measures help to avoid a sharp decrease in BP.

Effect on Ability to Drive and Operate Machinery

During treatment with Zoniksem ND, caution is recommended when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions, as dizziness may occur when using the drug, especially at the beginning of the course of treatment.

Overdose

In case of an overdose of the Lisinopril/Hydrochlorothiazide combination, the following symptoms are possible marked decrease in BP, collapse, tachycardia, rapid breathing, palpitations, bradycardia, cough, dizziness, dry mouth, urinary retention, constipation, anxiety, water-electrolyte imbalance, renal failure.

Treatment gastric lavage and/or administration of activated charcoal, restoration of water-electrolyte balance in a hospital setting. In case of a marked decrease in BP, the patient should be placed in the supine position with legs elevated; then, measures aimed at increasing blood volume (intravenous administration of 0.9% sodium chloride solution) should be carried out. If necessary, angiotensin II may be used; for bradycardia – atropine or placement of an artificial pacemaker. Monitoring of diuresis, serum urea, creatinine, and electrolyte concentrations is necessary. Hemodialysis is effective.

Drug Interactions

Concomitant use of lisinopril and hydrochlorothiazide with potassium-sparing diuretics (spironolactone, triamterene, amiloride), potassium preparations, potassium-containing salt substitutes increases the risk of hyperkalemia, especially in patients with chronic renal failure.

Oral hypoglycemic agents (sulfonylurea derivatives) and insulin the use of ACE inhibitors may enhance the hypoglycemic effect of oral hypoglycemic agents and insulin in patients with diabetes mellitus; with their simultaneous use, an increase in glucose tolerance is possible, which may require dose adjustment of oral hypoglycemic agents and insulin.

Concomitant use with vasodilators, barbiturates, phenothiazines, tricyclic antidepressants increases the hypotensive effect.

Non-steroidal anti-inflammatory drugs (indomethacin, etc.), estrogens reduce the antihypertensive effect of lisinopril.

Concomitant use of lisinopril and hydrochlorothiazide with lithium preparations leads to slowed excretion of lithium and increased cardiotoxic and neurotoxic effects of lithium.

Antipsychotic agents (neuroleptics) may enhance the hypotensive effect of lisinopril.

Concomitant use with antacids, cholestyramine or colestipol leads to reduced absorption of lisinopril and hydrochlorothiazide in the gastrointestinal tract.

Gold preparations when using ACE inhibitors, including lisinopril, in patients receiving gold preparations (sodium aurothiomalate) intravenously, nitritoid reactions (nausea, vomiting, marked decrease in BP, facial flushing) have been observed.

Allopurinol, cytostatics, immunosuppressants, glucocorticosteroids (for systemic use) and procainamide concomitant use of these drugs with ACE inhibitors may increase the risk of leukopenia.

Concomitant use with glucocorticosteroids, adrenocorticotropic hormone, carbenoxolone, amphotericin B may enhance electrolyte imbalance, especially potassium.

Concomitant use with lovastatin increases the risk of hyperkalemia.

Cyclosporine increases the risk of impaired renal function and hyperkalemia.

Concomitant use with sotalol increases the risk of arrhythmia.

Due to the risk of hypokalemia, caution should be exercised when using hydrochlorothiazide concomitantly with drugs that cause torsades de pointes tachycardia, such as some antipsychotic and other agents.

General anesthetic agents ACE inhibitors may enhance the hypotensive effect of some general anesthetic agents.

Sympathomimetics may weaken the antihypertensive effect of lisinopril.

Diuretics (thiazide and “loop”) the use of diuretics in high doses can lead to hypovolemia (due to a decrease in blood volume), and the addition of lisinopril to therapy can lead to a marked decrease in BP.

The combination of lisinopril and hydrochlorothiazide weakens the effect of oral hypoglycemic agents, norepinephrine, epinephrine, and anti-gout agents, enhances the effects (including side effects) of cardiac glycosides, the action of peripheral muscle relaxants, and reduces the excretion of quinidine.

Lisinopril and Hydrochlorothiazide reduces the effect of oral contraceptives.

Ethanol enhances the hypotensive effect of lisinopril and hydrochlorothiazide.

Concomitant use with methyldopa increases the risk of hemolysis.

Storage Conditions

At a temperature not exceeding 25°C (77°F), in the original packaging. Keep out of reach of children.

Shelf Life

The shelf life is 3 years.

Dispensing Status

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.