Lisinopril-Vertex, tablets 20 mg 30 pcs

Pharmacodynamics

A ACE inhibitor, reduces the formation of angiotensin II from angiotensin I. Decreased angiotensin II leads to a direct reduction in aldosterone release. Reduces bradykinin degradation and increases prostaglandin synthesis. Reduces total peripheral vascular resistance (TPR), blood pressure (BP), preload, pulmonary capillary pressure, causes an increase in minute blood volume (MOB) and increases myocardial exercise tolerance in patients with chronic heart failure (CHF). Dilates arteries more than veins. Some effects are attributed to effects on the tissue renin-angiotensin-aldosterone system (RAAS). Long-term use reduces myocardial and arterial wall resistance hypertrophy. It improves the blood supply to the ischemic myocardium.

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

The onset of antihypertensive action is in 1 hour. The maximum effect is observed after 6-7 hours. Antihypertensive effect lasts for 24 hours. The duration of the effect also depends on the size of the dose. In arterial hypertension the effect is noted in the first days after the start of treatment, the stable effect develops after 1-2 months.

Pharmacokinetics

The average absorption of lisinopril is about 25%, with considerable interindividual variability (6-60%). Food does not affect the absorption of lisinopril.

Maximum plasma concentration of about 90 ng/ml is reached after 6 hours. Bioavailability is 25%. Weakly bound to plasma proteins. Blood-brain barrier and placental barrier permeability is low. It is practically not metabolized and is excreted unchanged by the kidneys. The elimination half-life is 12 hours. Absorption and clearance of lisinopril are decreased in patients with CHF, with cirrhosis and in elderly patients.

Disordered renal function leads to increased AUC (area under the curve “plasma concentration – time”) and elimination half-life of lisinopril, but these changes become clinically significant only when glomerular filtration rate is less than 30 ml/min.

Pharmacokinetics in selected patient groups

In patients with chronic heart failure, the absorption and clearance of lisinopril are reduced, with a bioavailability of 16%.
In patients with renal insufficiency (creatinine clearance less than 30 ml/min) the concentration of lisinopril is several times higher than in plasma of healthy volunteers with prolongation of time to maximum concentration in plasma and longer half-life.

In elderly patients the plasma concentration of lisinopril is increased by an average of 60% and the area under the curve “concentration-time” is 2 times greater than in younger patients.

In patients with cirrhosis, the bioavailability of lisinopril is reduced by 30% and clearance is reduced by 50% compared to patients with normal liver function.

Indications

– essential and renovascular arterial hypertension (AH) (in monotherapy or in combination with other hypotensive agents);
– chronic heart failure (CHF) (in combination therapy);
– early treatment of acute myocardial infarction in combination therapy (in the first 24 hours with stable hemodynamic indexes to support these indexes and prevent left ventricular dysfunction and heart failure);
– diabetic nephropathy (decrease of albuminuria in patients with type 1 diabetes with normal BP and in patients with type 2 diabetes with hypertension).

Active ingredient

Composition

Each tablet contains:

Active ingredient:

lisinopril dihydrate (equivalent to lisinopril) 2.5 mg, 5 mg, 10 mg or 20 mg;

Associates:

Lactose monohydrate 77.5 mg/75.0 mg/70.0 mg/65.0 mg, respectively,

Corn starch 49.0 mg,

povidone 6.0 mg,

talc 3.13 mg,

magnesium stearate 1.3 mg,

Dyes (sunset yellow 0.02 mg in tablets containing 2.5 mg and 5 mg lisinopril; azorubin dye 0.02 mg in tablets containing 10 mg lisinopril; titanium dioxide 0.02 mg in tablets containing 20 mg lisinopril).

How to take, the dosage

Overly, once daily in the morning, regardless of meals, preferably at the same time.

Essential hypertension: initial dose – 10 mg/day, maintenance dose – 20 mg/day, maximum daily dose – 40 mg. A stable antihypertensive effect develops in 1-2 months, which should be taken into account when increasing the dose. If application of the drug in maximum dose does not cause sufficient therapeutic effect, additional prescription of other hypotensive agent is possible.

In patients who have previously received diuretics, they should be discontinued 2-3 days before the start of the drug. If diuretics cannot be withdrawn, the initial dose of lisinopril should not exceed 5 mg/day.

Renovascular hypertension and other conditions with increased RAAS activity: The initial dose is 2.5-5 mg/day with monitoring of BP, renal function and serum potassium content. The maintenance dose is established depending on the value of BP.

In chronic renal insufficiency (ChRI) a dose is determined depending on creatinine clearance (CK): at CK 30-70 ml/min – 5-10 mg/day, at CK 10-30 ml/min – 2.5-5 mg/day, less than 10 ml/min, including patients on hemodialysis – 2.5 mg/day. The maintenance dose is determined depending on the BP (under control of renal function, blood potassium and sodium content).

CHF (simultaneously with diuretics and/or cardiac glycosides): initial dose – 2.5 mg/day, with gradual increase by 2.5 mg after 3-5 days to maintenance daily dose of 5-10 mg/day. The maximum daily dose is 20 mg. If possible, the dose of diuretic should be reduced before starting lisinopril.

Older patients often have a more pronounced long-term antihypertensive effect due to the decreased excretion rate of lisinopril (it is recommended to start treatment with 2.5 mg/day – ½ tablet of 5 mg).

Acute myocardial infarction (as part of combined therapy in the first 24 h with stable hemodynamic parameters): 5 mg in the first 24 h, then 5 mg daily,

10 mg in two days and then 10 mg once daily. The course of treatment is at least 6 weeks.

At the beginning of treatment or during the first 3 days after acute myocardial infarction in patients with low systolic blood pressure (120 mmHg or less) a lower dose of 2.5 mg is prescribed. In case of BP lowering (systolic BP less or equal to 100 mmHg) the daily dose of 5 mg is temporarily reduced to 2.5 mg, if necessary. In case of prolonged marked BP lowering (systolic BP lower than 90 mmHg for more than 1 hour), the drug should be discontinued.

Diabetic nephropathy: initial dose is 10 mg/day which is increased to 20 mg/day, if necessary to achieve values of diastolic BP below 75 mmHg measured in sitting position for type 1 diabetic patients and below 90 mmHg in sitting position for type 2 diabetic patients.

Interaction

In concomitant use with potassium-saving diuretics (spironolactone, triamterene, amiloride), potassium preparations, salt substitutes containing potassium – the risk of hyperkalemia increases, especially in patients with impaired renal function. Therefore they can be administered together only on the basis of an individual decision of the physician with regular monitoring of serum potassium and renal function.
With simultaneous use with beta-adrenoblockers, “slow” calcium channel blockers, diuretics and other hypotensive agents increase the antihypertensive effect of the drug.

Lisinopril can be used simultaneously with beta-adrenoblockers, acetylsalicylic acid (in doses less than 300 mg/day), thrombolytics, nitrates.

In concomitant use with vasodilators, barbiturates, phenothiazines, tricyclic antidepressants, ethanol – increase of the antihypertensive effect of the drug.

When used concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs) (including selective cyclooxygenase-2 inhibitors), estrogens, as well as with adrenostimulants – decrease of antihypertensive effect of lisinopril.

With concomitant use with lithium preparations – slowing of lithium elimination from the body (enhancement of cardiotoxic and neurotoxic effects of lithium).

In concomitant use with antacids and colestiramine – reduction of absorption in the gastrointestinal tract.

The drug increases neurotoxicity of salicylates, weakens the effects of hypoglycemic oral agents, norepinephrine (noradrenaline), epinephrine (adrenaline) and antipodagric agents, increases the effects (including side effects) of cardiac glycosides, effects of peripheral muscle relaxants, reduces quinidine excretion.

Reduces the effect of oral contraceptives. Concomitant use of methyldopa increases the risk of hemolysis.
Concomitant use with selective serotonin reuptake inhibitors may lead to severe hyponatremia.
Concomitant use with allopurinol, procainamide, cytostatics may lead to leukopenia.

When concomitant use of ACE inhibitors and gold drugs (sodium aurothiomalate) intravenously, a symptomcomplex including facial hyperemia, nausea, vomiting and arterial hypotension has been described.

Special Instructions

A pronounced decrease in BP most often occurs with a decrease in circulating blood volume caused by diuretic therapy, reduction of salt in food, hemodialysis, diarrhea, or vomiting. In patients with chronic heart failure with or without concomitant renal failure, a marked decrease in BP is possible. It is more often found in patients with severe stage of chronic heart failure, as a consequence of high doses of diuretics, hyponatremia or impaired renal function. In such patients, treatment should be started under strict control of a physician (choose the dosage of the drug and diuretics with caution). Similar rules should be followed when prescribing for patients with coronary heart disease, cerebrovascular insufficiency, where a sharp decrease in BP may lead to myocardial infarction or stroke. Before the start of treatment, if possible, sodium concentration should be normalized and/or circulating blood volume should be replenished, the effect of the initial dose of the drug on the patient should be carefully monitored. Treatment of symptomatic arterial hypotension consists of ensuring bed rest and, if necessary, IV fluid administration (physiological solution infusion). Transient arterial hypotension is not a contraindication for treatment with Lisinopril, however, temporary withdrawal or dose reduction may be required.

Lisinopril treatment is contraindicated in case of cardiogenic shock and in acute myocardial infarction if vasodilator administration may significantly worsen hemodynamic parameters, for example when systolic blood pressure is less than 100 mm Hg.
In patients with acute myocardial infarction, decreased renal function (plasma creatinine concentration greater than 177 μmol/L and/or proteinuria greater than 500 mg/24 h) is contraindicated for use of Lisinopril. If renal failure develops during treatment with lisinopril (creatinine concentration in blood plasma is more than 265 µmol/l or twice the baseline level), the physician should decide on the necessity of discontinuing the treatment.

In bilateral renal artery stenosis and renal artery stenosis of the single kidney, as well as in hyponatremia and/or decreased circulating blood volume or circulatory failure, hypotension caused by taking Lisinopril may lead to decreased renal function with subsequent development of reversible (after drug withdrawal) acute renal failure. A slight transient increase in blood urea and creatinine may be observed in cases of impaired renal function, especially during concomitant treatment with diuretics. In cases of significant decrease of renal function (creatinine clearance less than 30 ml/min) caution and control of renal function are required.

Angioedema of the face, limbs, lips, tongue, epiglottis and/or larynx has rarely been observed in patients treated with ACE inhibitors, including Lisinopril, may occur during any period of treatment. In such a case, treatment with Lisinopril should be stopped as soon as possible and the patient should be monitored until the symptoms have completely resolved. In cases of edema of the face and lips only, the condition usually resolves without treatment, but antihistamines may be prescribed. Angioedema with laryngeal edema may be fatal. When the tongue, epiglottis or larynx is involved, airway obstruction may occur, so appropriate therapy (0.3-0.5 ml of epinephrine (adrenaline) solution 1:1000 subcutaneously, administration of glucocorticosteroids, antihistamines) and/or measures to ensure airway patency should be immediately undertaken.
In patients who have a history of angioedema not associated with previous treatment with ACE inhibitors, there may be an increased risk of its development during treatment with an ACE inhibitor.

Anaphylactic reactions have also been noted in patients on hemodialysis using high flow dialysis membranes (AN69®) who are simultaneously taking lisinopril. In such cases, another type of dialysis membrane or another hypotensive agent should be considered. Anaphylactic reactions may occur when low-density lipoprotein apheresis is performed with dextran sulfate.

In some cases of desensitization to venom of moths (wasps, bees, etc.) treatment with ACE inhibitors was accompanied by hypersensitivity reactions. This can be avoided by temporary interruption of ACE inhibitor therapy.
In patients undergoing major surgery or during general anesthesia, ACE inhibitors (particularly lisinopril) may block angiotensin II formation. The BP reduction associated with this mechanism of action is corrected by increasing circulating blood volume. Before surgical procedures (including dentistry), the surgeon/anesthesiologist should be warned about the use of lisinopril.

Use of the recommended doses of the drug in elderly patients may be accompanied by increased concentration of lisinopril in blood; therefore, the dose selection requires special attention and is made depending on renal function and BP of the patient.

However, in elderly and young patients the antihypertensive effect of lisinopril is expressed to the same extent.
When using ACE inhibitors, coughing has been noted. Cough is dry and prolonged, which disappears after discontinuation of ACE inhibitor treatment. In differential diagnosis of cough, cough caused by use of ACE inhibitors must also be considered.

In some cases, hyperkalemia has been noted. The risk factors for development of hyperkalemia include renal insufficiency, diabetes mellitus, intake of potassium preparations or preparations causing increase of potassium content in blood (for example, heparin), especially in patients with impaired renal function. Regular monitoring of blood plasma potassium ions, glucose, urea and lipids is required during the drug treatment.
It is not recommended to drink alcoholic beverages during the treatment period, because alcohol increases antihypertensive effect of the drug.
It is necessary to be careful when performing physical exercises and in hot weather (risk of dehydration and excessive pressure decrease due to the reduced volume of circulating blood).

Since the potential risk of agranulocytosis cannot be excluded, periodic monitoring of blood counts is required.
Based on the results of epidemiological studies it is suggested that simultaneous use of ACE inhibitors and insulin as well as hypoglycemic agents for oral administration may lead to hypoglycemia. The highest risk of development is observed during the first weeks of combined therapy, as well as in patients with impaired renal function. In patients with diabetes mellitus, careful control of glycemia is required, especially during the first month of ACE inhibitor therapy. ACE inhibitors may lead to cholestatic jaundice with progression to fulminant liver necrosis, therefore it is necessary to discontinue the drug in case of increase of liver transaminases activity and appearance of cholestasis symptoms.

The effect of the drug on the ability to drive and operate vehicles
If side effects on the central nervous system appear, it is not recommended to drive vehicles or perform high-risk work.

Contraindications

– hypersensitivity to lisinopril, to other ACE inhibitors and components of the drug;
– history of angioedema, including history of angioedema in combination with ACE inhibitors;
– hereditary angioedema Quincke or idiopathic edema;
– pregnancy;
– lactation;
– age under 18 years (efficacy and safety have not been established);
– lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

With caution
Aortic orifice stenosis, hypertrophic obstructive cardiomyopathy, bilateral renal artery stenosis, artery stenosis of the single kidney, condition after renal transplantation, severe renal failure (creatinine clearance (CK) less than 30 ml/min.), primary hyperaldosteronism, arterial hypotension, bone marrow suppression, hyponatremia (increased risk of arterial hypotension in patients on low-salt or no-salt diet), hypovolemic conditions (including diarrhea, vomiting), systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), diabetes mellitus, hyperkalemia, coronary heart disease, cerebrovascular disease (including cerebrovascular insufficiency), severe chronic heart failure, hemodialysis using high-flow dialysis membranes (AN69®), advanced age.

Side effects

The most common side effects: dizziness, headache, increased fatigue, diarrhea, dry cough, nausea.

Cardiovascular system: marked BP decrease, chest pain, orthostatic hypotension, tachycardia, bradycardia, appearance or worsening of heart failure symptoms, atrioventricular conduction disorder, myocardial infarction, palpitations.

From the central nervous system: emotional lability, impaired concentration, paraesthesia, somnolence, convulsive twitching of the muscles of the limbs and lips, increased fatigue, asthenic syndrome, confusion.

With the organs of hematopoiesis: leukopenia, neutropenia, agranulocytosis, thrombocytopenia, anemia (decreased concentration, hemoglobin, hematocrit, erythropenia).

Respiratory system: dyspnea, dry cough, bronchospasm.

Digestive system: dry oral mucosa, anorexia, dyspepsia, changes in taste, abdominal pain, pancreatitis, jaundice (hepatocellular or cholestatic), hepatitis.

Skin side: increased sweating, alopecia, photosensitization, itching.

River system disorders: renal dysfunction, oliguria, anuria, acute renal failure, uremia, proteinuria, decreased potency.

Allergic reactions: Angioneurotic edema of the face, extremities, lips, tongue, epiglottis and/or larynx, skin rash, urticaria, fever, positive results of antinuclear antibody test, increased CRP, eosinophilia, leukocytosis, intestinal angioneurotic edema.

Other: myalgia, arthralgia/arthritis, vasculitis.

When ACE inhibitors and gold drugs (sodium aurothiomalate) are used concomitantly intravenously, a symptom complex including facial hyperemia, nausea, vomiting, and arterial hypotension has been described.

Laboratory findings: hyperkalemia, hyponatremia, increased activity of “hepatic” transaminases, hyperbilirubinemia, hypercreatininemia, increased concentration of urea.

Overdose

Symptoms:

A marked decrease in BP, dry oral mucosa, drowsiness, delayed urination, constipation, impaired water-electrolyte balance, renal failure, rapid breathing, tachycardia, palpitations, bradycardia, dizziness, restlessness, increased irritability.

Treatment:

gastric lavage, activated charcoal administration, putting the patient in a horizontal position with elevated legs, replenishment of circulating blood volume – intravenous 0.9% sodium chloride solution or other plasma exchange solutions, if necessary – vasopressor drugs, control of cardiovascular and respiratory system functions, BP, BCC, urea, creatinine, water-electrolyte balance. In case of stable bradycardia – usage of artificial pacemaker.
Hemodialysis is effective.

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