Lisinopril AML (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

ATC Code

C09BB03 (Lisinopril and amlodipine)

Active Substances

Lisinopril (Rec.INN WHO registered)

Amlodipine (Rec.INN WHO registered)

Dosage Forms

	Lisinopril AML	Tablets 5 mg+10 mg: 30, 50 or 60 pcs.
		Tablets 5 mg+20 mg: 30, 50 or 60 pcs.
		Tablets 10 mg+20 mg: 30, 50 or 60 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat-cylindrical, with a bevel and a score.

Excipients: microcrystalline cellulose 102 – 124.62 mg, sodium carboxymethyl starch – 5 mg, magnesium stearate – 1.5 mg, colloidal anhydrous silicon dioxide (anhydrous aerosil) – 1 mg.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (5) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Tablets white or almost white, round, flat-cylindrical, with a bevel.

Excipients: microcrystalline cellulose 102 – 160.19 mg, sodium carboxymethyl starch – 7 mg, magnesium stearate – 2 mg, colloidal anhydrous silicon dioxide (anhydrous aerosil) – 2 mg.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (5) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Tablets white or almost white, round, flat-cylindrical, with a bevel and a score.

Excipients: microcrystalline cellulose 102 – 249.24 mg, sodium carboxymethyl starch – 10 mg, magnesium stearate – 3 mg, colloidal anhydrous silicon dioxide (anhydrous aerosil) – 2 mg.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (5) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Combined antihypertensive drug

Pharmacotherapeutic Group

Combined antihypertensive agent (CCB + ACE inhibitor)

Pharmacological Action

Combined antihypertensive drug containing amlodipine and lisinopril.

Amlodipine is a calcium channel blocker, a dihydropyridine derivative. It has antihypertensive and antianginal action. It blocks the transmembrane transition of calcium ions into cardiomyocytes and smooth muscle cells of the vascular wall. The antihypertensive action of amlodipine is due to a direct relaxing effect on the smooth muscle cells of the vascular wall. The antianginal action is due to the expansion of coronary and peripheral arteries and arterioles: in angina, it reduces the severity of myocardial ischemia; by expanding peripheral arterioles, it reduces total peripheral vascular resistance, reduces afterload on the heart, and reduces myocardial oxygen demand; by expanding coronary arteries and arterioles in unchanged and ischemic areas of the myocardium, it increases oxygen supply to the myocardium (especially in vasospastic angina); prevents spasm of the coronary arteries (including that caused by smoking).

It has a long-term dose-dependent antihypertensive effect. In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure (in the supine and standing positions) for 24 hours. The antihypertensive effect develops slowly, so the development of acute arterial hypotension is not typical. In patients with stable angina, a single daily dose increases exercise tolerance, slows the development of angina attacks and ischemic ST segment depression, and reduces the frequency of angina attacks and the consumption of nitroglycerin and other nitrates.

It reduces the degree of left ventricular myocardial hypertrophy. It does not affect myocardial contractility and conduction, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases glomerular filtration rate, and has a weak natriuretic effect.

In diabetic nephropathy, it does not increase the severity of microalbuminuria. It does not have any adverse effect on metabolism and plasma lipid concentrations, can be used in the treatment of patients with bronchial asthma, diabetes mellitus and gout. A significant decrease in blood pressure is observed after 6-10 hours, the duration of the effect is 24 hours.

In patients with cardiovascular diseases (including coronary atherosclerosis with single-vessel disease and up to stenosis of 3 or more arteries, atherosclerosis of the carotid arteries), who have had myocardial infarction, percutaneous transluminal coronary angioplasty, or in patients with angina, the use of amlodipine prevents an increase in the thickness of the carotid intima-media complex, reduces mortality from myocardial infarction, stroke, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting; leads to a reduction in the number of hospitalizations for unstable angina and progression of chronic heart failure; reduces the frequency of interventions aimed at restoring coronary blood flow.

It does not increase the risk of death or the development of complications and fatal outcomes in patients with chronic heart failure (NYHA class III-IV) on the background of therapy with digoxin, diuretics and ACE inhibitors. In patients with chronic heart failure (NYHA class III-IV) of non-ischemic etiology, there is a possibility of pulmonary edema when using amlodipine.

Lisinopril is an ACE inhibitor, reduces the formation of angiotensin II from angiotensin I. A decrease in the concentration of angiotensin II leads to a direct decrease in the release of aldosterone. Reduces the degradation of bradykinin and increases the synthesis of prostaglandins. Reduces total peripheral vascular resistance, blood pressure, preload, pulmonary capillary pressure, causes an increase in cardiac output and an increase in myocardial tolerance to physical activity in patients with chronic heart failure. Dilates arteries to a greater extent than veins. Some effects are explained by the impact on the tissue renin-angiotensin system. With long-term use, it reduces hypertrophy of the myocardium and walls of resistive arteries.

Improves blood supply to the ischemic myocardium.

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

The onset of action is 1 hour after oral administration. The maximum hypotensive effect is determined after 6-7 hours and lasts for 24 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 was noted after abrupt withdrawal of lisinopril. 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 increase in the incidence of hypoglycemia.

Amlodipine+Lisinopril

The combination of amlodipine and lisinopril in one drug allows achieving comparable blood pressure control and preventing the development of possible side effects caused by one of the active substances.

Pharmacokinetics

Amlodipine

After oral administration, amlodipine is slowly and almost completely absorbed from the gastrointestinal tract. Simultaneous food intake does not affect the absorption of amlodipine. C_max in blood plasma is reached 6-12 hours after administration. The mean absolute bioavailability is 64-80%. The mean V_d is 21 L/kg of body weight, indicating that most of the amlodipine is in the tissues, and a smaller part is in the blood. Most of the amlodipine in the blood (97.5%) is bound to plasma proteins. C_ss in blood plasma is reached after 7-8 days of constant amlodipine administration. Amlodipine penetrates the blood-brain barrier and placental barrier.

Amlodipine undergoes slow but active metabolism in the liver in the absence of a significant first-pass effect through the liver. Metabolites do not have significant pharmacological activity.

After a single dose of amlodipine, T_1/2 varies from 35 to 50 hours, with repeated use it is approximately 45 hours. About 60% of the orally administered dose is excreted by the kidneys mainly in the form of metabolites, 10% – unchanged, 20-25% – through the intestine with bile. The total clearance of amlodipine is 0.116 ml/s/kg (7 ml/min/kg, 0.42 L/h/kg). Amlodipine is not removed by hemodialysis.

Prolongation of T_1/2 in patients with hepatic insufficiency suggests that with long-term use, the accumulation of amlodipine in the body will be higher (increases to 60 hours).

Lisinopril

After oral administration, about 25% of lisinopril is absorbed from the gastrointestinal tract. Simultaneous food intake does not affect the absorption of lisinopril. Absorption can vary from 6 to 60%, on average it is 30%, bioavailability is 25-29%. After oral administration, C_max of lisinopril in blood plasma is reached after 6-8 hours. Weakly binds to plasma proteins. Permeability through the blood-brain barrier and placental barrier is low.

Lisinopril is not biotransformed in the body. It is excreted by the kidneys unchanged. T_1/2 is 12 hours.

In patients with chronic heart failure, the absorption and clearance of lisinopril are reduced, bioavailability is 16%.

In patients with renal insufficiency (creatinine clearance <30 ml/min), the concentration of lisinopril is several times higher than the concentrations in the blood plasma of healthy volunteers, and an increase in the time to reach C_max in the blood plasma and an increase in T_1/2 are noted.

In elderly patients, the plasma concentration of lisinopril and AUC are 2 times greater than in young patients. In elderly patients, the plasma concentration of lisinopril is increased by an average of 60%.

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

Amlodipine+Lisinopril

Interaction between the active substances of the drug is unlikely. The values of AUC, C_max, time to reach C_max, as well as T_1/2 do not change compared to the indicators of each individual active substance. Food intake does not affect the absorption of the active substances. The long circulation of both active substances in the body allows the drug to be taken once a day.

Indications

Essential hypertension in patients for whom combination therapy is indicated.

ICD codes

Dosage Regimen

The drug is taken orally, regardless of the time of food intake, with a sufficient amount of liquid.

The recommended dose is 1 tablet once a day, daily at the same time. The maximum daily dose is 1 tablet.

The drug is indicated only for those patients in whom the optimal maintenance dose of lisinopril and amlodipine corresponds to the fixed doses: 5 mg and 5 mg, 5 mg and 10 mg, 5 mg and 20 mg, 10 mg and 10 mg, 10 mg and 20 mg, respectively. The dose of the drug is selected after previously conducted titration of doses of individual components. If correction of the drug dose is necessary, dose titration should be carried out using amlodipine and lisinopril separately.

In patients with impaired renal function, renal function, plasma potassium and sodium levels should be monitored during therapy with the drug. If renal function deteriorates, the drug should be discontinued. Such patients are recommended to individually select doses of individual active components.

Slowing of the excretion of amlodipine is possible in patients with impaired liver function. Clear recommendations regarding the dose of the drug in such cases have not been established, so the drug should be prescribed with caution to patients with impaired liver function.

In elderly patients, the drug should be used with caution. Clinical studies have not obtained data on changes in the efficacy or safety profile of amlodipine or lisinopril depending on age.

The safety and efficacy of the drug in children and adolescents have not been established.

Adverse Reactions

Undesirable adverse reactions are presented by system-organ classes in accordance with the MedDRA classification and with the frequency of occurrence: very common (≥1/10); common (from ≥1/100 to 1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10,000 to 1/1000); very rare (<1/10,000); frequency unknown (cannot be estimated from the available data).

Amlodipine

Blood and lymphatic system disorders very rare – thrombocytopenic purpura, leukopenia, thrombocytopenia.

Allergic reactions uncommon – urticaria; very rare – angioedema.

Metabolism and nutrition disorders very rare – hyperglycemia.

Psychiatric disorders uncommon – mood lability, insomnia, unusual dreams, increased excitability, depression, anxiety; very rare – apathy, agitation, amnesia.

Nervous system disorders common – headache, dizziness, increased fatigue, drowsiness; uncommon – asthenia, malaise, hypoesthesia, paresthesia, peripheral neuropathy, tremor, muscle rigidity, insomnia, taste perversion; rare – convulsions; very rare – migraine, peripheral neuropathy, ataxia, parosmia.

Eye disorders uncommon – diplopia, accommodation disturbance, xerophthalmia, conjunctivitis, eye pain, visual impairment.

Ear and labyrinth disorders uncommon – tinnitus.

Cardiac disorders common – palpitations, peripheral edema (ankles and feet), flushing; uncommon – marked decrease in blood pressure, orthostatic hypotension; rare – development or worsening of chronic heart failure; very rare – cardiac arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), myocardial infarction, chest pain, syncope, vasculitis, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea, rhinitis, epistaxis; very rare – cough.

Gastrointestinal disorders common – nausea, abdominal pain; uncommon – vomiting, constipation, diarrhea, flatulence, dyspepsia, anorexia, dry oral mucosa, thirst; rare – gingival hyperplasia, increased appetite; very rare – pancreatitis, gastritis, jaundice (usually cholestatic), hyperbilirubinemia, increased activity of hepatic transaminases, hepatitis.

Renal and urinary disorders uncommon – frequent urination, painful urination, nocturia; very rare – dysuria, polyuria.

Reproductive system and breast disorders uncommon – erectile dysfunction, gynecomastia.

Skin and subcutaneous tissue disorders uncommon – skin itching, rash (including erythematous and maculopapular rash); rare – dermatitis; very rare – erythema multiforme, alopecia, urticarial rash, xeroderma, increased sweating, cold sweat, skin pigmentation disorder.

Musculoskeletal and connective tissue disorders uncommon – arthralgia, muscle cramps, myalgia, back pain, arthrosis; rare – myasthenia.

General disorders and administration site conditions uncommon – peripheral edema, pain of unspecified localization, increase/decrease in body weight.

Lisinopril

Blood and lymphatic system disorders rare – decrease in hemoglobin and hematocrit; very rare – bone marrow function depression, lymphadenopathy, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, hemolytic anemia, anemia; frequency unknown – erythrocytopenia.

Allergic reactions rare – urticaria, angioedema of the face, extremities, lips, tongue, epiglottis and/or larynx; very rare – intestinal angioedema.

Endocrine disorders frequency unknown – syndrome of inappropriate ADH secretion.

Metabolism and nutrition disorders very rare – hypoglycemia.

Psychiatric disorders common – sleep disturbance; uncommon – mood lability; rare – confusion; frequency unknown – bewilderment, depression.

Nervous system disorders common – dizziness, headache; uncommon – paresthesia, drowsiness, dysgeusia; rare – asthenic syndrome, confusion; frequency unknown – syncope, convulsive twitching of the muscles of the face and extremities.

Cardiac disorders common – excessive decrease in blood pressure; uncommon – chest pain, myocardial infarction (due to a marked decrease in blood pressure in high-risk patient groups), cerebrovascular accident (due to a marked decrease in blood pressure in high-risk patient groups), Raynaud’s syndrome; rare – tachycardia, bradycardia, worsening of chronic heart failure, AV conduction disturbance, palpitations, orthostatic hypotension; frequency unknown – vasculitis.

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

From the digestive systemoften – hepatic failure; infrequently – dyspepsia, nausea, taste perversion, abdominal pain; rarely – dryness of the oral mucosa; very rarely – pancreatitis, hepatocellular and cholestatic jaundice, hepatitis, intestinal angioedema; frequency unknown – anorexia.

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

From the reproductive system and mammary glandinfrequently – decreased potency; rarely – gynecomastia.

From the skin and subcutaneous tissueinfrequently – skin rash, pruritus; rarely – alopecia, psoriasis, urticarial rash, photosensitization; very rarely – increased sweating, pemphigus, cutaneous pseudolymphoma, Stevens-Johnson syndrome, toxic epidermal necrolysis, exudative multiforme erythema.

From the musculoskeletal systemfrequency unknown – myalgia, arthralgia/arthritis.

From laboratory and instrumental investigationsinfrequently – hyperkalemia, hyponatremia, increased serum urea and creatinine concentration; rarely – increased activity of hepatic enzymes, hyperbilirubinemia; very rarely – increased ESR, increased titer of antinuclear antibodies; frequency unknown – eosinophilia, leukocytosis.

Otherinfrequently – increased fatigue, asthenia; very rarely – autoimmune diseases; frequency unknown – fever (there are reports of the development of a lupus-like syndrome, which may include fever, myalgia, arthralgia/arthritis, increased titer of antinuclear antibodies, increased ESR, eosinophilia, leukocytosis, and possibly also the development of rash, photosensitivity reactions or other skin manifestations).

Contraindications

Hypersensitivity to lisinopril or any other ACE inhibitor, amlodipine or any other dihydropyridine derivative, or to any of the excipients; history of angioedema, incl. in connection with the use of ACE inhibitors; hereditary or idiopathic angioedema; shock (including cardiogenic); unstable angina (except for Prinzmetal’s angina); severe arterial hypotension (systolic BP less than 90 mm Hg); hemodynamically significant obstruction of the left ventricular outflow tract (e.g., in severe aortic stenosis, hypertrophic obstructive cardiomyopathy), hemodynamically significant mitral stenosis; hemodynamically unstable heart failure after acute myocardial infarction; concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m²); concomitant use with angiotensin II receptor antagonists in patients with diabetic nephropathy; pregnancy; breastfeeding period; age under 18 years (efficacy and safety not established).

With cautionsevere renal impairment; bilateral renal artery stenosis or renal artery stenosis in patients with a single kidney; condition after kidney transplantation; azotemia; hyperkalemia; impaired liver function; primary aldosteronism; arterial hypotension; cerebrovascular diseases (incl. cerebral circulatory insufficiency); coronary artery disease; coronary insufficiency; sick sinus syndrome (severe bradycardia, tachycardia); chronic heart failure of non-ischemic origin FC III-IV; aortic stenosis; mitral stenosis; acute myocardial infarction (and within 1 month after myocardial infarction); autoimmune connective tissue diseases (incl. scleroderma, SLE); suppression of bone marrow hematopoiesis; adherence to a diet with salt restriction; conditions associated with a decrease in circulating blood volume (incl. vomiting and diarrhea); hemodialysis using high-flux dialysis membranes (e.g., AN69^®); use in elderly patients.

Use in Pregnancy and Lactation

Use of this combination is contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

With cautionimpaired liver function.

Use in Renal Impairment

With cautionsevere renal impairment; bilateral renal artery stenosis or renal artery stenosis in patients with a single kidney; condition after kidney transplantation.

Pediatric Use

Contraindicated for use under the age of 18 years (efficacy and safety not established).

Geriatric Use

This combination should be used with caution in elderly patients.

Special Precautions

When using this combination, the recommendations for the use of individual components should be taken into account.

Amlodipine

Maintenance of dental hygiene and observation by a dentist is necessary (to prevent soreness, bleeding and gingival hyperplasia).

In elderly patients, the T_1/2 of amlodipine may increase and clearance may decrease. Dose adjustment is not required, but more careful monitoring of patients in this category is necessary.

Although calcium channel blockers do not have a withdrawal syndrome, it is advisable to discontinue treatment with amlodipine by gradually reducing the dose of the drug.

During the use of amlodipine in patients with chronic heart failure of non-ischemic origin class III and IV according to NYHA classification, an increased incidence of pulmonary edema was noted, despite the absence of signs of worsening heart failure.

In some patients receiving slow calcium channel blockers, reversible biochemical changes in the sperm head were detected, which may be clinically significant during IVF. However, there is currently insufficient clinical data regarding the potential effect of amlodipine on fertility. In a preclinical study, adverse effects on fertility in males were identified.

Lisinopril

Excessive decrease in BP most often occurs with a decrease in circulating blood volume caused by diuretic therapy, reduction of salt in the diet, dialysis, diarrhea and vomiting. In patients with chronic heart failure, both with and without concomitant renal failure, symptomatic arterial hypotension may develop. Arterial hypotension was more often detected in patients with severe heart failure as a result of the use of a diuretic in high doses, hyponatremia or impaired renal function. In such patients, therapy should be started under strict medical supervision (carefully titrate the dose of lisinopril and diuretics). Similar rules should be followed when prescribing lisinopril to patients with coronary artery disease, cerebrovascular insufficiency, in whom a sharp decrease in BP can lead to myocardial infarction or stroke.

In case of excessive decrease in BP, the patient should be laid down and, if necessary, fluid loss should be replenished (IV infusion of 0.9% sodium chloride solution). A transient hypotensive reaction is not a contraindication for taking the next dose of lisinopril.

When using lisinopril in some patients with chronic heart failure but with normal or low BP, a decrease in BP may be observed, which is usually not a reason to discontinue therapy. If arterial hypotension becomes symptomatic, it is necessary to reduce the dose or discontinue lisinopril therapy.

In patients at risk of developing symptomatic arterial hypotension (on a salt-restricted or salt-free 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.

The antihypertensive effect of the initial dose of lisinopril should be monitored.

Neutropenia/agranulocytosis, thrombocytopenia and anemia may occur during treatment with ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia rarely develops. The drug should be prescribed with particular caution to patients with systemic connective tissue diseases, while taking immunosuppressants, allopurinol or procainamide, or when these risk factors are combined, especially in patients with impaired renal function. Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing this combination to such patients, it is recommended to periodically monitor the number of leukocytes in the blood plasma. Patients should report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

As with the use of other ACE inhibitors, lisinopril should be prescribed with caution to patients with mitral valve stenosis and left ventricular outflow tract obstruction (aortic stenosis or hypertrophic obstructive cardiomyopathy).

In acute myocardial infarction, standard therapy is indicated (thrombolytics, acetylsalicylic acid as an antiplatelet agent, beta-blockers).

Lisinopril can be used in combination with IV nitroglycerin or with the use of nitroglycerin in the form of a transdermal system.

Lisinopril therapy should not be started in patients with acute myocardial infarction who are at risk of further serious hemodynamic deterioration after the use of vasodilators (patients with systolic BP of 100 mm Hg or lower, patients with cardiogenic shock). During the first 3 days after myocardial infarction, the dose of lisinopril should be reduced if systolic BP is 120 mm Hg or lower. Maintenance doses of lisinopril should be reduced to 5 mg or temporarily to 2.5 mg if systolic BP is 100 mm Hg or lower. If arterial hypotension persists (systolic BP less than 90 mm Hg for more than 1 hour), lisinopril should not be continued.

In patients with chronic heart failure, excessive decrease in BP after initiation of treatment with ACE inhibitors may lead to further deterioration of renal function. Cases of acute renal failure have been reported.

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 concentration was observed, usually reversible after discontinuation of treatment and more common in patients with renal failure.

Lisinopril is not used in acute myocardial infarction in patients with severe renal impairment, established by a change in serum creatinine concentration exceeding 177 µmol/l, and/or proteinuria exceeding 500 mg/day. If renal dysfunction develops during lisinopril therapy (serum creatinine concentration exceeding 265 µmol/l, or doubling of the value compared to the pre-treatment level), the need for further use of lisinopril should be assessed.

Angioedema of the face, extremities, lips, tongue, epiglottis and/or larynx, which may occur at any time during therapy, has been rarely reported in patients receiving treatment with an ACE inhibitor, including lisinopril. In such a case, lisinopril therapy should be discontinued as soon as possible and the patient should be monitored until the symptoms completely regress. In cases where edema occurs only on the face and lips, this condition most often resolves without treatment, but antihistamines may be used.

Angioedema with laryngeal edema can be fatal. Swelling of the tongue, epiglottis or larynx can cause airway obstruction, so appropriate therapy should be administered immediately (0.3-0.5 ml of 1:1000 epinephrine (adrenaline) solution s.c.) and/or measures should be taken to ensure airway patency. It has been noted that angioedema developed more often in Black patients taking ACE inhibitors than in patients of other races.

Intestinal angioedema has been rarely observed in patients taking ACE inhibitors. These patients complained of abdominal pain (with or without nausea and vomiting); in some cases, there was no preceding facial angioedema and C-1 esterase activity was within normal limits. Intestinal angioedema was diagnosed by CT scan of the gastrointestinal tract or ultrasound, or during surgery; symptoms resolved after discontinuation of the ACE inhibitor. When conducting a differential diagnosis of abdominal pain in patients taking ACE inhibitors, the development of intestinal angioedema should be considered.

Patients who have a history of angioedema not associated with previous ACE inhibitor treatment may have an increased risk of its development during treatment with an ACE inhibitor.

In patients receiving ACE inhibitors during a desensitization course (e.g., to hymenoptera venom), life-threatening anaphylactic reactions may occur in very rare cases. This can be avoided by temporarily discontinuing the ACE inhibitor before starting each desensitization procedure.

The use of ACE inhibitors can lead to the development of cholestatic jaundice with progression up to fulminant hepatic necrosis, so lisinopril should be discontinued if liver transaminase activity increases and symptoms of cholestasis appear.

Anaphylactic reactions have also been observed in patients undergoing hemodialysis using high-flux membranes (e.g., AN69^®) and taking ACE inhibitors concomitantly. If hemodialysis is necessary, another type of membrane or another antihypertensive drug should be used.

A dry, prolonged cough has been observed with the use of ACE inhibitors, which disappeared after discontinuation of the ACE inhibitor. When making a differential diagnosis of cough, cough caused by the use of an ACE inhibitor must also be considered.

In patients whose condition requires extensive surgery or general anesthesia with drugs that cause arterial hypotension, lisinopril may block the formation of angiotensin II during compensatory release of renin. Excessive decrease in BP, which is considered a consequence of this mechanism, can be corrected by increasing the circulating blood volume. Before surgery (including dental surgery), the patient should inform the surgeon/anesthesiologist about the use of an ACE inhibitor.

Cases of hyperkalemia have been reported. Risk factors for the development of hyperkalemia include renal failure, diabetes mellitus and concomitant use of potassium-sparing diuretics (spironolactone, eplerenone (a derivative of spironolactone), triamterene and amiloride), potassium preparations or salt substitutes containing potassium, especially in patients with impaired renal function. If it is necessary to use lisinopril and the specified drugs concomitantly, precautions are recommended and serum potassium levels should be regularly monitored.

In patients with diabetes mellitus taking oral hypoglycemic drugs or receiving insulin, careful monitoring of plasma glucose concentration should be carried out during the first month of treatment with an ACE inhibitor.

It has been proven that concomitant use of angiotensin II receptor antagonists, ACE inhibitors or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). For this reason, the combined use of angiotensin II receptor antagonists, ACE inhibitors or aliskiren is not recommended. If the use of this therapy is necessary, specialist supervision, careful monitoring of renal function, BP and serum electrolyte levels is recommended. ACE inhibitors, angiotensin II receptor antagonists should not be used in patients with diabetic nephropathy.

In patients with severe autoimmune systemic connective tissue diseases (incl. SLE, scleroderma), lisinopril should be used with caution.

In elderly patients, the use of lisinopril in standard doses leads to a higher concentration of lisinopril in the blood, so special caution is required when determining the dose, although no differences in the antihypertensive effect of lisinopril in elderly and young patients have been identified.

Effect on the ability to drive vehicles and mechanisms

Due to the possible excessive decrease in BP, occurrence of dizziness, drowsiness and similar adverse reactions, caution should be exercised when performing potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

Amlodipine

Amlodipine can be used for the treatment of arterial hypertension together with thiazide diuretics, alpha-blockers, beta-blockers or ACE inhibitors. In patients with stable angina, amlodipine can be combined with other antianginal agents, for example, with long-acting or short-acting nitrates, beta-blockers.

Unlike other calcium channel blockers, no clinically significant interaction of amlodipine (third generation calcium channel blocker) with NSAIDs, incl. with indomethacin, was found.

In laboratory animals, cases of fatal ventricular fibrillation and collapse were noted against the background of verapamil use and IV administration of dantrolene, accompanied by hyperkalemia. Due to the risk of hyperkalemia, concomitant use of slow calcium channel blockers, incl. amlodipine, should be avoided in patients susceptible to malignant hyperthermia, as well as in the treatment of malignant hyperthermia.

Concomitant use of inducers of the CYP3A4 isoenzyme (e.g., rifampicin, St. John’s wort preparations) and amlodipine may lead to a decrease in the plasma concentration of amlodipine. Caution should be exercised when using this combination concomitantly with inducers of the CYP3A4 isoenzyme.

Potent inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole, itraconazole) may lead to an increase in the plasma concentration of amlodipine to a greater extent than diltiazem. Amlodipine and inhibitors of the CYP3A4 isoenzyme should be used with caution.

It is possible to enhance the antianginal and antihypertensive effects of calcium channel blockers when used concomitantly with thiazide and loop diuretics, ACE inhibitors, beta-blockers and nitrates, as well as to enhance their antihypertensive effect when used concomitantly with alpha-blockers, antipsychotics.

Although a negative inotropic effect was not usually observed in studies of amlodipine, nevertheless, some calcium channel blockers may enhance the severity of the negative inotropic effect of antiarrhythmic drugs that cause QT interval prolongation (e.g., amiodarone and quinidine).

Amlodipine can be used concomitantly with antibiotics and oral hypoglycemic agents.

Concomitant multiple use of amlodipine at a dose of 10 mg and simvastatin at a dose of 80 mg leads to an increase in simvastatin exposure by 77%. In such cases, the simvastatin dose should be limited to 20 mg.

Antiviral agents (ritonavir) increase the plasma concentrations of calcium channel blockers, incl. amlodipine.

Neuroleptics and isoflurane enhance the hypotensive effect of dihydropyridine derivatives.

Calcium preparations may reduce the effect of calcium channel blockers.

With the combined use of calcium channel blockers with lithium preparations, an increase in the manifestation of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) is possible.

Various studies of the interaction of amlodipine with cyclosporine in patients after kidney transplantation show that the use of this combination may not lead to any effect, or may increase the minimum concentration of cyclosporine to varying degrees up to 40%. These data should be taken into account and the concentration of cyclosporine should be monitored in this group of patients with simultaneous use of cyclosporine and amlodipine.

It is not recommended to use grapefruit juice and amlodipine simultaneously, because with genetic polymorphism of the CYP3A4 isoenzyme, an increase in the bioavailability of amlodipine and, as a result, an increase in the hypotensive effect is possible.

With simultaneous use of diltiazem at a dose of 180 mg and amlodipine at a dose of 5 mg in elderly patients (from 69 to 87 years) with arterial hypertension, an increase in the systemic exposure of amlodipine by 57% is noted. Simultaneous use of amlodipine and erythromycin in healthy volunteers (from 18 to 43 years) does not lead to significant changes in amlodipine exposure (increase in AUC by 22%). Although the clinical significance of these effects is not fully understood, they may be more pronounced in elderly patients.

With simultaneous use with baclofen, an increase in the antihypertensive effect is possible. Blood pressure and kidney function should be monitored, and if necessary, the dose of amlodipine should be adjusted.

With simultaneous use with glucocorticoids and tetracosactide, a decrease in the antihypertensive effect is possible (fluid and sodium ion retention as a result of the action of corticosteroids).

Tricyclic antidepressants/general anesthetics may enhance the antihypertensive effect and increase the risk of orthostatic hypotension.

Lisinopril

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

With simultaneous use with diuretics, an excessive decrease in blood pressure is possible.

Simultaneous use of lisinopril with beta-blockers, slow calcium channel blockers, diuretics, tricyclic antidepressants/neuroleptics enhances the severity of the antihypertensive effect.

Concomitant use of ACE inhibitors and hypoglycemic agents (insulins, oral hypoglycemic agents) may enhance their hypoglycemic effect up to the development of hypoglycemia. This effect is most likely to be observed during the first weeks of simultaneous therapy, as well as in patients with impaired renal function.

Sympathomimetics may reduce the hypotensive effect of ACE inhibitors; careful monitoring of the achievement of the desired effect is necessary.

With simultaneous use with NSAIDs (indomethacin, etc.), including acetylsalicylic acid ≥3 g/day, estrogens, as well as adrenomimetics – a decrease in the antihypertensive effect of lisinopril.

With simultaneous use with lithium preparations – slowing down the excretion of lithium from the body.

Simultaneous use with antacids and cholestyramine slows down absorption from the gastrointestinal tract.

Ethanol enhances the effect of lisinopril.

Dual blockade of the RAAS through simultaneous use of angiotensin II receptor antagonists, ACE inhibitors or aliskiren is associated with an increased incidence of arterial hypotension, hyperkalemia and impaired renal function (including renal failure) compared with the use of a single drug acting on the RAAS.

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

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

Simultaneous use of lisinopril with acetylsalicylic acid as an antiplatelet agent, thrombolytics, beta-blockers and/or nitrates is not contraindicated.

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

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

Simultaneous use of muscle relaxants with ACE inhibitors may lead to a pronounced decrease in blood pressure.

With simultaneous use with co-trimoxazole (sulfamethoxazole and trimethoprim), the risk of hyperkalemia increases.

With simultaneous use with SSRIs (escitalopram, paroxetine, fluoxetine, sertraline), severe hyponatremia may develop.

Simultaneous use of estramustine, mTOR inhibitors (sirolimus, everolimus, temsirolimus), neutral endopeptidase inhibitors (omapatrilat, ilepatril, daglutril, sacubitril) with ACE inhibitors is accompanied by an increased risk of angioedema.

Linagliptin, saxagliptin, sitagliptin, vildagliptin, when used concomitantly with ACE inhibitors, increase the risk of angioedema due to suppression of dipeptidyl peptidase-4 (DPP-IV) activity by the gliptin.

With simultaneous use of racecadotril (an enkephalinase inhibitor used to treat acute diarrhea) with ACE inhibitors, the risk of angioedema may increase.

Tissue plasminogen activators (alteplase, reteplase, tenecteplase) increase the risk of angioedema when used concomitantly with ACE inhibitors.

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.