Ekvator^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter, Plc. (Hungary)

Or

Gedeon Richter-Rus, JSC (Russia)

Packaging and Quality Control Release

GEDEON RICHTER, Plc. (Hungary)

Or

GEDEON RICHTER-RUS, JSC (Russia)

Contact Information

GEDEON RICHTER, Plc. (Hungary)

ATC Code

C09BB03 (Lisinopril and Amlodipine)

Active Substances

Amlodipine (Rec.INN registered by WHO)

Lisinopril (Rec.INN registered by WHO)

Dosage Forms

	Ekvator®	Tablets 5 mg+10 mg: 30 pcs.
		Tablets 5 mg+20 mg: 30 pcs.
		Tablets 10 mg+20 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat with a bevel, with a score on one side and with an engraving “A+L” on the other; the break line (score) is intended only for breaking to facilitate swallowing, and not for dividing into equal doses.

Excipients: magnesium stearate, sodium carboxymethyl starch (type A), microcrystalline cellulose (type 101), microcrystalline cellulose (type 12).

10 pcs. – blisters (3) – cardboard packs.

Tablets white or almost white, round, biconvex, with an engraving “CF2” on one side.

Excipients: magnesium stearate, sodium carboxymethyl starch (type A), microcrystalline cellulose (type 101), microcrystalline cellulose (type 12).

10 pcs. – blisters (3) – cardboard packs.

Tablets white or almost white, round, biconvex; with an engraving “CF3” on one side.

Excipients: magnesium stearate, sodium carboxymethyl starch (type A), microcrystalline cellulose (type 101), microcrystalline cellulose (type 12).

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; ACE inhibitors in combination with other agents; ACE inhibitors in combination with calcium channel blockers

Pharmacological Action

Ekvator^® is a combined drug containing active substances – Amlodipine and Lisinopril.

Amlodipine

A dihydropyridine derivative – a slow calcium channel blocker (CCB), reduces the transmembrane transition of calcium ions into the cell (to a greater extent in vascular smooth muscle cells than in cardiomyocytes).

It has a long-term dose-dependent antihypertensive effect. The antihypertensive effect is due to a direct vasodilating effect on vascular smooth muscles. In arterial hypertension, a single dose provides a clinically significant reduction in BP for 24 hours (in the patient’s “lying” and “standing” position). Orthostatic hypotension when using amlodipine is quite rare.

Amlodipine does not cause a decrease in exercise tolerance or left ventricular ejection fraction. It reduces the degree of left ventricular myocardial hypertrophy. It does not affect myocardial contractility and conductivity, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases the 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 and can be used in the therapy of patients with bronchial asthma, diabetes mellitus and gout. A significant decrease in BP is observed after 6-10 hours, the duration of the effect is 24 hours.

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

Lisinopril

Lisinopril is an ACE inhibitor that prevents the conversion of angiotensin I to angiotensin II. The decrease in angiotensin II content leads to a direct reduction in aldosterone secretion. Lisinopril reduces the degradation of bradykinin and increases the synthesis of prostaglandins. It reduces systemic vascular resistance, BP, preload and pulmonary capillary pressure. Lisinopril provides a more pronounced dilation of arteries than veins. Some effects of lisinopril are mediated by its influence on the tissue renin-angiotensin system. Its long-term use leads to a reduction in myocardial hypertrophy and the walls of resistive arteries.

Lisinopril improves myocardial blood supply in ischemia. The effect occurs within 1 hour after oral administration of lisinopril. The maximum effect develops within 6-7 hours; the duration of the effect persists for 24 hours. In patients with arterial hypertension, the effect is noted within the first days after the start of treatment; a stable effect is achieved within 1-2 months of treatment. No cases of a significant increase in BP were noted upon abrupt withdrawal of lisinopril. Lisinopril provides both a reduction in BP and a decrease in albuminuria. In patients with hyperglycemia, Lisinopril promotes the restoration of the function of the damaged glomerular endothelium. In patients with diabetes mellitus, Lisinopril does not affect blood glucose concentration; the use of lisinopril does not lead to an increase in the frequency of hypoglycemia cases.

Ekvator^®

The combined drug containing Amlodipine and Lisinopril makes it possible to prevent the development of possible side effects caused by one of the active substances. For example, a slow calcium channel blocker, by causing dilation of arterioles, can lead to sodium and fluid retention in the body, which, in turn, can lead to activation of the renin-angiotensin-aldosterone system. The ACE inhibitor blocks this process and normalizes the response to salt load.

Pharmacokinetics

Amlodipine

Absorption

After oral administration, Amlodipine is well absorbed from the gastrointestinal tract. The average absolute bioavailability of amlodipine is 64-80%. C_max in blood serum is observed after 6-12 hours. Food intake does not affect the absorption of amlodipine.

Distribution

Most of the amlodipine in the blood (97.5%) is bound to plasma proteins. C_ss is achieved after 7-8 days of therapy. The average V_d is 21 L/kg of body weight, which indicates that most of the amlodipine is in the tissues, and a smaller part is in the blood. Amlodipine penetrates the blood-brain barrier.

Metabolism and excretion

Amlodipine undergoes slow but active metabolism in the liver in the absence of a significant first-pass effect. Metabolites do not have significant pharmacological activity. T_1/2 from plasma varies from 35 to 50 hours, which allows taking the drug once a day. T_1/2 upon repeated administration is approximately 45 hours. About 60% of the orally administered dose is excreted by the kidneys mainly in the form of metabolites, 10% – unchanged, and 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 from blood plasma by hemodialysis.

Pharmacokinetics in specific patient groups

Elderly patients (over 65 years old) In elderly patients (over 65 years old), the excretion of amlodipine is slowed down (T_1/2 – 65 hours) compared to young patients, but this difference has no clinical significance.

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

Patients with renal insufficiency Renal insufficiency does not significantly affect the kinetics of amlodipine.

Lisinopril

Absorption

When lisinopril is taken orally, 25% of the active substance is absorbed in the gastrointestinal tract. The absorption of lisinopril does not depend on food intake. The average absorption level is 30%, bioavailability is 29%.

Distribution

C_max in blood plasma is reached within 6-8 hours after oral administration. Lisinopril is poorly bound to plasma proteins and poorly penetrates the blood-brain barrier.

Metabolism

Lisinopril does not undergo biotransformation in the body.

Excretion

T_1/2 is 12 hours.

Pharmacokinetics in specific patient groups

In patients with CHF, the absorption and clearance of lisinopril are reduced. In this category of patients, the absolute bioavailability of lisinopril decreases by approximately 16%, but AUC increases by an average of 125% compared to healthy volunteers.

Patients with renal insufficiency. Impaired renal function leads to an increase in AUC and T_1/2 of lisinopril, but these changes become clinically significant only when GFR decreases below 30 ml/min/1.73 m².

In mild and moderate renal insufficiency (CC from 30 to 80 ml/min), the mean AUC value increases by 13%, while in severe renal insufficiency (CC from 5 to 30 ml/min), an increase in the mean AUC value by 4.5 times is observed.

Patients with hepatic insufficiency. In patients with liver cirrhosis, the absorption of lisinopril is reduced (by approximately 30%), but the exposure to the drug increases (by approximately 50%) compared to healthy volunteers due to reduced clearance.

Elderly patients (over 65 years old). In elderly patients, the plasma concentration of lisinopril and AUC are 2 times higher than in young patients.

Ekvator^®

Interaction between the active substances of the drug Ekvator^® is unlikely. The values of AUC, C_max, time to reach C_max, as well as T_1/2, do not undergo changes 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 taking the drug once a day.

Indications

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

The drug Ekvator^® is indicated as a replacement therapy in adult patients with adequate BP control while taking amlodipine and lisinopril simultaneously in the specified doses.

ICD codes

Dosage Regimen

Orally, regardless of food intake, daily, at the same time, with a sufficient amount of water.

The drug Ekvator^® is indicated only for those patients for whom the selected optimal maintenance doses of amlodipine and lisinopril are

• For the drug Ekvator^® tablets 5 mg + 10 mg – 5 mg of amlodipine and 10 mg of lisinopril,
• For the drug Ekvator^® tablets 5 mg + 20 mg – 5 mg of amlodipine and 20 mg of lisinopril,
• For the drug Ekvator^® tablets 10 mg + 20 mg – 10 mg of amlodipine and 20 mg of lisinopril.

If dose adjustment is necessary, the advisability of selecting the dose of individual components can be considered.

The recommended dose of the drug Ekvator^® is 1 tablet.

The maximum daily dose of the drug Ekvator^® is 1 tablet.

The maximum daily doses of active substances in monotherapy: amlodipine – 10 mg, lisinopril – 40 mg.

In case of development of arterial hypotension at the beginning of therapy with the drug Ekvator^® in case of development of arterial hypotension, the patient should lie on their back, suspend taking the drug and consult a doctor. Transient arterial hypotension usually does not require discontinuation of the drug, but the need to reduce the dose should be assessed. If dose selection is necessary, the drugs Amlodipine and Lisinopril should be used separately.

Missed dose

If a dose is missed, the patient should continue regular intake according to the recommended regimen, i.e., take the tablet at the next scheduled intake. A double dose of the drug should not be taken to compensate for a missed dose.

Special patient groups

Elderly patients (over 65 years old)

Treatment of elderly patients should be carried out with caution. Clinical studies have not revealed age-related changes in the efficacy or safety profile of amlodipine and lisinopril. To determine the optimal maintenance dose, it is necessary to determine the dosing regimen individually, using Lisinopril and Amlodipine separately.

Patients with impaired renal function

To determine the optimal initial and maintenance dose for patients with renal insufficiency, it is necessary to titrate the doses and determine the dosing regimen individually, using Lisinopril and Amlodipine separately. During therapy with the drug Ekvator^®, renal function, as well as the content of potassium and sodium in the blood serum, should be monitored. In case of deterioration of renal function, the drug Ekvator^® should be discontinued and therapy with correctly selected doses of individual components should be prescribed.

Patients with impaired hepatic function

Delayed excretion of amlodipine is possible in patients with impaired liver function. Clear recommendations regarding the dose of the drug Ekvator^® in such cases have not been established, so the drug should be prescribed with caution to patients with impaired liver function. To determine the optimal initial and maintenance dose for patients with hepatic insufficiency, it is necessary to titrate the doses and determine the dosing regimen individually, using Lisinopril and Amlodipine separately. Treatment should be started with lower doses, with caution.

Children and adolescents (under 18 years old). The safety and efficacy of the drug Ekvator^® in children and adolescents have not been established. Data are not available.

Adverse Reactions

The frequency of adverse reactions in patients taking the combined drug did not exceed that in patients receiving one of the active substances. Adverse reactions corresponded to data previously obtained for amlodipine and/or lisinopril. Adverse reactions were mild, transient and rarely required discontinuation of therapy. The most frequent adverse reactions when using the combined drug were headache (8%), cough (5%) and dizziness (3%).

The frequency of adverse reactions is given separately for lisinopril and amlodipine. Below are the adverse drug reactions (ADRs) registered during separate use of amlodipine and lisinopril.

Definition of the frequency of adverse reactions: very common – 1/10 cases (≥10%), common – 1/100 cases (≥1% and <10%), uncommon – 1/1000 cases (≥0.1% and <1%), rare – 1/10,000 cases (≥0.01% and <0.1%), very rare – less than 1/10,000 cases (<0.01%), frequency unknown – frequency could not be established based on available data.

In each group, adverse reactions are presented in descending order of their severity.

* A symptom complex has been reported which may include one or more of the following symptoms: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibody (ANA) test, increased ESR, eosinophilia and leukocytosis, skin rash, photosensitivity or other skin changes.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product in order to ensure continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to lisinopril or any other ACE inhibitor;
• Hypersensitivity to amlodipine or any other dihydropyridine derivative;
• Hypersensitivity to any of the excipients;
• History of angioedema, including that associated 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;
• Unstable hemodynamic parameters in acute myocardial infarction (and within 1 month after it);
• 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 body surface area);
• Concomitant use with angiotensin II receptor antagonists (ARAs) in patients with diabetic nephropathy;
• Concomitant use with sacubitril/valsartan (administration of Ekvator^® should not be started earlier than 36 hours after the last dose of sacubitril/valsartan);
• Pregnancy;
• Breastfeeding period;
• Children under 18 years of age (efficacy and safety have not been established).

With caution

Aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, arterial hypotension, cerebrovascular diseases (including cerebral circulatory insufficiency), coronary artery disease, chronic heart failure of non-ischemic origin FC III-IV, Prinzmetal’s angina, sick sinus syndrome (severe tachycardia or bradycardia), severe autoimmune systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), use of potassium-sparing diuretics, potassium preparations and potassium-based salt substitutes, hyperkalemia, hyponatremia, myelosuppression, diabetes mellitus, bilateral renal artery stenosis, renal artery stenosis in patients with a single kidney, renovascular hypertension, status after kidney transplantation, renal failure, azotemia, hemodialysis using high-permeability membranes, primary hyperaldosteronism, salt-restricted diet, conditions associated with reduced circulating blood volume (including vomiting and diarrhea), elderly age, hepatic failure, concomitant use with inhibitors or inducers of the CYP3A4 isoenzyme, concomitant use with drugs containing aliskiren, or angiotensin II receptor antagonists (increased risk of arterial hypotension, hyperkalemia and renal failure with dual blockade of the RAAS), immunosuppressive therapy, concomitant use with allopurinol or procainamide, or a combination of these complicating factors (risk of neutropenia and agranulocytosis), concomitant use with lithium preparations, burdened allergic history, concomitant desensitization with hymenoptera venom allergen, concomitant LDL apheresis procedure using dextran sulfate, gout, hyperuricemia, use during major surgical interventions or during general anesthesia, in patients of the Black race.

Use in Pregnancy and Lactation

Pregnancy

The use of Ekvator^® is contraindicated during pregnancy.

There are no data on the use of Ekvator^® in pregnant women from adequate controlled clinical studies. If pregnancy is detected, treatment with Ekvator^® should be discontinued immediately. Women planning a pregnancy should consult a doctor to prescribe antihypertensive therapy with an established safety profile during pregnancy.

Amlodipine

The safety of amlodipine use during pregnancy has not been established. In preclinical studies, fetotoxic and embryotoxic effects of amlodipine were not identified. In rats, Amlodipine increased the duration of the gestational period and labor. Some other calcium channel blockers have teratogenic effects.

Lisinopril

The use of ACE inhibitors in the second and third trimesters of pregnancy can lead to fetal and neonatal death. Careful monitoring of newborns and infants exposed to ACE inhibitors in utero is recommended for the timely detection of a significant decrease in blood pressure, oliguria and hyperkalemia. The occurrence of oligohydramnios, hypoplasia of the facial bones, deformation of the facial and skull bones, pulmonary hypoplasia and abnormalities in the development of the kidneys in the child is possible.

Women of childbearing potential should use effective methods of contraception during treatment with lisinopril.

Lisinopril can cross the placental barrier. Treatment with lisinopril should not be started during pregnancy. Women planning a pregnancy should consult a doctor to prescribe antihypertensive therapy with an established safety profile during pregnancy.

Breastfeeding period

The use of Ekvator^® during breastfeeding is contraindicated.

Amlodipine

Experience with the drug shows that Amlodipine is excreted in breast milk. The average milk/plasma ratio for amlodipine concentration was 0.85 among 31 lactating women who had pregnancy-induced hypertension and received Amlodipine at an initial dosage of 5 mg/day. The drug dose was adjusted if necessary (depending on the average daily dose and weight: 6 mg and 98.7 mcg/kg, respectively). The estimated daily dose of amlodipine received by the infant through breast milk is 4.17 mcg/kg.

The use of amlodipine during breastfeeding is contraindicated. If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Lisinopril

There are no data on the penetration of lisinopril into breast milk.

Use in Hepatic Impairment

The drug should be used with caution in hepatic failure.

Use in Renal Impairment

The drug should be used with caution in bilateral renal artery stenosis, renal artery stenosis in patients with a single kidney, status after kidney transplantation, renal failure.

Pediatric Use

Contraindication: children and adolescents under 18 years of age (efficacy and safety of the drug in this age group have not been established).

Geriatric Use

The drug should be used with caution in elderly patients.

Special Precautions

Ekvator^® should not be used to relieve a hypertensive crisis.

When admitted to the hospital, the patient must inform the doctor about taking Ekvator^®.

When using Ekvator^®, the warnings regarding its individual components listed below should be taken into account.

Related to 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 may increase and the clearance of the drug may decrease. Dose adjustment is not required, but more careful monitoring of patients in this category is necessary.

The efficacy and safety of amlodipine use in hypertensive crisis have not been established.

Withdrawal syndrome

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. Amlodipine does not prevent the development of withdrawal syndrome upon abrupt discontinuation of beta-blockers.

Cardiovascular diseases

In rare cases, in patients with coronary artery disease (especially with severe obstructive coronary artery disease), an increase in the frequency, duration and/or severity of angina attacks was noted after starting calcium channel blockers or after increasing their dose.

During the use of amlodipine in patients with chronic heart failure class III and IV by NYHA of non-ischemic origin, an increase in the frequency of pulmonary edema was noted, despite the absence of signs of worsening heart failure.

Peripheral edema

Mild or moderate peripheral edema was the most frequent adverse event of amlodipine in clinical studies. The incidence of peripheral edema increases with increasing amlodipine dose. Peripheral edema associated with the use of amlodipine should be carefully differentiated from the symptoms of progressive left ventricular heart failure.

Effect on fertility

In some patients receiving calcium channel blockers, reversible biochemical changes in the sperm head were found, 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.

Related to lisinopril

Symptomatic arterial hypotension

A significant decrease in blood pressure most often occurs with a decrease in circulating blood volume caused by the use of diuretics, a decrease in the amount of salt in the diet, dialysis, diarrhea or vomiting (see “Drug Interactions”, “Adverse Reactions”). In patients with chronic heart failure, with or without renal impairment, symptomatic arterial hypotension may develop. It develops more often in patients with severe heart failure, which is associated with the use of high doses of diuretics, hyponatremia or impaired renal function. Such patients require careful medical supervision (with careful selection of doses of lisinopril and diuretics). The same recommendations apply to patients with coronary artery disease and cerebrovascular insufficiency, when a rapid decrease in blood pressure can lead to the development of myocardial infarction or stroke.

Patients with a marked decrease in blood pressure should be placed in a horizontal position; if necessary, an infusion of 0.9% sodium chloride solution is performed. Transient arterial hypotension is not a contraindication to taking the next dose of lisinopril.

In patients with chronic heart failure with normal or low blood pressure, the use of lisinopril may lead to a decrease in blood pressure; as a rule, this does not require discontinuation of treatment. If arterial hypotension becomes symptomatic, the indications for reducing the dose of lisinopril or discontinuing it should be assessed.

In patients at risk of developing symptomatic arterial hypotension (patients on a salt-free diet or a diet low in salt) with or without hyponatremia, as well as in patients receiving high doses of diuretics, these deviations (loss of water and salts) must be compensated before starting treatment.

The effect of the starting dose of lisinopril on blood pressure should be monitored.

Acute myocardial infarction

The use of Ekvator^® in patients with acute myocardial infarction is not recommended due to insufficient clinical experience.

Renal failure

In patients with chronic heart failure, a significant decrease in blood pressure that occurs after the start of therapy with ACE inhibitors can lead to worsening of renal function. Cases of acute renal failure have been reported.

In patients with bilateral renal artery stenosis or stenosis of the renal artery of a single kidney, cases of increased serum urea and creatinine concentrations associated with the use of ACE inhibitors have been reported; as a rule, these disorders were transient and ceased after discontinuation of lisinopril. They occurred more often in patients with renal failure.

Kidney Transplantation

There is no experience with the use of lisinopril in patients who have recently undergone kidney transplantation.

Hypersensitivity, Angioedema

Rare cases of angioedema of the face, extremities, lips, tongue, epiglottis, and/or larynx have been reported in patients treated with ACE inhibitors, including Lisinopril, which could occur at any time during treatment. In such cases, Lisinopril should be discontinued immediately; patients should be monitored until symptoms have completely resolved. Cases of angioedema of the face and lips are usually transient and do not require any treatment; antihistamines may be prescribed.

Angioedema of the larynx can be fatal. Angioedema of the tongue, epiglottis, or larynx may lead to secondary airway obstruction, so appropriate therapy should be initiated immediately (0.3-0.5 ml of a 1:1000 solution of epinephrine (adrenaline) subcutaneously) and/or measures should be taken to ensure airway patency.

In rare cases, intestinal angioedema has developed during therapy with ACE inhibitors. In these cases, patients experienced abdominal pain as an isolated symptom or in combination with nausea or vomiting, in some instances, without preceding facial angioedema and with normal C1-esterase levels. The diagnosis was made using abdominal CT, ultrasound, or at the time of surgery. Symptoms resolved after discontinuation of ACE inhibitors. Therefore, the possibility of intestinal angioedema should be considered in the differential diagnosis of patients receiving ACE inhibitors who present with abdominal pain.

In patients with a history of angioedema not related to ACE inhibitor use, the use of ACE inhibitors may be associated with a higher risk of developing angioedema (see “Contraindications”).

Anaphylactic Reactions Associated with Hymenoptera Venom Desensitization

There are reports of very rare, life-threatening anaphylactic reactions that developed in patients taking ACE inhibitors during desensitization with hymenoptera venom. To prevent such cases, ACE inhibitors should be temporarily discontinued prior to desensitization.

Hemodialysis

Anaphylactic reactions have also been reported in patients undergoing hemodialysis using high-flux membranes (e.g., AN69) who were simultaneously prescribed ACE inhibitors. In such patients, the possibility of using other dialysis membranes or other antihypertensive drugs should be considered.

Cough

The use of ACE inhibitors may be associated with a cough. A persistent dry cough usually disappears after discontinuation of the ACE inhibitor. The possibility of a cough associated with the use of ACE inhibitors should be considered in the differential diagnosis.

Surgery/General Anesthesia

The use of blood pressure-lowering drugs during major surgery or general anesthesia may lead to suppression of angiotensin II formation in response to compensatory renin secretion. A significant decrease in blood pressure, considered a result of this effect, can be controlled by reducing circulating blood volume.

Patients taking ACE inhibitors should inform their surgeon/anesthesiologist before undergoing surgery (including dental procedures).

Serum Potassium Levels

Cases of hyperkalemia have been reported. Risk factors for hyperkalemia include renal failure, diabetes mellitus, and the concomitant use of potassium-sparing diuretics (spironolactone, triamterene, as well as amiloride), as well as potassium supplements and potassium-based salt substitutes, especially in patients with impaired renal function.

If concomitant use of lisinopril and the aforementioned drugs is necessary, caution should be exercised and serum potassium levels should be regularly monitored.

Dual Blockade of the RAAS

Concomitant administration of ACE inhibitors, angiotensin II receptor blockers, or aliskiren has been shown to increase the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, the use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren for dual blockade of the RAAS is not recommended.

If there is an absolute indication for dual blockade of the RAAS, it should be carried out under the close supervision of a specialist with frequent monitoring of blood pressure, renal function, and electrolyte levels.

Concomitant use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Concomitant use of ACE inhibitors with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Neutropenia/Agranulocytosis/Thrombocytopenia/Anemia

Neutropenia/agranulocytosis, thrombocytopenia, and anemia may occur during treatment with ACE inhibitors. In patients with normal renal function and in the absence of other complicating factors, neutropenia is rare. Neutropenia and agranulocytosis are reversible and disappear after discontinuation of the ACE inhibitor.

Ekvator^® should be prescribed with particular caution to patients with systemic connective tissue diseases, those taking immunosuppressants, allopurinol, or procainamide, or with a combination of these risk factors, especially patients with impaired renal function. Some patients have developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing Ekvator^® to such patients, it is recommended to periodically monitor the white blood cell count. Patients should report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

Mitral Stenosis/Aortic Stenosis/Hypertrophic Cardiomyopathy

ACE inhibitors should be used with caution in patients with mitral stenosis, as well as in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic cardiomyopathy).

Hepatic Failure

Very rarely, cholestatic jaundice has occurred during treatment with ACE inhibitors. With the progression of this syndrome, fulminant liver necrosis develops, sometimes with a fatal outcome. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in liver enzyme activity occurs during treatment with ACE inhibitors, Ekvator^® should be discontinued and the patient should be carefully monitored.

Diabetes Mellitus

When using lisinopril in patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentrations should be regularly monitored during the first month of therapy.

Elderly Age

In elderly patients, the use of 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 between elderly and young patients have been identified.

Ethnic Differences

Patients of Black race develop angioedema more frequently than patients of other races when taking ACE inhibitors. ACE inhibitors may have a less pronounced antihypertensive effect in patients of Black race compared to patients of other races. This difference may be due to the fact that Black patients with arterial hypertension more often have low renin activity.

Effect on the Ability to Drive and Operate Machinery

There are no data on the effect on the ability to drive and operate machinery. Due to the possibility of excessive blood pressure reduction, dizziness, drowsiness, and other side effects at the beginning of treatment, patients should refrain from driving cars and other vehicles, operating machinery, and performing other work that requires concentration.

Overdose

Amlodipine

Symptoms: marked decrease in blood pressure with possible development of reflex tachycardia and excessive peripheral vasodilation (risk of severe and persistent arterial hypotension, including the development of shock and death).

Treatment: gastric lavage, administration of activated charcoal (especially within the first 2 hours after overdose), maintenance of cardiovascular function, elevation of the lower extremities, monitoring of heart and lung function, control of circulating blood volume and diuresis. To restore vascular tone – use of vasoconstrictors (in the absence of contraindications to their use); to eliminate the effects of calcium channel blockade – intravenous administration of calcium gluconate. Hemodialysis is not effective.

Lisinopril

Symptoms: marked decrease in blood pressure, dry mouth, drowsiness, urinary retention, constipation, anxiety, irritability.

Treatment: symptomatic therapy, infusion of 0.9% sodium chloride solution and vasopressors (if possible), blood pressure control, maintenance of water and electrolyte balance. Hemodialysis may be performed (see section “Special Instructions” – Hemodialysis).

Drug Interactions

Amlodipine

Contraindicated Drug Combinations

Dantrolene (intravenous administration)

Cases of fatal ventricular fibrillation and collapse have been observed in laboratory animals with the use of verapamil and intravenous dantrolene, accompanied by hyperkalemia. Due to the risk of hyperkalemia, concomitant use of slow calcium channel blockers, including amlodipine, should be avoided in patients susceptible to malignant hyperthermia, as well as during the treatment of malignant hyperthermia.

Not Recommended Drug Combinations

Grapefruit Juice

Concomitant administration of amlodipine with grapefruit or grapefruit juice is not recommended, as it may increase the bioavailability of amlodipine in some patients, leading to an enhanced blood pressure-lowering effect.

Drug Combinations Requiring Special Caution

Inducers of CYP3A4 Isoenzyme

When used concomitantly with known inducers of CYP3A4, the plasma concentration of amlodipine may fluctuate. For this reason, both blood pressure monitoring and dose adjustment of the drug should be performed during and after concomitant use, especially with potent inducers of CYP3A4 (e.g., rifampicin, preparations of St. John’s wort (Hypericum perforatum)).

Inhibitors of CYP3A4 Isoenzyme

Concomitant administration of amlodipine and strong or moderate CYP3A4 inhibitors (protease inhibitors, e.g., ritonavir, azole antifungals, macrolides, e.g., erythromycin or clarithromycin, verapamil or diltiazem) may lead to a significant increase in amlodipine concentration. The clinical manifestations of these pharmacokinetic deviations may be more pronounced in elderly patients. Therefore, monitoring of clinical status and adjustment of the dose of Ekvator^® may be required.

Drug Combinations Requiring Caution

Simvastatin

Multiple administration of amlodipine 10 mg in combination with simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin monotherapy. Therefore, patients receiving Amlodipine should take simvastatin at a daily dose not exceeding 20 mg.

Calcium Supplements

May reduce the effect of calcium channel blockers.

Lithium Preparations

When calcium channel blockers are used concomitantly with lithium preparations (no data for amlodipine), an increase in their neurotoxicity manifestations (nausea, vomiting, diarrhea, ataxia, tremor, or tinnitus) is possible.

Baclofen

Enhancement of the antihypertensive effect. Blood pressure and renal function should be monitored, and the dose of amlodipine should be adjusted if necessary.

Amifostine

Enhancement of the antihypertensive effect of amlodipine is possible.

Glucocorticoids

Reduction of the antihypertensive effect (fluid and sodium retention due to the action of corticosteroids).

Tricyclic Antidepressants, Antipsychotics

There is an increased risk of orthostatic hypotension and enhancement of the antihypertensive effect (additive effect).

Tacrolimus

When used concomitantly with amlodipine, there is a risk of increased plasma concentration of tacrolimus. To avoid tacrolimus toxicity when used concomitantly with amlodipine, plasma concentration of tacrolimus should be monitored in patients and the dose of tacrolimus should be adjusted if necessary.

Tasonermin

Concomitant use of Amlodipine may increase the systemic exposure of tasonermin in plasma. In such cases, regular monitoring of tasonermin in the blood and dose adjustment if necessary is required.

Interaction of Amlodipine with Other Drugs

For the treatment of arterial hypertension, Amlodipine can be safely used with thiazide diuretics, alpha-blockers, beta-blockers, and ACE inhibitors. In patients with stable angina, simultaneous use of amlodipine with other antianginal drugs, such as long-acting and short-acting nitrates, beta-blockers, is possible.

Enhancement of the antianginal and antihypertensive effects of calcium channel blockers is likely when used concomitantly with thiazide and “loop” diuretics, ACE inhibitors, beta-blockers, and nitrates, as well as enhancement of their antihypertensive effect when co-administered with alpha₁-blockers and antipsychotics.

Amlodipine does not cause a negative inotropic effect. Nevertheless, some calcium channel blockers may increase the severity of the negative inotropic effect of antiarrhythmic drugs that cause QT interval prolongation (e.g., amiodarone and quinidine).

Unlike other calcium channel blockers, no significant interaction has been identified between amlodipine (3rd generation calcium channel blocker) and NSAIDs, including indomethacin.

It is safe to prescribe Amlodipine with oral hypoglycemic drugs.

A single dose of sildenafil 100 mg in patients with essential arterial hypertension did not affect the pharmacokinetics of amlodipine.

Concomitant multiple administration of amlodipine 10 mg and atorvastatin 80 mg resulted in no significant change in the pharmacokinetic parameters of atorvastatin at steady state.

Ethanol (beverages containing alcohol) Amlodipine does not have a significant effect on the pharmacokinetics of ethanol with single and multiple administration at a dose of 10 mg.

Interaction studies of cyclosporine and amlodipine have not been conducted in healthy volunteers and in special patient groups, except for patients after kidney transplantation. Various studies of the interaction between amlodipine and cyclosporine in patients after kidney transplantation show that the use of this combination may not have any effect, or may increase the minimum concentration of cyclosporine to varying degrees up to 40%. Cyclosporine concentration should be monitored in patients after kidney transplantation.

With concomitant use of amlodipine and digoxin, renal clearance and serum digoxin concentration do not change.

When warfarin is used concomitantly with amlodipine, prothrombin time does not change.

When used concomitantly with cimetidine, the pharmacokinetics of amlodipine do not change.

Amlodipine does not affect the degree of binding of digoxin, phenytoin, warfarin, and indomethacin to plasma proteins in vitro.

Aluminum and magnesium-containing antacids a single dose of such antacids together with amlodipine does not have a significant effect on the pharmacokinetics of amlodipine.

mTOR inhibitors (mammalian Target of Rapamycin): mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus) are substrates of CYP3A4. Since Amlodipine is a weak inhibitor of CYP3A4, concomitant use may increase the exposure of mTOR inhibitors.

Lisinopril

Contraindicated Drug Combinations

Aliskiren

Concomitant use of ACE inhibitors with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) is contraindicated.

The use of ACE inhibitors with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy.

Not Recommended Drug Combinations

Angiotensin II Receptor Antagonists (ARBs)

The literature has reported that in patients with established atherosclerotic disease, chronic heart failure, or diabetes mellitus with target organ damage, concomitant therapy with an ACE inhibitor and an ARB is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening of renal function (including acute renal failure) compared to the use of only one drug affecting the RAAS. Dual blockade (e.g., combination of an ACE inhibitor with an ARB) should be limited to individual cases with careful monitoring of renal function, potassium levels, and blood pressure.

Potassium Supplements, Potassium-Sparing Diuretics (spironolactone, triamterene, amiloride, eplerenone) or Potassium-Containing Salt Substitutes

Hyperkalemia (potentially fatal) may develop, especially in cases of impaired renal function (additional effects associated with hyperkalemia). ACE inhibitors should not be used concomitantly with substances that increase plasma potassium levels, except in cases of hypokalemia. The combination of lisinopril and the aforementioned agents is not recommended. If, nevertheless, concomitant use is indicated, they should be used with caution and with regular monitoring of serum potassium levels.

Lithium Preparations

When lithium preparations and ACE inhibitors are used concomitantly, a reversible increase in serum lithium concentration and associated toxic effects may be observed. Concomitant use of lisinopril and lithium preparations is not recommended. If such therapy is necessary, regular monitoring of serum lithium concentration should be performed.

Drug Combinations Requiring Special Caution

Insulin and Oral Hypoglycemic Agents

Epidemiological studies have shown that the 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 concomitant therapy, as well as in patients with impaired renal function.

Baclofen

It enhances the antihypertensive effect of ACE inhibitors. Blood pressure levels should be carefully monitored and, if necessary, the dose of antihypertensive drugs should be adjusted.

Diuretics

In patients taking diuretics, especially those that remove fluid and/or salts, a significant decrease in blood pressure may be observed at the beginning of therapy with an ACE inhibitor. The risk of developing antihypertensive effects can be reduced by discontinuing the diuretic, replenishing fluid or salt loss before starting ACE inhibitor therapy. For arterial hypertension in patients with prior diuretic therapy, which could have led to excessive fluid and/or salt excretion, diuretics should be discontinued before starting the drug Ekvator^®.
Renal function (creatinine concentration) should be monitored during the first weeks of using the drug Ekvator^®.

NSAIDs, including acetylsalicylic acid at a dose of ≥3 g/day

Concomitant use of ACE inhibitors with NSAIDs (acetylsalicylic acid at a dose exerting an anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) may lead to a decrease in the antihypertensive effect of ACE inhibitors. Concomitant use of ACE inhibitor drugs and NSAIDs may lead to deterioration of renal function, including the development of acute renal failure and an increase in serum potassium levels, especially in patients with reduced renal function. Caution should be exercised when prescribing this combination, especially in elderly patients. Patients need to compensate for fluid loss and carefully monitor renal function, both at the beginning of treatment and during the treatment process.

Estramustine, mTOR inhibitors (sirolimus, everolimus, temsirolimus), neutral endopeptidase inhibitors (omapatrilat, ilepatril, daglutril, sacubitril), valsartan

Concomitant use with ACE inhibitors is associated with an increased risk of angioedema.

DPP-4 inhibitors (gliptins)

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

Neutral endopeptidase (NEP) inhibitors

An increased risk of angioedema has been reported with the concomitant use of ACE inhibitors and racecadotril (an enkephalinase inhibitor).

When ACE inhibitors are used concomitantly with medicinal products containing sacubitril (a neprilysin inhibitor), the risk of developing angioedema increases, therefore the concomitant use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril. Prescription of drugs containing sacubitril is contraindicated in patients receiving ACE inhibitors, as well as within 36 hours after discontinuation of ACE inhibitors.

Drug combinations requiring caution during use

Other antihypertensive agents (e.g., beta-blockers, slow calcium channel blockers, diuretics) and vasodilators

Enhancement of the antihypertensive effect of the drug is possible. Caution should be exercised when co-administering with nitroglycerin, other nitrates or other vasodilators, as this may lead to an additional decrease in blood pressure.

Antacids and cholestyramine

Concomitant use with antacids and cholestyramine leads to suppression of gastrointestinal absorption.

Tricyclic antidepressants, antipsychotics, general anesthetics, barbiturates, phenothiazine, ethanol

Concomitant use may enhance the effect of lisinopril.

Sympathomimetics

Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.

Muscle relaxants

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

Gold preparations

Rare cases of nitritoid reactions (a symptom complex including facial skin flushing, nausea, dizziness and arterial hypotension, which can be very severe) have been described in patients taking ACE inhibitors, including lisinopril, who were receiving intravenous gold preparations (sodium aurothiomalate), after administration of an injectable preparation containing gold (e.g., sodium aurothiomalate), and were reported more frequently in patients receiving ACE inhibitor treatment.

Co-trimoxazole (sulfamethoxazole and trimethoprim)

Increased risk of hyperkalemia.

Selective serotonin reuptake inhibitors (escitalopram, paroxetine, fluoxetine, sertraline)

Severe hyponatremia may develop with concomitant use of SSRIs.

Allopurinol, procainamide, cytostatics (5-fluorouracil, vincristine, docetaxel)

Leukopenia may develop.

Tissue plasminogen activators (alteplase, reteplase, tenecteplase)

Increased risk of angioedema with concomitant use with ACE inhibitors. Observational studies have shown an increased incidence of angioedema in patients taking ACE inhibitors after using alteplase for thrombolytic therapy of ischemic stroke.

Storage Conditions

The drug should be stored in the original packaging to protect it from light and moisture, in a place inaccessible to children at a temperature not exceeding 25°C (77°F).

Ekvator^® tablets, 5 mg + 10 mg: the shelf life of the drug manufactured by JSC “Gedeon Richter” is 4 years, by JSC “GEDEON RICHTER – RUS” is 3 years.

Ekvator^® tablets, 5 mg + 20 mg: shelf life is 3 years.

Ekvator^® tablets, 10 mg + 20 mg: shelf life is 3 years.

Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed 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.