Amlipine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMLIPIN (AMLIPIN)

Composition:

Active substances: amlodipine, lisinopril;

One tablet contains amlodipine (as amlodipine besylate) 5 mg, lisinopril (as lisinopril dihydrate) 5 mg;

Excipients: maize starch; calcium hydrogen phosphate; lactose monohydrate; povidone; magnesium stearate; sodium starch glycolate (type A);

Coating composition: hypromellose, titanium dioxide (E 171), talc, iron oxide red (E 172), propylene glycol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablets, ranging in color from red to dark pink.

Pharmacotherapeutic group.

Angiotensin-converting enzyme (ACE) inhibitors in combination with calcium channel blockers, lisinopril and amlodipine. ATC code C09B B03.

Pharmacological Properties

Pharmacodynamics

Lisinopril

Lisinopril is an inhibitor of the enzyme peptidyl-dipeptidase. It inhibits angiotensin-converting enzyme (ACE), which catalyzes the conversion of angiotensin I into the vasoconstrictor peptide angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE leads to reduced concentrations of angiotensin II, resulting in decreased vasoconstrictor activity and reduced aldosterone secretion. The latter reduction may lead to increased plasma potassium levels.

Since the primary mechanism of lisinopril’s antihypertensive effect is believed to be suppression of the renin-angiotensin-aldosterone system, lisinopril reduces arterial pressure even in patients with low renin levels. ACE is identical to kininase II, the enzyme responsible for bradykinin degradation. Whether increased concentrations of bradykinin, a potent vasodilator peptide, contribute to the therapeutic effects of lisinopril has not yet been fully established.

Amlodipine

Amlodipine is a dihydropyridine derivative (a calcium channel blocker or calcium ion antagonist) that inhibits calcium ion influx through cell membranes into vascular smooth muscle and myocardial cells. The antihypertensive mechanism of amlodipine is due to a direct relaxant effect on vascular smooth muscle.

Daily administration of amlodipine once daily produces clinically significant reductions in arterial pressure in patients with hypertension, both in the upright and supine positions, over a 24-hour period. Due to its slow onset of action, a rapid hypotensive effect does not occur.

Amlodipine has no adverse effects on metabolic processes or plasma lipid concentrations and can be used in the treatment of patients with bronchial asthma, diabetes mellitus, and gout.

Pharmacokinetics

Lisinopril

Absorption

After oral administration, lisinopril plasma concentrations reach peak levels within 7 hours, although in patients with acute myocardial infarction, a slight delay in the time to peak plasma concentration has been observed. Based on urinary excretion data, the average extent of lisinopril absorption is approximately 25%, with interpatient variability ranging from 6% to 60% within the studied dose range (5 to 80 mg). In patients with heart failure, the absolute bioavailability of lisinopril is reduced to approximately 16%. Absorption of lisinopril is not affected by food intake.

Distribution and Protein Binding

Lisinopril does not bind to plasma proteins except for circulating angiotensin-converting enzyme (ACE). Studies in rats have shown that lisinopril scarcely penetrates the blood-brain barrier.

Biological Transformation and Elimination

Lisinopril is not metabolized in the body and is excreted unchanged in the urine. With repeated administration, the effective elimination half-life of lisinopril is 12.6 hours. Renal clearance of lisinopril in healthy volunteers is approximately 50 mL/min. The decline in plasma concentration exhibits a prolonged terminal elimination half-life, which does not favor accumulation of lisinopril in the body. This terminal half-life likely reflects saturable binding to ACE and is not dose-dependent.

Patients with Hepatic Impairment

Impaired liver function in patients with cirrhosis resulted in reduced lisinopril absorption (approximately 30% lower based on urinary excretion data), but the effect of lisinopril was increased (approximately 50% higher) compared to healthy volunteers due to reduced clearance.

Patients with Renal Impairment

Impaired renal function reduces the excretion of lisinopril, which is eliminated by the kidneys, but this reduction becomes clinically significant only when the glomerular filtration rate is less than 30 mL/min. In mild to moderate renal impairment (creatinine clearance from 30 to 80 mL/min), the mean area under the concentration-time curve (AUC) increases by only 13%, whereas in severe renal impairment (creatinine clearance from 5 to 30 mL/min), the mean AUC increases by 4.5 times. Lisinopril is removed from the body during hemodialysis. After 4 hours of hemodialysis, plasma lisinopril concentration decreases on average by 60%, and dialysis clearance ranges from 40 to 55 mL/min.

Patients with Heart Failure

In patients with heart failure, higher plasma concentrations of lisinopril are observed compared to healthy volunteers (mean AUC increased by 125%), but based on urinary excretion data, absorption of lisinopril is reduced by approximately 16% compared to healthy individuals.

Elderly Patients

In elderly patients, higher plasma concentrations of lisinopril and higher AUC values (approximately 60% higher) are observed compared to younger patients.

Amlodipine

Absorption

After administration of therapeutic doses, amlodipine is well absorbed, reaching peak plasma concentrations within 6–12 hours after administration. Absolute bioavailability is estimated to be between 64% and 80%. Food intake does not affect the bioavailability of amlodipine.

Distribution and Protein Binding

The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of amlodipine is bound to plasma proteins.

Biological Transformation and Elimination

The terminal elimination half-life from plasma is approximately 35–50 hours, which supports once-daily dosing of amlodipine. Amlodipine is extensively metabolized in the liver to inactive metabolites, with only 10% of the parent compound and 60% of metabolites excreted in the urine.

Patients with Hepatic Impairment

Clinical data on amlodipine use in patients with hepatic impairment are very limited. In patients with hepatic impairment, clearance of amlodipine is reduced, leading to an increase in elimination half-life and AUC by approximately 40–60%.

Elderly Patients

The time to reach peak plasma concentration of amlodipine is practically the same in elderly and younger patients. In elderly patients, there is a tendency toward reduced clearance of amlodipine, resulting in increased AUC and elimination half-life.

Patients with Renal Impairment

Amlodipine is extensively biotransformed into inactive metabolites. Approximately 10% of amlodipine is excreted unchanged in the urine. Changes in amlodipine plasma concentrations do not correlate with the degree of renal impairment. Standard doses of amlodipine can be used in patients with renal impairment. Amlodipine is not removed by dialysis.

Clinical characteristics.

Indications.

Essential hypertension.

Contraindications.

Related to lisinopril:

• Hypersensitivity to lisinopril, to other angiotensin-converting enzyme (ACE) inhibitors, or to any component of the medicinal product;
• History of angioedema associated with previous ACE inhibitor therapy, hereditary or idiopathic angioedema;
• Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²);
• Concomitant use with sacubitril/valsartan. The medicinal product must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use");
• Use in patients undergoing hemodialysis with high-flux membranes (e.g., AN 69).

Related to amlodipine:

• Hypersensitivity to amlodipine, other dihydropyridine derivatives, or any component of the medicinal product;
• Severe arterial hypotension;
• Shock (including cardiogenic shock);
• Left ventricular outflow tract obstruction (e.g., severe aortic stenosis);
• Hemodynamically unstable heart failure following myocardial infarction.

Related to the combination of lisinopril/amlodipine:

• Pregnancy or planned pregnancy, breastfeeding (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Related to lisinopril

Antihypertensive medicinal products

Concomitant use of lisinopril with other antihypertensive agents (e.g., nitroglycerin, other nitrates, or other vasodilators) may result in an additional reduction in blood pressure.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers (ARBs), or aliskiren is associated with an increased risk of hypotension, hyperkalaemia, and renal dysfunction (including acute renal failure) compared to monotherapy (see sections "Contraindications" and "Special warnings and precautions for use").

Medicinal products that may increase the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections "Contraindications" and "Special warnings and precautions for use").

Concomitant use of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, sirolimus, everolimus), neutral endopeptidase (NEP) inhibitors (e.g., racecadotril), vildagliptin, or tissue plasminogen activator may increase the risk of angioedema.

Diuretics

When lisinopril is used concomitantly with diuretics, the antihypertensive effect is enhanced and a pronounced reduction in blood pressure may occur. The risk of symptomatic hypotension with lisinopril may be reduced by discontinuing the diuretic prior to initiating lisinopril therapy (see sections "Special warnings and precautions for use" and "Dosage and administration").

Potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other agents that may increase plasma potassium levels

Although plasma potassium levels generally remained within normal limits in clinical trials, hyperkalaemia was observed in some patients. Risk factors for hyperkalaemia include renal impairment, type 2 diabetes, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), dietary supplements, or potassium-containing salt substitutes.

Concomitant use of these agents with ACE inhibitors may lead to hyperkalaemia, particularly in patients with renal impairment. If concomitant use of the above-mentioned agents with lisinopril is necessary, regular monitoring of plasma potassium levels and renal function parameters is recommended.

Cyclosporine

Hyperkalaemia may occur when ACE inhibitors are used concomitantly with cyclosporine. Plasma potassium levels should be monitored when these agents are used together.

Heparin

Hyperkalaemia may occur when ACE inhibitors are used concomitantly with heparin. Plasma potassium levels should be monitored when these agents are used together.

Lithium

Elevated and potentially toxic plasma lithium concentrations have been reported with concomitant use of lithium and ACE inhibitors. Concomitant use of lithium with thiazide diuretics may increase the risk of lithium toxicity and may exacerbate lithium toxicity already present with ACE inhibitor therapy. Concomitant use of lisinopril and lithium is not recommended; however, if use of this combination is necessary, plasma lithium concentrations should be monitored (see section "Special warnings and precautions for use").

Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g/day

NSAIDs (e.g., acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and non-selective NSAIDs) may attenuate the antihypertensive effect of ACE inhibitors.

In some patients with impaired renal function who are taking NSAIDs, concomitant use of ACE inhibitors may have an additive effect on increasing plasma potassium levels and further worsening renal function, including possible acute renal failure. These effects are usually reversible. Therefore, this combination should be used with caution, particularly in elderly patients. Patients should maintain adequate hydration and be closely monitored for renal function at the initiation of concomitant therapy and periodically during treatment.

Gold-containing medicinal products

In patients receiving injectable gold-containing medicinal products (sodium aurothiomalate) and concomitant therapy with ACE inhibitors, including lisinopril, nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) have been reported more frequently.

Tricyclic antidepressants/antipsychotics/anesthetics

Concomitant use of certain anesthetics, tricyclic antidepressants, and antipsychotics with ACE inhibitors may lead to further reduction in blood pressure (see section "Special warnings and precautions for use").

Sympathomimetics

Sympathomimetic agents may reduce the antihypertensive effect of ACE inhibitors.

Antidiabetic agents

Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycaemic agents) may enhance the blood glucose-lowering effect, increasing the risk of hypoglycaemia. This effect usually occurs during the first weeks of combination therapy and in patients with renal impairment.

Co-trimoxazole (trimethoprim/sulfamethoxazole)

Patients receiving co-trimoxazole (trimethoprim/sulfamethoxazole) concomitantly may have an increased risk of hyperkalaemia.

Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates

Lisinopril may be used concomitantly with acetylsalicylic acid at cardioprotective doses, thrombolytics, beta-blockers, and/or nitrates.

Antacids

Concomitant use reduces the bioavailability of ACE inhibitors.

Ethanol

Concomitant use with ethanol enhances the hypotensive effect of lisinopril.

Related to amlodipine

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in the effect of amlodipine, which may also increase the risk of hypotension. The clinical manifestations of these pharmacokinetic variations may be more pronounced in elderly patients. Therefore, clinical monitoring with possible dose adjustment of amlodipine is recommended.

CYP3A4 inducers

When used concomitantly with known CYP3A4 inducers, plasma concentrations of amlodipine may be altered. Therefore, blood pressure should be monitored and dose adjustments made during and after concomitant use, particularly with strong CYP3A4 inducers (e.g., rifampicin, St. John's wort).

The use of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients this may increase the bioavailability of amlodipine, thereby enhancing its hypotensive effect.

Dantrolene (infusion)

In animal studies, ventricular fibrillation and cardiovascular collapse with concomitant hyperkalaemia and fatal outcome were observed after administration of verapamil and intravenous dantrolene. Due to the risk of hyperkalaemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and for the treatment of malignant hyperthermia.

Tacrolimus

There is a risk of increased plasma levels of tacrolimus when used concomitantly with amlodipine, although the pharmacokinetic mechanism of this interaction is not fully understood. To avoid tacrolimus toxicity, regular monitoring of tacrolimus plasma levels and, if necessary, dose adjustment are required when used concomitantly with amlodipine.

mTOR inhibitors

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When used concomitantly with mTOR inhibitors, amlodipine may potentiate their effects.

Cyclosporine

Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other patient groups, except in patients with transplanted kidneys, in whom variable increases in cyclosporine trough concentrations (on average 0–40%) have been observed. In kidney transplant patients receiving amlodipine, monitoring of cyclosporine concentrations should be considered, and cyclosporine dosage reduced if necessary.

Simvastatin

Concomitant administration of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. In patients taking amlodipine, the dose of simvastatin should be limited to 20 mg daily.

The antihypertensive effect of amlodipine is enhanced by other medicinal products with antihypertensive properties.

Amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine.

Special precautions for use

The medicinal product is intended for replacement therapy in patients with adequate blood pressure control on concomitant administration of lisinopril and amlodipine at the specified doses.

All special precautions listed below related to the use of individual components also apply to this combination medicinal product.

Lisinopril-related

Symptomatic hypotension

Symptomatic hypotension is rarely observed in patients with uncomplicated hypertension. A significant decrease in blood pressure in patients with hypertension receiving lisinopril may occur due to a reduction in circulating blood volume resulting from diuretic therapy, a strict salt-free diet, dialysis, diarrhoea, vomiting, or in patients with pronounced renin-dependent hypertension.

Cases of symptomatic hypotension have been reported in patients with heart failure, with or without concomitant renal impairment. Such cases are most likely in patients with more severe degrees of heart failure due to the use of high doses of loop diuretics, hyponatraemia, or functional renal impairment. Patients at increased risk of symptomatic hypotension should be monitored for hypotensive effects after the initial dose. These recommendations apply to patients with ischaemic heart disease and cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

In the event of hypotension, the patient should be placed in a supine position with legs elevated, and fluid volume should be replenished (intravenous administration of physiological saline) if necessary. Transient hypotension is not a contraindication to continued use of the medicinal product, and further dosing usually does not cause problems once blood pressure has been restored by increasing circulating blood volume.

In some patients with heart failure and normal or low blood pressure, lisinopril may cause an additional reduction in systemic arterial pressure. This is a known effect and usually does not require discontinuation of therapy. If hypotension becomes symptomatic, dose reduction or discontinuation of lisinopril may be required.

Hypotension in acute myocardial infarction

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

Aortic and mitral valve stenosis/hypertrophic cardiomyopathy

As with other angiotensin-converting enzyme (ACE) inhibitors, lisinopril should be used with caution in patients with mitral valve stenosis or left ventricular outflow tract obstruction such as aortic stenosis or hypertrophic cardiomyopathy.

Renal impairment

In patients with impaired renal function (creatinine clearance <80 ml/min), the initial dose of lisinopril should be adjusted according to the patient's creatinine clearance and subsequently based on the patient's response to treatment. In such patients, plasma potassium and creatinine levels should be monitored.

In patients with heart failure, hypotension after initiation of ACE inhibitors may lead to further deterioration in renal function. Acute renal failure, usually reversible, may occur in such patients.

In some patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney receiving ACE inhibitors, increases in blood urea and plasma creatinine may occur, usually reversible upon discontinuation of the drug; therefore, lisinopril is contraindicated in such patients. In patients with concomitant renovascular hypertension, there is an increased risk of severe hypotension and renal failure. Treatment of these patients should be initiated with low doses under close medical supervision and dose titration should be performed cautiously. Since diuretic therapy may predispose to the above-mentioned conditions, diuretics should be discontinued, and renal function should be monitored during the first weeks of lisinopril therapy.

In some patients with hypertension without marked signs of renovascular disease, increases in blood urea and plasma creatinine have been observed, mostly minimal or transient, more pronounced with concomitant use of lisinopril and diuretics, and most commonly in patients with prior renal impairment. This condition may require dose reduction and/or discontinuation of the diuretic and/or lisinopril.

Lisinopril therapy should not be initiated in patients with acute myocardial infarction and marked renal impairment (plasma creatinine level above 177 µmol/L and/or proteinuria >500 mg/day). If renal impairment develops during lisinopril therapy (plasma creatinine concentration exceeds 265 µmol/L or doubles the pre-treatment value), lisinopril should be discontinued.

Proteinuria

Rare cases of proteinuria have been reported, particularly in patients with reduced renal function or after high doses of lisinopril. In cases of clinically significant proteinuria (over 1 g/day), lisinopril should be used only after assessing the benefit-risk ratio of treatment and with continuous monitoring of clinical and biochemical parameters.

Hypersensitivity/angioedema

Isolated cases of angioedema of the face, extremities, lips, tongue, vocal cords, and/or larynx have been reported in patients receiving ACE inhibitors, including lisinopril. These events may occur at any time during treatment. In such cases, lisinopril should be discontinued immediately, and appropriate monitoring should be instituted to ensure complete resolution of symptoms before patient discharge. Even in cases of tongue swelling without respiratory distress, prolonged observation may be required, as antihistamines and corticosteroids may be insufficient.

Very rare fatal cases of angioedema due to laryngeal or tongue swelling have been reported. In cases of swelling of the tongue, glottis, or larynx, which may likely cause airway obstruction, immediate appropriate emergency treatment should be initiated. This may include administration of adrenaline and/or airway support. The patient should remain under close medical supervision until complete and sustained resolution of symptoms.

The incidence of angioedema in patients of Black race receiving ACE inhibitors is significantly higher than in patients of other races.

Patients with a history of angioedema unrelated to ACE inhibitor use may have a substantially higher risk of developing angioedema when receiving an ACE inhibitor (see section "Contraindications").

Concomitant use of ACE inhibitors with rac-cadicotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (e.g., airway or tongue swelling with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction"). Caution should be exercised when initiating rac-cadicotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving an ACE inhibitor.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Sacubitril/valsartan therapy may be initiated only 36 hours after the last dose of the medicinal product. The medicinal product may be initiated only 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Anaphylactic reactions in patients undergoing haemodialysis

A high risk of anaphylactic reactions has been reported in patients undergoing haemodialysis with high-flux dialysis membranes (e.g., AN 69) while receiving concomitant ACE inhibitor therapy. In such patients, consideration should be given to using a different type of dialysis membrane or an alternative class of antihypertensive agents.

Anaphylactoid reactions during LDL apheresis

Life-threatening anaphylactoid reactions rarely occur during low-density lipoprotein (LDL) apheresis using dextran sulphate in combination with ACE inhibitor therapy. These reactions can be avoided by temporarily discontinuing the ACE inhibitor before each apheresis.

Desensitisation

Continuous anaphylactic reactions have been observed in patients receiving ACE inhibitors during desensitisation therapy (e.g., with hymenoptera venom). Such reactions were avoided in these patients by temporarily discontinuing ACE inhibitors, but reappeared upon accidental re-administration of lisinopril.

Hepatic impairment

Rarely, treatment with ACE inhibitors has been associated with a syndrome beginning with cholestatic jaundice or hepatitis and progressing to sudden and rapidly developing hepatic necrosis (sometimes fatal). The mechanism of this syndrome is unknown. Patients who develop jaundice or marked elevations in liver enzymes while taking ACE inhibitors should discontinue lisinopril and receive appropriate treatment.

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia, and anaemia have been observed in patients receiving ACE inhibitors. Neutropenia occurs rarely in patients with normal renal function and without special risk factors. Lisinopril should be used with particular caution in patients with vascular collagenosis receiving immunosuppressive agents, allopurinol, procainamide, or with multiple such risk factors, especially with prior renal impairment. Serious infections, sometimes unresponsive to intensive antibiotic therapy, have been observed in some of these patients. Regular monitoring of the white blood cell count is recommended during lisinopril therapy in such patients, and patients should be instructed to report any signs of infection to their physician.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalaemia, and renal impairment (including acute renal failure). Therefore, dual blockade with ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.

If such combination therapy is considered absolutely necessary, it should be administered only under specialist supervision and with careful monitoring of renal function, blood pressure, and electrolyte levels. ACE inhibitors and angiotensin II receptor blockers should not be used with aliskiren in patients with diabetic nephropathy (see section "Interaction with other medicinal products and other forms of interaction").

Ethnic differences

The incidence of angioedema during ACE inhibitor therapy is higher in Black patients compared to patients of other races. As with other ACE inhibitors, lisinopril may be less effective in reducing blood pressure in Black patients compared to patients of other races, possibly due to the higher prevalence of low-renin hypertension in these patients.

Cough

Cough may occur during ACE inhibitor therapy. It is typically a non-productive, persistent cough that resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/anaesthesia

During major surgery or anaesthesia with agents that lower blood pressure, lisinopril inhibits the formation of angiotensin II, potentially leading to compensatory renin secretion. If hypotension develops via this mechanism, it can be corrected by physically increasing circulating blood volume.

Hyperkalaemia

ACE inhibitors may cause hyperkalaemia due to suppression of aldosterone release. This effect is usually minor in patients with normal renal function. However, hyperkalaemia may occur in patients with impaired renal function and/or in patients taking potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), or other drugs that increase plasma potassium levels (e.g., heparin, trimethoprim, or co-trimoxazole, also known as trimethoprim/sulfamethoxazole), particularly aldosterone antagonists or angiotensin receptor blockers. Caution is advised when using potassium-sparing diuretics and angiotensin receptor blockers in patients taking ACE inhibitors. Plasma potassium levels and renal function should be monitored in such patients (see section "Interaction with other medicinal products and other forms of interaction").

Use in diabetic patients

Careful monitoring of blood glucose levels is required during the first month of ACE inhibitor therapy in diabetic patients taking oral hypoglycaemic agents or insulin (see section "Interaction with other medicinal products and other forms of interaction").

Lithium

Concomitant use of lithium and lisinopril is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Pregnancy

ACE inhibitor therapy should not be initiated during pregnancy. Except in cases where continued ACE inhibitor therapy is considered necessary, women planning pregnancy should be switched to an alternative antihypertensive agent with an established safety profile in pregnancy. Upon confirmation of pregnancy, ACE inhibitor therapy should be discontinued immediately, and alternative therapy should be initiated if necessary.

Amlodipine-related

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

Use in patients with heart failure

Amlodipine should be used with caution in patients with heart failure. In a long-term placebo-controlled study in patients with severe heart failure (NYHA class III and IV), pulmonary oedema was reported more frequently in the group receiving amlodipine than in the placebo group.

Calcium channel blockers, including amlodipine, should be prescribed with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular events and mortality.

Use in patients with hepatic impairment

In patients with hepatic impairment, the elimination half-life of amlodipine is prolonged and AUC is increased, but appropriate dosing recommendations have not been established. Therefore, amlodipine therapy should be initiated at the lowest dose within the dosing range, and dose initiation and escalation should be performed cautiously. In patients with severe hepatic impairment, slow dose titration and careful monitoring may be required.

Use in patients with renal impairment

Amlodipine may be administered to such patients at usual doses. Plasma amlodipine concentrations do not correlate with the degree of renal impairment. Amlodipine is not removed by dialysis.

Use in elderly patients

Dose escalation should be cautious in elderly patients (see section "Posology and method of administration").

Precautions related to excipients

The medicinal product contains lactose monohydrate and should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

The medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

The medicinal product is contraindicated in pregnant women and women planning pregnancy (see section "Contraindications").

There is no adequate experience with the use of lisinopril and amlodipine in pregnant women from controlled clinical studies. However, use of both active substances is not recommended or is contraindicated (see information on active substances in section "Composition").

If pregnancy is confirmed during treatment with the medicinal product, its use should be discontinued immediately, and if necessary, replaced with another medicinal product approved for use during pregnancy (see section "Special precautions for use").

Initiation of treatment with the medicinal product during pregnancy is not recommended. If continued treatment with the medicinal product is considered necessary, women planning pregnancy should be switched to alternative antihypertensive agents with a known safety profile during pregnancy.

Use of lisinopril

Epidemiological data on the risk of teratogenicity associated with ACE inhibitor use in the first trimester of pregnancy are inconclusive, although a slight increase in risk cannot be excluded. If continued ACE inhibitor therapy is considered necessary, women planning pregnancy should be switched to alternative antihypertensive agents with a known safety profile during pregnancy. Upon confirmation of pregnancy, ACE inhibitor therapy should be discontinued immediately, and alternative therapy should be initiated if necessary.

It is known that ACE inhibitor use during the second and third trimesters of pregnancy induces fetotoxicity (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). If an ACE inhibitor has been used from the second trimester of pregnancy, ultrasound assessment of renal and skull function is recommended. Newborns and infants whose mothers received ACE inhibitors should be closely monitored for timely detection of hypotension (see sections "Contraindications" and "Special precautions for use").

Use of amlodipine

The safety of amlodipine use in pregnant women has not been established.

Reproductive toxicity has been observed in animal studies with high doses.

Breastfeeding

The medicinal product is contraindicated during breastfeeding (see section "Contraindications").

Use of lisinopril

Due to the lack of information on the use of lisinopril during breastfeeding, alternative agents with established safety profiles should be used, particularly when breastfeeding a newborn or preterm infant (see section "Contraindications").

Use of amlodipine

Amlodipine is excreted in breast milk. The fraction of the maternal dose received by the infant is estimated at an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. The medicinal product is contraindicated during breastfeeding; alternative medicinal products with established safety profiles should be used, particularly when breastfeeding a newborn or preterm infant (see section "Contraindications").

Fertility

Use of lisinopril

There are no adequate controlled clinical studies on the effect of lisinopril on fertility.

Use of amlodipine

Reversible biochemical changes in sperm heads have been reported in some patients treated with calcium channel blockers. Clinical data on the effect of amlodipine on fertility are insufficient. In one study in rats, adverse effects on male fertility were observed.

Ability to influence reaction speed when driving or operating machinery

The medicinal product may impair the ability to drive or operate machinery. Lisinopril may cause dizziness, fatigue; amlodipine may cause dizziness, headache, fatigue, nausea. Patients should refrain from driving or operating machinery until their individual response to the medicinal product is known.

Method of Administration and Dosage

The medication is intended for oral administration. Tablets can be taken independently of food intake.

Adults

The recommended dose is 1 tablet daily. If necessary, the daily dose may be doubled. Maximum daily dose – 2 tablets.

Patients with Hepatic Impairment

To determine the optimal initial and maintenance dosage in patients with impaired liver function, dose titration should be performed individually using the separate components of the medication – lisinopril and amlodipine. Clear dosage recommendations for amlodipine in patients with mild to moderate hepatic impairment have not been established; therefore, treatment should be initiated at the lowest recommended dose. Pharmacokinetic studies of amlodipine in patients with severe hepatic impairment have not been conducted. Dosing of amlodipine in patients with severe hepatic impairment should begin at the lowest dose, with gradual titration to the optimal dose.

Patients with Renal Impairment

To determine the optimal initial and maintenance dosage in patients with impaired renal function, dose titration should be performed individually using the separate components of the medication – lisinopril and amlodipine.

During treatment, continuous monitoring of renal function, as well as plasma potassium and sodium levels, is required. If renal function deteriorates, the medication should be discontinued and replaced with therapy using individual components with appropriate dose adjustments. Amlodipine is not removed by dialysis.

Elderly Patients

No age-related changes in the efficacy or safety profile of amlodipine or lisinopril have been observed. To determine the optimal maintenance dose in elderly patients, dose titration should be performed individually using a free combination of lisinopril and amlodipine.

Children

The medication is contraindicated in children (under 18 years of age).

Overdose

Related to Lisinopril

Data on human overdose are limited.

Symptoms

Symptoms associated with ACE inhibitor overdose may include arterial hypotension, circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

Treatment

In case of overdose, intravenous administration of physiological saline is recommended. If arterial hypotension develops, the patient should be placed in a supine position. Infusion of angiotensin II and/or intravenous administration of catecholamines may also be considered. If ingestion was recent, measures to eliminate lisinopril should be undertaken (e.g., induction of emesis, gastric lavage, administration of sorbents and sodium sulfate). Lisinopril can be removed from systemic circulation by hemodialysis (see section "Special Instructions"). In cases of bradycardia refractory to pharmacological treatment, implantation of a pacemaker is indicated. Continuous monitoring of vital signs, electrolyte levels, and plasma creatinine concentration is required.

Related to Amlodipine

Data on intentional human overdose are limited.

Symptoms

Overdose may lead to excessive peripheral vasodilation with reflex tachycardia. Profound and prolonged systemic arterial hypotension has been reported, progressing to shock with fatal outcome.

Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Factors contributing to the development of non-cardiogenic pulmonary edema may include early resuscitation measures (including fluid overload) aimed at supporting perfusion and cardiac output.

Treatment

In cases of clinically significant arterial hypotension due to amlodipine overdose, active measures to support the cardiovascular system are required, including frequent monitoring of cardiovascular and respiratory parameters, placing the patient in a supine position with legs elevated above the head, and monitoring circulating blood volume and diuresis.

Administration of vasopressors may be necessary to restore vascular tone and arterial pressure, provided there are no contraindications to their use. Intravenous calcium gluconate may have a beneficial effect in reversing the effects caused by calcium channel blockade.

In some cases, gastric lavage may be effective. Studies in healthy volunteers have shown that administration of activated charcoal within 2 hours after ingestion of 10 mg amlodipine reduces the rate of amlodipine absorption.

Since amlodipine is highly bound to plasma proteins, dialysis is ineffective.

Overdose of the medication may result in excessive peripheral vasodilation leading to pronounced arterial hypotension and acute circulatory failure, electrolyte imbalances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Symptomatic treatment is recommended (placing the patient in a supine position, observation, and, if necessary, support of cardiovascular and respiratory functions, arterial pressure, circulating blood volume, electrolyte balance, and plasma creatinine concentration). In cases of pronounced arterial hypotension, the patient should be placed in a supine position with legs elevated above the head; if fluid administration is insufficient, supportive therapy with peripheral vasopressors may be required, provided there are no contraindications to their use. Infusion of angiotensin II may also be considered. Intravenous calcium gluconate may exert a beneficial effect in reversing calcium channel blockade effects. Due to the slow absorption of amlodipine, gastric lavage may be effective in some cases. Lisinopril can be removed from systemic circulation by hemodialysis. The use of high-flux polyacrylonitrile membranes during dialysis is not recommended.

Adverse Reactions

The adverse reactions reported are listed below by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (≤ 1/10,000), not known (frequency cannot be estimated from the available data).

Related to lisinopril

Blood and lymphatic system disorders:

Rare – decreased hemoglobin and hematocrit levels; very rare – bone marrow suppression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, hemolytic anemia, lymphadenopathy.

Immune system disorders:

Very rare – autoimmune disorders; not known – anaphylactic/anaphylactoid reaction.

Metabolism and nutrition disorders:

Very rare – hypoglycemia.

Psychiatric disorders:

Uncommon – mood changes, sleep disturbances, hallucinations; rare – confusion; not known – depression.

Nervous system disorders:

Common – headache, dizziness; uncommon – vertigo, paraesthesia, taste disturbances, loss of balance, disorientation; rare – smell disturbances; not known – loss of consciousness.

Cardiac disorders:

Uncommon – myocardial infarction (likely due to excessive reduction in blood pressure in high-risk patients; see section "Special precautions"), palpitations, tachycardia.

Vascular disorders:

Common – orthostatic disturbances (including arterial hypotension); uncommon – acute cerebrovascular accident (stroke), likely due to excessive reduction in blood pressure in high-risk patients (see section "Special precautions"), Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders:

Common – cough; uncommon – rhinitis; very rare – bronchospasm, sinusitis, glossitis, allergic alveolitis/eosinophilic pneumonia.

Gastrointestinal disorders:

Common – diarrhea, vomiting; uncommon – nausea, abdominal pain, dyspepsia; rare – dry mouth, decreased appetite, taste disturbances; very rare – pancreatitis, intestinal angioneurotic edema, constipation.

Hepatobiliary disorders:

Very rare – cholestatic or hepatocellular hepatitis, jaundice, hepatic failure (see section "Special precautions").

Skin and subcutaneous tissue disorders:

Uncommon – rash, pruritus; rare – urticaria, alopecia, psoriasis, hypersensitivity reactions/angioedema of the face, lips, tongue, extremities, larynx and/or pharynx (see section "Special precautions"); very rare – increased sweating, bullous eruption, toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome, exudative multiform erythema, cutaneous lymphoma.

A symptom complex has been reported that may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibodies (ANA) test, increased erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, skin rashes, photosensitivity or other skin changes.

Renal and urinary disorders:

Common – renal dysfunction; rare – uremia, acute renal failure; very rare – oliguria/anuria.

Endocrine disorders:

Rare – inappropriate antidiuretic hormone secretion.

Reproductive system and breast disorders:

Uncommon – impotence; rare – gynecomastia.

General disorders and administration site conditions:

Uncommon – increased fatigue, asthenia.

Investigations:

Uncommon – increased plasma concentrations of urea, creatinine, liver enzymes and potassium; rare – increased plasma bilirubin, hyponatremia, proteinuria.

Related to amlodipine

Blood and lymphatic system disorders:

Very rare – leukopenia, thrombocytopenia.

Immune system disorders:

Very rare – allergic reactions.

Metabolism and nutrition disorders:

Very rare – hyperglycemia.

Psychiatric disorders:

Uncommon – depression, mood changes (including anxiety), insomnia; rare – confusion.

Neurological disorders:

Common – somnolence, dizziness, headache (mainly at the beginning of treatment); uncommon – tremor, dysgeusia, syncope, hypesthesia, paraesthesia; very rare – hypertonia, peripheral neuropathy; not known – extrapyramidal disorders.

Eye disorders:

Common – visual disturbances (including diplopia).

Ear and labyrinth disorders:

Uncommon – tinnitus.

Cardiac disorders:

Common – palpitations; uncommon – arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation); very rare – myocardial infarction.

Vascular disorders:

Common – flushing; uncommon – arterial hypotension; very rare – vasculitis.

Respiratory, thoracic and mediastinal disorders:

Common – dyspnea; uncommon – cough, rhinitis.

Gastrointestinal disorders:

Common – abdominal pain, nausea, dyspepsia, intestinal motility disturbances (including diarrhea and constipation); uncommon – vomiting, dry mouth; very rare – pancreatitis, gastritis, gingival hyperplasia.

Hepatobiliary disorders:

Very rare – hepatitis, jaundice, elevated liver enzymes (most commonly associated with cholestasis).

Skin and subcutaneous tissue disorders:

Uncommon – alopecia, purpura, skin discoloration, increased sweating, pruritus, rash, exanthema, urticaria; very rare – angioedema, multiform erythema, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity; not known – toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders:

Common – leg swelling, muscle cramps; uncommon – arthralgia, myalgia, back pain.

Renal and urinary disorders:

Uncommon – urinary disorders, nocturia, increased frequency of urination.

Reproductive system and breast disorders:

Uncommon – impotence, gynecomastia.

General disorders and administration site conditions:

Very common – edema; common – increased fatigue, asthenia; uncommon – chest pain, pain, malaise.

Investigations:

Uncommon – increased or decreased body weight.

Rare cases of extrapyramidal syndrome have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is highly important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a dry place, out of reach of children.

Packaging.

10 tablets in a blister. 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLID MEDITSIN ILACH SAN. VE TIDJ. A.SH./
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and place of business.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine