Liram

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LIRAM (LIRAM)

Composition:

Active substances: lisinopril, amlodipine;

1 tablet contains:

lisinopril 10 mg (as lisinopril dihydrate);

amlodipine 5 mg (as amlodipine besylate);

Excipients: microcrystalline cellulose, sodium starch glycolate, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets, round-shaped with a flat surface, beveled edges, and a score line.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors in combination with calcium channel blockers. Lisinopril and amlodipine.

ATC code C09B B03.

Pharmacological Properties

Pharmacodynamics

Liram is a fixed-dose combination drug containing two active substances: lisinopril and amlodipine.

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 angiotensin II concentrations, resulting in decreased vasoconstrictor activity and reduced aldosterone secretion. The latter may lead to increased serum potassium levels.

Since the mechanism by which lisinopril lowers blood pressure involves suppression of the renin-angiotensin-aldosterone system, lisinopril reduces blood pressure even in patients with hypertension and low renin levels. ACE is identical to kininase II, the enzyme responsible for bradykinin degradation. Whether increased concentrations of bradykinin, a potent vasodilator peptide, play a role in the therapeutic effects of lisinopril has not yet been established.

Amlodipine

Amlodipine is a dihydropyridine calcium channel blocker (a slow calcium channel inhibitor or calcium ion antagonist) that inhibits calcium ion influx through cell membranes into myocardial and vascular smooth muscle cells.

The antihypertensive mechanism of amlodipine is due to direct relaxation of vascular smooth muscle.

The precise reasons for the beneficial effect of amlodipine in angina are not fully defined; however, it is known that reduction of total ischemic burden occurs via two mechanisms:

• Amlodipine causes peripheral arteriolar dilation, thereby reducing total peripheral vascular resistance against which the heart must pump (afterload). Since heart rate remains stable, cardiac unloading results in reduced myocardial energy consumption and decreased myocardial oxygen demand.
• The mechanism of action of amlodipine may also involve dilation of major coronary arteries and arterioles, both normal and those located in ischemic zones. This leads to increased oxygen delivery to the myocardium in patients with vasospastic angina (Prinzmetal's angina, or variant angina).

Once-daily administration of amlodipine provides clinically significant reduction in blood pressure in patients with arterial hypertension in both supine and upright positions over 24 hours. Due to its slow onset of action, a rapid hypotensive effect does not occur.

In patients with angina, once-daily dosing of amlodipine increases exercise tolerance, prolongs the time to onset of angina episodes, delays the development of ST-segment depression (by 1 mm), and reduces the frequency of angina attacks and nitroglycerin use.

Amlodipine has no adverse effects on metabolism or plasma lipid concentrations and can be used in patients with bronchial asthma, type II diabetes, and gout.

Pharmacokinetics

Lisinopril

Lisinopril is an orally administered ACE inhibitor that does not contain a sulfhydryl group.

Absorption

After oral administration, peak plasma concentrations are reached within 7 hours, although in patients with acute myocardial infarction, a slight delay in time to peak serum 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

Lisinopril does not bind to plasma proteins, except for circulating ACE. Studies in rats have shown that lisinopril poorly penetrates the blood-brain barrier.

Elimination

Lisinopril is not metabolized in the body and is excreted unchanged in urine. With repeated dosing, 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 serum concentration exhibits a prolonged terminal elimination phase, which does not favor accumulation of the active substance in the body. This terminal half-life likely reflects saturable binding to ACE and is not dose-dependent.

Pharmacokinetic characteristics in special patient populations

Hepatic insufficiency

Impaired liver function in patients with hepatic cirrhosis leads to reduced absorption of lisinopril (approximately 30% lower based on urinary excretion data), but the drug's effect is increased (approximately 50%) compared to healthy volunteers due to reduced clearance.

Renal insufficiency

In renal impairment, lisinopril elimination is reduced, as the drug is primarily excreted by the kidneys, but this reduction becomes clinically significant only when glomerular filtration rate is less than 30 mL/min. In mild to moderate renal impairment (creatinine clearance of 30–80 mL/min), the mean area under the concentration-time curve (AUC) increases by only 13%, whereas in severe renal impairment (creatinine clearance of 5–30 mL/min), the mean AUC increases by 4.5-fold. Lisinopril can be removed from the body by hemodialysis. After 4 hours of hemodialysis, plasma lisinopril concentration decreases by an average of 60%, and dialysis clearance ranges from 40 to 55 mL/min.

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 blood concentrations and higher AUC values of lisinopril (approximately 60% higher) are observed compared to younger patients.

Amlodipine

Absorption, distribution, and plasma protein binding

After administration in therapeutic doses, amlodipine is well absorbed, reaching peak plasma concentrations 6–12 hours after dosing. Absolute bioavailability is estimated to be between 64% and 80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Food intake does not affect the bioavailability of amlodipine.

Metabolism and elimination

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

Pharmacokinetic characteristics in special patient populations

Hepatic insufficiency

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

Elderly patients

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

Increased AUC and elimination half-life in patients with congestive heart failure are consistent with expectations for this age group.

Fixed-dose combination product

No pharmacokinetic interactions between the active components of the medicinal product have been described. Pharmacokinetic parameters (AUC, Cmax, tmax, t1/2) do not differ from those observed after administration of the active components separately.

Food intake does not affect the absorption of Liram tablets in the gastrointestinal tract.

Clinical characteristics.

Indications.

Essential arterial hypertension in adults.

The medicinal product Liram is indicated for adult patients whose blood pressure is adequately controlled with concomitant administration of lisinopril and amlodipine at similar doses.

Contraindications.

Associated with lisinopril:

• Hypersensitivity to lisinopril or to any other angiotensin-converting enzyme (ACE) inhibitor;
• History of angioedema associated with previous ACE inhibitor therapy;
• Hereditary or idiopathic angioedema;
• Pregnancy or planned pregnancy, breastfeeding (see section "Use in pregnancy or breastfeeding");
• Concomitant use of Liram with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see section "Interaction with other medicinal products and other forms of interaction");
• Concomitant use with sacubitril/valsartan; initiation of Liram is not recommended within 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Associated with amlodipine:

• Hypersensitivity to amlodipine or to any other dihydropyridine derivatives;
• Severe arterial hypotension;
• Shock (including cardiogenic);
• Obstruction of the left ventricular outflow tract (severe aortic valve stenosis);
• Hemodynamically unstable heart failure following acute myocardial infarction.

Associated with the medicinal product Liram:

• All the contraindications listed above related to the use of individual components also apply to the combined preparation Liram;
• Hypersensitivity to any of the excipients of Liram (see section "Composition").

Interaction with other medicinal products and other forms of interaction.

Interactions associated with lisinopril

Antihypertensive agents

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

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

Dual blockade of RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers (ARBs), or aliskiren is associated with an increased risk of hypotension, hyperkalemia, and renal dysfunction (including acute renal failure) compared to monotherapy (see sections "Contraindications" and "Special precautions for use").

Medicinal products that may increase the risk of angioedema

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

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

Diuretics

The antihypertensive effect is usually enhanced when a diuretic is added to lisinopril therapy. In patients already receiving diuretics, particularly those recently initiated on diuretic therapy, excessive reduction in blood pressure may rarely occur upon addition of lisinopril. The risk of symptomatic hypotension with lisinopril can be minimized by discontinuing the diuretic prior to starting lisinopril (see sections "Special precautions for use" and "Dosage and administration").

Potassium-containing dietary supplements or salt substitutes, potassium-sparing diuretics, and other medicinal products that may increase serum potassium levels

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients during treatment with lisinopril. Potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or salt substitutes may lead to a significant increase in serum potassium levels, particularly in patients with impaired renal function. Caution should be exercised when lisinopril is used concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to have effects similar to potassium-sparing diuretics like amiloride. Therefore, concomitant use of lisinopril with the above-mentioned medicinal products is not recommended. If concomitant use is necessary, these medicinal products should be used with caution and with periodic monitoring of serum potassium levels (see section "Special precautions for use").

Cyclosporine. Concomitant use of ACE inhibitors and cyclosporine may lead to hyperkalemia. Monitoring of serum potassium levels is recommended.

Heparin. Concomitant use of ACE inhibitors and heparin may lead to hyperkalemia. Monitoring of serum potassium levels is recommended.

When lisinopril is administered concomitantly with a potassium-sparing diuretic, diuretic-induced hypokalemia may be reduced.

Lithium preparations

Concomitant use of lithium and ACE inhibitors has been associated with reversible increases in serum lithium concentrations and lithium toxicity. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and may exacerbate lithium toxicity already elevated due to ACE inhibitor use. Concomitant use of lisinopril and lithium preparations is not recommended; however, if such combination is deemed necessary, serum lithium levels should be closely monitored (see section "Special precautions for use").

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid

≥ 3 g/day

Concomitant use of ACE inhibitors with NSAIDs (acetylsalicylic acid at anti-inflammatory doses, cyclooxygenase-2 [COX-2] inhibitors, and nonselective NSAIDs) may result in reduced antihypertensive effect of ACE inhibitors. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including development of acute renal failure, and increased serum potassium levels, particularly in patients with reduced renal function. These effects are reversible. Caution should be exercised when using combination therapy, especially in elderly patients. Patients should receive adequate hydration, and renal function should be carefully monitored both at the start of combination therapy and during treatment.

Gold

Nitritoid reactions (symptoms of vasodilation, including flushing, nausea, dizziness, and hypotension, which may be severe) after administration of injectable gold-containing preparations (e.g., sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitor therapy.

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 precautions for use").

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Hypoglycemic agents

It is known that concomitant use of ACE inhibitors and hypoglycemic medicinal products (insulin, oral hypoglycemic agents) may enhance the hypoglycemic effect, increasing the risk of hypoglycemia. This phenomenon most commonly occurs during the first weeks of combination therapy and in patients with renal impairment.

Medicinal products that suppress bone marrow function (immunosuppressants, allopurinol, procainamide)

Concomitant use with lisinopril increases the risk of neutropenia and/or agranulocytosis (see section "Special precautions for use").

Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates

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

Alcohol potentiates the hypotensive effect of lisinopril.

Estrogens. Concomitant administration may reduce the antihypertensive effect of lisinopril due to fluid retention.

Interactions associated with amlodipine

Effect of other medicinal products on amlodipine

Inhibitors of CYP3A4 isoenzyme

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 amlodipine concentration, increasing the risk of hypotension. Clinical manifestations of these pharmacokinetic variations may be more pronounced in elderly patients. Therefore, medical monitoring of patients is recommended, and dose adjustment of amlodipine may be required.

Clarithromycin is a CYP3A4 inhibitor. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Strict medical monitoring is recommended when amlodipine is used concomitantly with clarithromycin.

Inducers of CYP3A4 isoenzyme

When used concomitantly with known inducers of CYP3A4 isoenzyme, amlodipine blood concentrations may change. Therefore, blood pressure should be monitored and dose adjustments of the drugs may be necessary during and after combination therapy, especially with potent CYP3A4 inducers (such as rifampicin, Hypericum perforatum).

Concomitant intake of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients this may lead to increased bioavailability of amlodipine, thereby enhancing its hypotensive effect.

Dantrolene (infusion)

In animal studies, ventricular fibrillation and cardiovascular collapse with concomitant hyperkalemia and subsequent death were observed after verapamil administration followed by intravenous dantrolene. Due to the risk of hyperkalemia, 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.

Effect of amlodipine on other medicinal products

The hypotensive effect of amlodipine is enhanced by the corresponding effects of other medicinal products with antihypertensive properties.

Tacrolimus

Concomitant use of tacrolimus and amlodipine may lead to increased blood concentrations of tacrolimus; the mechanism of this interaction is not fully understood. To avoid tacrolimus toxicity, blood concentrations of tacrolimus should be monitored during amlodipine therapy, and the dose of tacrolimus should be adjusted if necessary.

Mammalian target of rapamycin (mTOR) inhibitors

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. Concomitant use of amlodipine with mTOR inhibitors may enhance the effects of the latter.

Cyclosporine

No interaction studies between cyclosporine and amlodipine have been conducted in healthy volunteers or other populations, except in kidney transplant patients, in whom increased cyclosporine blood concentrations (on average by 0–40%) have been observed. Therefore, in such patients, cyclosporine blood concentrations should be monitored during amlodipine therapy, and the cyclosporine dose should be reduced if necessary.

Simvastatin

Concomitant repeated administration of 10 mg amlodipine and 80 mg simvastatin resulted in a 77% increase in simvastatin concentration compared to simvastatin monotherapy. The simvastatin dose should be limited to 20 mg daily in patients taking amlodipine.

It is known from clinical interaction studies that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Special precautions for use.

All the special precautions for use listed below, related to the use of individual components, also apply to the combined medicinal product LiRam.

Special precautions for use related to lisinopril

Symptomatic arterial hypotension

Symptomatic arterial hypotension is rarely observed in patients with uncomplicated arterial hypertension.

A significant decrease in blood pressure may occur in patients with reduced circulating blood volume due to diuretic therapy, a strict low-salt diet, dialysis, diarrhea, or vomiting, as well as in patients with pronounced renin-dependent arterial hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Cases of symptomatic hypotension have been reported in patients with heart failure, with or without renal insufficiency. Such cases are most likely in patients with more severe heart failure due to high doses of loop diuretics, hyponatremia, or functional renal insufficiency. Patients at increased risk of symptomatic arterial hypotension should be monitored for hypotensive effects after the initial dose. These recommendations apply to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke. In case of arterial hypotension, the patient should be laid down in a supine position with legs elevated and fluid volume should be replenished (intravenous administration of normal saline), if necessary. Transient arterial hypotension is not a contraindication for continued use of the drug, and further administration usually does not cause problems after blood pressure has increased due to increased circulating blood volume.

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

Arterial hypotension in acute myocardial infarction

Lisinopril should not be initiated in patients with acute myocardial infarction who are prone to further serious hemodynamic deterioration after 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 arterial hypotension persists (systolic blood pressure less than 90 mm Hg for more than 1 hour), lisinopril should be discontinued.

Stenosis of aortic and mitral valves / hypertrophic cardiomyopathy

As with all ACE inhibitors, lisinopril should be administered with caution to patients with mitral valve stenosis and 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 according to the patient's response to treatment. Routine monitoring of serum potassium and creatinine levels is part of standard medical practice in treating such patients.

In patients with heart failure, arterial hypotension after initiation of ACE inhibitors may lead to further deterioration of renal function. In such cases, acute renal failure, usually reversible, has been reported.

In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney receiving ACE inhibitors, increased blood urea nitrogen and serum creatinine concentrations may occur, usually reversible after discontinuation of the drug. This is particularly likely in patients with pre-existing renal impairment.

In patients with concomitant renovascular hypertension, there is an increased risk of severe arterial hypotension and renal failure. Treatment of such patients should be initiated under close medical supervision with low doses and cautious dose titration. Since diuretic therapy may promote the development of 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 arterial hypertension without significant prior renovascular hypertension, increases in blood urea nitrogen and serum creatinine concentrations have been observed, usually mild and transient, especially when lisinopril was used concomitantly with diuretics. This is particularly likely in patients with pre-existing renal impairment. Dose reduction and/or discontinuation of diuretics and/or lisinopril may be required.

In acute myocardial infarction, lisinopril therapy should not be initiated in patients with signs of renal impairment defined as serum creatinine concentration exceeding 177 µmol/L and/or proteinuria exceeding 500 mg/24 hours. If renal function impairment develops during lisinopril therapy (serum creatinine concentration > 265 µmol/L or twice the baseline value), the physician should consider discontinuation of lisinopril.

Proteinuria

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

Increased sensitivity, angioedema

Isolated cases of angioedema of the face, hands, feet, lips, tongue, glottis, and/or larynx have been reported in patients receiving ACE inhibitors, including lisinopril. Angioedema may occur at any time during treatment. In such cases, lisinopril should be immediately discontinued, appropriate treatment initiated, and medical observation continued until all symptoms have resolved before patient discharge. Even in cases of tongue swelling without respiratory distress, patients may require prolonged observation, as treatment with antihistamines and corticosteroids may be insufficient.

Very rare cases of death due to angioedema associated with laryngeal or tongue swelling have been reported. Patients with involvement of the tongue, glottis, or larynx may develop airway obstruction, especially in patients who have previously undergone airway surgery. In such cases, immediate emergency medical assistance should be provided, which may include administration of adrenaline and/or airway support. The patient should remain under close physician supervision until symptoms have completely and stably resolved.

Intestinal angioedema has been very rarely reported in patients receiving ACE inhibitor therapy. These patients complained of abdominal pain (with or without nausea and vomiting); in some cases, there was no prior history of facial angioedema and C-1 esterase levels were normal. Diagnosis of angioedema should include computed tomography or ultrasound imaging, or surgical consultation, and symptoms should resolve after discontinuation of ACE inhibitors. Intestinal angioedema should be considered in the differential diagnosis of patients receiving ACE inhibitors who present with abdominal pain.

ACE inhibitors cause angioedema more frequently in patients of non-Caucasian race than in patients of other races.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be more susceptible to developing angioedema during ACE inhibitor use (see section "Contraindications").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Sacubitril/valsartan therapy should not be initiated earlier than 36 hours after the last dose of lisinopril. Lisinopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with racécadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and 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"). Patients already receiving ACE inhibitors should initiate treatment with racécadotril, mTOR inhibitors, and vildagliptin with caution.

Anaphylactoid reactions in patients undergoing hemodialysis

Anaphylactoid reactions have been reported in patients undergoing dialysis with high-flux, highly permeable dialysis membranes (e.g., AN 69) while concurrently receiving an ACE inhibitor. Consideration should be given to using a different type of dialysis membrane or antihypertensive agent of another class in such patients.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis

In isolated cases, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulfate. Such reactions can be avoided by withholding ACE inhibitor therapy before each apheresis session.

Desensitization

Sustained anaphylactoid reactions have occurred in patients receiving ACE inhibitors during desensitization to hymenoptera venom (e.g., Hymenoptera venom). Anaphylactoid reactions were avoided in such patients by temporarily discontinuing ACE inhibitors, but recurred after accidental re-administration.

Hepatic impairment

Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice, progressing to fulminant necrosis, and (sometimes) resulting in death. The mechanism of this syndrome is unclear. Patients receiving lisinopril who develop jaundice or markedly elevated liver enzyme activity should discontinue lisinopril and remain under appropriate medical supervision.

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia is rare. Neutropenia and agranulocytosis are reversible and resolve after discontinuation of the ACE inhibitor.

Lisinopril should be used with particular caution in patients with systemic connective tissue diseases, immunosuppressive therapy, allopurinol, or procainamide, or in combination with these risk factors, especially with pre-existing renal impairment. Serious infections, which in several cases were unresponsive to intensive antibiotic therapy, have developed in some of these patients. Periodic laboratory testing (blood count with leukocyte differential) is recommended during lisinopril therapy in such patients, and they should be warned to report any early signs of infection.

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

Concomitant use of ACE inhibitors, angiotensin II receptor blockers (ARBs), or aliskiren increases the risk of arterial hypotension, hyperkalemia, and renal impairment (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, ARBs, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

If dual RAAS blockade is absolutely indicated, careful monitoring by a specialist and mandatory monitoring of renal function, fluid and electrolyte balance, and blood pressure are required.

ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.

Race

ACE inhibitors cause angioedema more frequently in patients of non-Caucasian race than in patients of other races. As with other ACE inhibitors, lisinopril may be less effective in lowering blood pressure in patients of non-Caucasian race compared to patients of other races, likely due to the higher prevalence of low-renin states in non-Caucasian patients with arterial hypertension.

Cough

Cough has been reported with ACE inhibitor use. The cough is usually non-productive, persistent, and resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/anesthesia

In patients undergoing major surgery or general anesthesia with hypotensive agents, lisinopril may block angiotensin II formation following compensatory renin release. If arterial hypotension develops, likely due to the above mechanism, correction can be achieved by increasing circulating blood volume.

Hyperkalemia

ACE inhibitors may cause hyperkalemia as they inhibit aldosterone secretion. This effect is usually clinically insignificant in patients with normal renal function. However, hyperkalemia may develop in patients with impaired renal function, type II diabetes, and/or those taking potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), or other drugs that may increase serum potassium levels (e.g., heparin, trimethoprim, or the combination drug co-trimoxazole (trimethoprim/sulfamethoxazole)), and particularly with aldosterone antagonists or angiotensin receptor blockers. Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients taking ACE inhibitors. Regular monitoring of serum potassium and renal function is recommended if concomitant use of these drugs is necessary (see section "Interaction with other medicinal products and other forms of interaction").

Patients with diabetes

In patients with diabetes receiving oral hypoglycemic agents or insulin, careful monitoring of glycemia should be performed during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

Lithium preparations

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

Special precautions for use related to amlodipine

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

Heart failure

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

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

Hepatic impairment

In patients with hepatic impairment, prolonged elimination half-life and increased AUC of amlodipine have been observed, but no specific dosing recommendations have been established. Therefore, amlodipine should be initiated at the lowest dose within the dosing range. Initiation and dose escalation should be done cautiously. Patients with severe hepatic impairment may require slow dose titration and careful monitoring.

Elderly patients

Dose escalation should be done cautiously in elderly patients (see sections "Pharmacokinetics" and "Dosage and administration").

Renal impairment

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

Special precautions for use related to LiRam

This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

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

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

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

Initiation of LiRam during pregnancy is not recommended. If continued treatment with LiRam 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 teratogenic risk associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive, although a slight increase in risk cannot be excluded. If continued treatment with an ACE inhibitor 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 treatment should be immediately discontinued and alternative therapy initiated if necessary.

It is known that ACE inhibitor use during the second and third trimesters of pregnancy induces fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If an ACE inhibitor was used from the second trimester of pregnancy, ultrasound assessment of renal and skull function is recommended. Close monitoring of newborns and breastfed infants whose mothers received ACE inhibitors is recommended to detect arterial hypotension promptly (see sections "Contraindications" and "Special precautions for use").

Use of amlodipine

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

It is known that reproductive toxicity was observed in animal studies with high doses. Use during pregnancy is possible only if no safer alternative treatment is available and when the disease itself poses a significant risk to the mother and fetus.

Period of breastfeeding

There is no information on the use of lisinopril during breastfeeding. Amlodipine is excreted in breast milk. The amount of amlodipine received by the infant through breast milk is estimated at an interquartile range of 3–7%, maximum 15%. The effect of amlodipine on the infant has not been evaluated.

The medicinal product LiRam is contraindicated during breastfeeding; alternative agents with established safety profiles should be used, especially when breastfeeding a newborn or preterm infant (see section "Contraindications").

Fertility

There are no adequate and well-controlled clinical studies on the effect of lisinopril and amlodipine on fertility.

Use of amlodipine

Reversible biochemical changes in sperm heads have been reported in some patients receiving calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient.

Ability to affect reaction speed when driving or operating machinery.

Related to lisinopril

When driving or operating machinery, the possible development of dizziness or fatigue should be considered.

Related to amlodipine

Amlodipine may have a slight or moderate effect on the ability to drive and operate machinery. Patients experiencing dizziness, headache, fatigue, or nausea may have impaired reaction ability. Caution is recommended, especially at the beginning of treatment.

According to the above, LiRam may affect the ability to drive vehicles and operate machinery (especially at the beginning of treatment).

Method of Administration and Dosage.

Doses

The recommended dose is 1 tablet per day. The maximum daily dose is 1 tablet.

Fixed-dose combination drugs are generally not suitable for initial therapy.

LIRAM tablets 10 mg/5 mg are indicated only for patients whose optimally titrated maintenance doses of lisinopril and amlodipine are 10 mg and 5 mg, respectively. If necessary, consideration should be given to switching to another strength of LIRAM containing different doses of the individual components.

Renal Impairment

For optimal selection of initial and maintenance doses in patients with renal impairment, dose titration should be performed individually using the separate components of the drug—lisinopril and amlodipine.

During treatment with LIRAM, renal function and serum potassium and sodium levels should be monitored. If renal function worsens, LIRAM should be discontinued and replaced with appropriately selected individual components. It should be noted that amlodipine is not removed during dialysis.

Hepatic Impairment

Dosage recommendations for patients with mild or moderate hepatic impairment have not yet been established; therefore, dose selection in such patients should be done cautiously, starting with the lowest possible dose (see sections "Pharmacokinetics" and "Special Warnings"). For optimal selection of initial and maintenance doses in patients with hepatic impairment, dose titration should be performed individually using lisinopril and amlodipine as monotherapies.

The pharmacokinetics of amlodipine in severe hepatic impairment have not been studied. Amlodipine therapy in patients with severe hepatic impairment should be initiated at the lowest dose, and dose titration should be performed slowly.

Elderly Patients (aged 65 years and older)

LIRAM should be prescribed with caution in elderly patients.

Clinical studies have not shown age-related changes in the efficacy or safety profiles of amlodipine or lisinopril. To determine the optimal maintenance dose for elderly patients, dose titration should be performed individually using lisinopril and amlodipine as monotherapies.

Method of Administration

Oral administration. Since food does not affect drug absorption, LIRAM can be taken independently of meals—before, during, or after food intake.

Children

The safety and efficacy of LIRAM in children (under 18 years of age) have not been established.

Overdose

There are no data on overdose with LIRAM in humans.

Overdose of Lisinopril

Data on lisinopril overdose in humans are limited. Symptoms associated with angiotensin-converting enzyme (ACE) inhibitor overdose may include arterial hypotension, circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. In case of overdose, intravenous administration of physiological saline solution 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 the drug was recently ingested, measures should be taken to remove lisinopril (e.g., inducing vomiting, gastric lavage, administration of sorbents and sodium sulfate). Lisinopril can be removed from systemic circulation by hemodialysis (see section "Special Warnings"). In cases of bradycardia refractory to medical therapy, implantation of a pacemaker is indicated. Continuous monitoring of vital signs, serum electrolytes, and serum creatinine concentration is required.

Overdose of Amlodipine

Data on intentional amlodipine overdose in humans are limited.

Symptoms

Overdose may lead to excessive peripheral vasodilation with reflex tachycardia. Severe 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. Early resuscitation measures (including fluid loading) to support perfusion and cardiac output may act as precipitating factors.

Treatment

In cases of clinically significant arterial hypotension due to amlodipine overdose, active cardiovascular support measures are required, including frequent monitoring of cardiovascular and respiratory parameters. The patient should be placed in a supine position with legs elevated, and circulating blood volume and diuresis should be monitored.

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

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 protein-bound, dialysis is ineffective.

Overdose of LIRAM

Overdose with LIRAM may result in excessive peripheral vasodilation with marked arterial hypotension and acute circulatory failure, electrolyte imbalances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Symptomatic treatment is recommended, including placing the patient in a supine position, close observation, and, if necessary, supportive care to maintain cardiovascular and respiratory functions, blood pressure, circulating blood volume, electrolyte balance, and serum creatinine concentration. In cases of pronounced arterial hypotension, the patient should be placed in a supine position with legs elevated. If fluid administration does not produce sufficient response, 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.

Lisinopril can be removed from systemic circulation by hemodialysis. The use of high-flux polyacrylonitrile membranes during dialysis is not recommended.

Adverse reactions

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Within each frequency category, adverse reactions are listed in order of decreasing severity.

Adverse reactions observed and reported during treatment with lisinopril and amlodipine separately

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

** Most frequently associated with cholestasis.

Clinical safety data suggest that lisinopril is generally well tolerated in children and adolescents with hypertension, and the safety profile in this age group is comparable to that in adults.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important and allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report suspected adverse reactions through the national adverse reaction reporting system.

Shelf life. 4 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep the medicine out of the reach of children!

Packaging. 10 tablets per blister; 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Public joint-stock company “Scientific and Production Center “Boryspilsky Chemical-Pharmaceutical Plant”.

Manufacturer’s address and location of manufacturing activities.

17, Miru Street, Kyiv, 03134, Ukraine.