LIRAM

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

Composition:

Active substances: lisinopril, amlodipine;

One tablet contains:

lisinopril 20 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, round-shaped tablets with a flat surface, bevelled 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 peptidyl-dipeptidase enzyme. 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 serum potassium levels.

Since the mechanism by which lisinopril lowers arterial pressure is based on suppression of the renin-angiotensin-aldosterone system, lisinopril reduces arterial pressure even in patients with low-renin hypertension. 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 ion influx inhibitor (a slow calcium channel blocker or calcium antagonist) that blocks calcium ion entry through membranes into myocardial and vascular smooth muscle cells.

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

The exact reasons for the beneficial effect of amlodipine in angina are not fully understood; however, it is known that reduction of total ischemic load 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 leads to 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 results in 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 arterial pressure in patients with arterial hypertension both in the upright and supine positions over 24 hours. Due to its slow onset of action, a rapid hypotensive effect does not occur.

In patients with angina, a single daily dose of amlodipine increases exercise tolerance, prolongs the time between angina attacks, 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 2 diabetes, and gout.

Pharmacokinetics.

Lisinopril

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

Absorption

After oral administration, peak plasma concentration is 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%. Lisinopril absorption 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 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 serum concentration exhibits a prolonged terminal elimination half-life, 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 groups

Hepatic impairment

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

Renal impairment

In renal impairment, lisinopril elimination is reduced since 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 30–80 ml/min), the mean area under the concentration-time curve (AUC) increases by only 13%, whereas in severe renal impairment (creatinine clearance 5–30 ml/min), the mean AUC increases by 4.5 times. Lisinopril can be removed from the body by hemodialysis. After 4 hours of hemodialysis, plasma lisinopril concentration decreases on average by 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 approximately 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 of lisinopril and higher AUC values (approximately 60% higher) are observed compared to younger patients.

Amlodipine

Absorption, distribution, plasma protein binding

After administration in therapeutic doses, amlodipine is well absorbed, reaching peak plasma concentration 6–12 hours after administration. 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.

Biological transformation and elimination

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

Pharmacokinetic characteristics in special patient groups

Hepatic impairment

Clinical data on amlodipine use in patients with hepatic impairment 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 of amlodipine 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 elimination half-life.

Increases in AUC and elimination half-life in patients with congestive heart failure were 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) were not different 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 Lirаm is indicated for adult patients whose blood pressure is adequately controlled with concomitant use of lisinopril and amlodipine at similar doses.

Contraindications

Related to 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").

Related to amlodipine:

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

Related to the medicinal product Liram:

• All contraindications listed above associated with the use of individual components also apply to the combination product Liram;
• Hypersensitivity to any of the excipients of Liram (see section "Composition").

Interaction with Other Medicinal Products and Other Forms of Interaction

Interactions related to lisinopril

Antihypertensive agents

Concomitant use of lisinopril with other antihypertensive agents (e.g., nitroglycerin and other nitrates or 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 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 of lisinopril is usually enhanced when a diuretic is added to the treatment regimen. 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 "Method of Administration and Dosage").

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 during lisinopril therapy, hyperkalemia may occur in some patients. Potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or salt substitutes may lead to significant increases in serum potassium, especially in patients with impaired renal function. Caution should be exercised when lisinopril is used concomitantly with other agents that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim has 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 agents 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 exacerbate lithium toxicity already present due to ACE inhibitor use. Concomitant use of lisinopril and lithium preparations is not recommended; however, if such combination is required, 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 reduce the antihypertensive effect of ACE inhibitors. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including acute renal failure, and increase 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 at the start and during combination therapy.

Gold

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

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

Sympathomimetic agents may reduce the antihypertensive effect of ACE inhibitors.

Hypoglycemic agents

It is known that concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemics) 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 cardioprotective 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 related to 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. The clinical manifestations of these pharmacokinetic variations may be more pronounced in elderly patients. Therefore, medical monitoring is recommended, and dose adjustment of amlodipine may be necessary.

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

Concomitant use with known inducers of CYP3A4 isoenzyme may alter amlodipine blood concentrations. Therefore, blood pressure should be monitored and dosage adjustments of the medications may be required during and after combination therapy, especially with potent CYP3A4 inducers (such as rifampicin, Hypericum perforatum).

Consumption 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 hyperkalemia and subsequent fatal outcome were observed after administration of verapamil and 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 in the treatment of malignant hyperthermia.

Effect of amlodipine on other medicinal products

The antihypertensive effect of amlodipine enhances the corresponding effect 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 adjusted if necessary.

Inhibitors of mammalian target of rapamycin (mTOR)

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%) were observed. Therefore, in such patients, cyclosporine blood concentrations should be monitored during amlodipine therapy, and the cyclosporine dose reduced if necessary.

Simvastatin

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

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 salt-free diet, dialysis, diarrhea, vomiting, or in patients with pronounced renin-dependent arterial hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Cases of symptomatic hypotension have been reported in patients with heart failure, with or without renal impairment. Such cases are most likely in patients with more severe heart failure due to high doses of loop diuretics, hyponatremia, or functional renal impairment. 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 infusion of physiological saline), if necessary. Transient arterial hypotension is not a contraindication to continued use of the drug, and further administration usually does not cause problems after blood pressure increases 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

Treatment with 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 obstruction of the left ventricular outflow tract, 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 concentrations is part of standard medical practice in treating such patients.

In patients with heart failure, arterial hypotension after initiation of ACE inhibitor therapy 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 who received ACE inhibitors, increased blood urea nitrogen and serum creatinine concentrations may occur, usually reversible after discontinuation of the drug. This is especially likely in patients with 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 these 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 pronounced prior renovascular hypertension, increases in blood urea nitrogen and serum creatinine concentrations have been observed, usually mild and transient, especially when lisinopril is used concomitantly with diuretics. This is particularly likely in patients with prior renal impairment. Dose reduction and/or discontinuation of diuretics and/or lisinopril may be required.

In acute myocardial infarction, treatment with lisinopril 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 discontinuing lisinopril.

Proteinuria

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

Hypersensitivity, angioedema

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 supervision ensured until all symptoms resolve 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 rarely, fatal cases 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 reported very rarely in patients receiving ACE inhibitor therapy. These patients complained of abdominal pain (with or without nausea and vomiting); in some cases, prior facial angioedema was absent and C-1 esterase levels were normal. Diagnosis of angioedema should include computed tomography or ultrasound imaging, or surgical evaluation, and symptoms should resolve after discontinuation of ACE inhibitors. Intestinal angioedema should be considered in the differential diagnosis in patients taking ACE inhibitors who complain of abdominal pain.

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

Patients who have previously experienced angioedema unrelated to ACE inhibitor therapy may be more prone to developing angioedema when using an ACE inhibitor (see section "Contraindications").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Treatment with sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of lisinopril. Treatment with lisinopril 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 racecadotril, 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 taking ACE inhibitors should initiate treatment with racecadotril, 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 drug 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. These reactions can be avoided by withholding ACE inhibitor therapy before each apheresis session.

Desensitization

In patients receiving ACE inhibitors during desensitization with insect venom (e.g., Hymenoptera venom), persistent anaphylactoid reactions have occurred. 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 significantly 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 risk factors, neutropenia is rare. Neutropenia and agranulocytosis are reversible and resolve after discontinuation of the ACE inhibitor.

Lisinopril should be administered with particular caution to patients with systemic connective tissue diseases, immunosuppressive therapy, allopurinol, or procainamide, or in combination of these risk factors, especially with prior renal impairment. Serious infections, sometimes 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 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 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 specialist supervision 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 non-Caucasian patients than in patients of other races. As with other ACE inhibitors, lisinopril may be less effective in lowering blood pressure in non-Caucasian patients than in patients of other races, likely due to the higher frequency 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 may be achieved by increasing circulating blood volume.

Hyperkalemia

ACE inhibitors may cause hyperkalemia because they inhibit aldosterone secretion. This effect is usually clinically insignificant in patients with normal renal function. However, 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), other drugs that may increase serum potassium (e.g., heparin, trimethoprim, or the combination drug co-trimoxazole (trimethoprim/sulfamethoxazole)), and especially aldosterone antagonists or angiotensin receptor blockers, hyperkalemia may develop. Potassium-sparing diuretics and angiotensin receptor blockers should be used cautiously in patients taking ACE inhibitors. If concomitant use of these drugs is necessary, regular monitoring of serum potassium and renal function is recommended (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 blood glucose is required 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 and 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 study 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 future mortality.

Hepatic impairment

In patients with hepatic impairment, the elimination half-life of amlodipine is prolonged and AUC is increased, but specific dosing recommendations have not 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 "Posology and method of administration").

Renal impairment

Amlodipine can be administered to such patients at usual doses. 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").

Adequate controlled clinical studies on the use of lisinopril and amlodipine in pregnant women are lacking. 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 LiRam, the drug must be discontinued immediately, and if necessary, replaced with another medicinal product approved for use in 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, but 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 therapy should be discontinued immediately, 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. Newborns and infants whose mothers took ACE inhibitors should be closely monitored for early detection of arterial 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. Use during pregnancy is possible only if no safer alternative treatment is available and if the condition itself poses a significant risk to the mother and fetus.

Period of breastfeeding

Information on lisinopril use during breastfeeding is lacking. Amlodipine is excreted in breast milk. The amount of amlodipine received by the infant from 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 drugs with established safety profiles should be used, especially when breastfeeding a newborn or preterm infant (see section "Contraindications").

Fertility

Adequate controlled clinical studies on the effect of lisinopril and amlodipine on fertility are lacking.

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

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

Accordingly, the medicinal product LiRam may affect the ability to drive and operate machinery (especially at the beginning of treatment).

Dosage and Administration

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 20 mg/5 mg tablets are indicated only for patients whose individually titrated optimal maintenance doses of lisinopril and amlodipine are 20 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 selecting the optimal 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 deteriorates, LIRAM should be discontinued and replaced with appropriately selected individual components. Note 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 performed cautiously, starting with the lowest possible dose (see sections "Pharmacokinetics" and "Special Precautions"). For determining optimal 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 patients with 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 to elderly patients with caution.

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

Administration

Oral use. 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 LIRAM overdose 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 imbalances, 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 adsorbents and sodium sulfate). Lisinopril can be removed from systemic circulation by hemodialysis (see section "Special Precautions"). In case of bradycardia unresponsive to medical therapy, implantation of an artificial 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. Profound and prolonged systemic arterial hypotension has also 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 maintain perfusion and cardiac output may act as triggering factors.

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. 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. It is known from studies in healthy volunteers that administration of activated charcoal within 2 hours after taking 10 mg of amlodipine reduces the rate of amlodipine absorption.

Since amlodipine is highly protein-bound, dialysis is ineffective.

Overdose of LIRAM

Overdose of 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 horizontal 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 recorded during treatment with lisinopril and amlodipine administered separately

* A symptom complex has been reported that may include one or more of the following symptoms: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibody (ANA) test, 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 of suspected adverse reactions

Reporting of suspected adverse reactions after drug authorization is important and enables ongoing 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 medicinal product 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 “Borshchahivskiy Chemical and Pharmaceutical Plant”.

Manufacturer’s address and location of operations.

17 Myru Street, Kyiv, 03134, Ukraine.