Zanidip^® COMBO (Tablets) Instructions for Use

Marketing Authorization Holder

Rusfik, LLC (Russia)

Manufactured By

Recordati Industria Chimica E Farmaceutica S.p.A. (Italy)

ATC Code

C09BB02 (Enalapril and lercanidipine)

Active Substances

Enalapril (Rec.INN registered by WHO)

Lercanidipine (Rec.INN registered by WHO)

Dosage Forms

	Zanidip® COMBO	Film-coated tablets, 10 mg+10 mg: 28 or 56 pcs.
		Film-coated tablets, 10 mg+20 mg: 28 or 56 pcs.
		Film-coated tablets, 20 mg+20 mg: 28 or 56 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex, with a light yellow core on the cross-section.

Excipients: lactose monohydrate – 102 mg, microcrystalline cellulose (type 101) – 40 mg, sodium carboxymethyl starch (type A) – 20 mg, povidone K30 – 8 mg, sodium bicarbonate – 8 mg, magnesium stearate – 2 mg.

Shell composition Opadry^® white (02F29056) – 6 mg [hypromellose-5cP – 3.825 mg, titanium dioxide (E171) – 1.275 mg, talc – 0.3 mg, macrogol-6000 – 0.6 mg].

14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.
28 pcs. – blisters (1) – cardboard packs.
28 pcs. – blisters (2) – cardboard packs.
56 pcs. – blisters (1) – cardboard packs.

Film-coated tablets yellow, round, biconvex, with a light yellow core on the cross-section.

Excipients: lactose monohydrate – 92 mg, microcrystalline cellulose (type 101) – 40 mg, sodium carboxymethyl starch (type A) – 20 mg, povidone K30 – 8 mg, sodium bicarbonate – 8 mg, magnesium stearate – 2 mg.

Shell composition Opadry^® yellow (02F22330) – 6 mg [hypromellose-5cP – 3.825 mg, titanium dioxide (E171) – 1.139 mg, talc – 0.3 mg, macrogol-6000 – 0.6 mg, quinoline yellow dye (E104) – 0.121 mg, yellow iron oxide dye (E172) – 0.015 mg].

14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.
28 pcs. – blisters (1) – cardboard packs.
28 pcs. – blisters (2) – cardboard packs.
56 pcs. – blisters (1) – cardboard packs.

Film-coated tablets orange, round, biconvex, with a light yellow core on the cross-section.

Excipients: lactose monohydrate – 204 mg, microcrystalline cellulose (type 101) – 80 mg, sodium carboxymethyl starch (type A) – 40 mg, povidone K30 – 16 mg, sodium bicarbonate – 16 mg, magnesium stearate – 4 mg.

Shell composition Opadry^® orange (02F23516) – 10 mg [hypromellose-5cP – 6.375 mg, titanium dioxide (E171) – 1.405 mg, talc – 0.5 mg, macrogol-6000 – 1 mg, yellow iron oxide dye (E172) – 0.625 mg, red iron oxide dye (E172) – 0.095 mg].

14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.
28 pcs. – blisters (1) – cardboard packs.
28 pcs. – blisters (2) – cardboard packs.
56 pcs. – blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Combined antihypertensive drug (slow calcium channel blocker + ACE inhibitor)

Pharmacotherapeutic Group

Combined antihypertensive agent (CCB + ACE inhibitor)

Pharmacological Action

Combined antihypertensive drug.

Lercanidipine is a selective calcium channel blocker, a dihydropyridine derivative. It inhibits the transmembrane flow of calcium ions into myocardial cells and vascular smooth muscle cells. The mechanism of the antihypertensive action is due to a direct relaxing effect on vascular smooth muscle cells, resulting in a decrease in total peripheral vascular resistance. Despite the relatively short plasma T_1/2, lercanidipine has a long-lasting antihypertensive effect due to its high membrane distribution coefficient. Due to its high vascular selectivity, lercanidipine does not have a negative inotropic effect.

Pronounced blood pressure reduction with reflex tachycardia rarely occurs due to the gradual development of vasodilation when taking lercanidipine.

Lercanidipine is a racemic mixture of (+)R and (-)S enantiomers. The antihypertensive effect of lercanidipine, like other asymmetric 1,4-dihydropyridine derivatives, is mainly determined by the S-enantiomer.

Enalapril is an ACE inhibitor, suppresses the formation of angiotensin II and eliminates its vasoconstrictive effect. It reduces blood pressure without causing an increase in heart rate and cardiac output. It reduces total peripheral vascular resistance, decreases afterload and preload on the heart. It reduces pressure in the right atrium and in the pulmonary circulation. It does not affect glucose metabolism, lipoproteins, or the function of the reproductive system.

Pharmacokinetics

No pharmacokinetic interaction was identified with the simultaneous use of lercanidipine and enalapril.

Lercanidipine is completely absorbed after oral administration, its C_max in plasma is reached in approximately 1.5-3 hours. The enantiomers of lercanidipine demonstrate a similar pharmacokinetic profile: they have the same time to reach maximum concentration (T_max), the same T_1/2. The C_max in plasma and AUC of the S-enantiomer of lercanidipine are, on average, 1.2 times greater than those of the R-enantiomer. Interconversion of the two enantiomers in vivo is absent.

Due to high first-pass metabolism through the liver, the absolute bioavailability of lercanidipine after food intake is about 10%. When taken orally on an empty stomach, the bioavailability in healthy volunteers was 1/3 of the bioavailability after food intake.

The bioavailability of lercanidipine when taken orally increases 4-fold if taken within 2 hours after a high-fat meal, therefore, the drug should be taken at least 15 minutes before meals. The pharmacokinetics of lercanidipine in the therapeutic dose range is non-linear. When lercanidipine was taken in doses of 10 mg, 20 mg, or 40 mg, the C_max in plasma was determined in a ratio of 1:3:8, respectively, and AUC – in a ratio of 1:4:18, suggesting progressive saturation during first-pass through the liver. Accordingly, bioavailability increases with increasing dose taken.

Lercanidipine is rapidly and actively distributed from plasma to tissues and organs. The binding of lercanidipine to plasma proteins exceeds 98%. Since plasma protein concentration decreases in patients with severe renal or hepatic impairment, this may lead to an increase in the free fraction of lercanidipine. Lercanidipine is actively metabolized by the CYP3A4 isoenzyme, mainly converting into inactive metabolites.

Elimination of lercanidipine occurs primarily through biotransformation. About 50% of the administered dose is excreted by the kidneys. The mean T_1/2 is, on average, 8-10 hours. Due to the tight binding of lercanidipine to the lipid membrane, the duration of the therapeutic action of lercanidipine is 24 hours. It does not accumulate upon repeated administration.

The pharmacokinetics of lercanidipine in elderly patients and patients with mild or moderate renal or hepatic impairment is similar to that in healthy volunteers. In patients with severe renal failure and patients on hemodialysis, the plasma concentration of lercanidipine increased by approximately 70%. In patients with moderate and severe hepatic impairment, the systemic bioavailability of lercanidipine is likely to increase, as lercanidipine is metabolized primarily in the liver.

After oral administration, enalapril is rapidly absorbed. C_max of enalapril in plasma is observed within 1 hour after oral administration. The absorption of enalapril after oral administration is about 60% and does not depend on food intake. After absorption, enalapril is rapidly and actively hydrolyzed to enalaprilat, a potent ACE inhibitor. C_max of enalaprilat in plasma is reached 3-4 hours after oral administration. The binding of enalaprilat to plasma proteins at therapeutic doses does not exceed 60%. Apart from conversion to enalaprilat, no other metabolic changes of enalapril have been identified. Enalapril is excreted by the kidneys: about 40% as enalaprilat and about 20% as unchanged enalapril. Exposure to enalapril and enalaprilat increases in patients with renal failure. In patients with mild and moderate renal impairment (creatinine clearance 40-60 ml/min) after taking enalapril at a dose of 5 mg once daily, the AUC of enalaprilat is approximately 2 times greater than in patients with normal renal function. In severe renal impairment (creatinine clearance < 30 ml/min), the AUC increases approximately 8-fold, and the T_1/2 of enalaprilat is also prolonged. Enalaprilat can be removed from the systemic circulation by hemodialysis. Dialysis clearance is 62 ml/min.

Indications

Essential hypertension (when monotherapy with enalapril or lercanidipine is ineffective).

ICD codes

Dosage Regimen

Take the tablet orally, once daily. Administer the dose at least 15 minutes before a meal to ensure adequate absorption.

Swallow the tablet whole with a glass of water; do not crush or chew.

The recommended initial dose is one tablet of Zanidip^® COMBO 10 mg+10 mg (lercanidipine/enalapril) per day.

Depending on the individual therapeutic response and tolerability, the dose may be increased. Titrate the dose gradually, with adjustments typically made at intervals of 2 to 4 weeks.

The maximum recommended daily dose is one tablet of Zanidip^® COMBO 10 mg+20 mg or 20 mg+20 mg.

For elderly patients, dosage must be individualized and depends on renal function; initiate therapy with caution.

In patients with mild to moderate renal impairment (creatinine clearance ≥30 ml/min), therapy should be initiated under close medical supervision. Do not use in patients with severe renal impairment (creatinine clearance <30 ml/min) or those on hemodialysis.

In patients with mild to moderate hepatic impairment, use with caution. The drug is contraindicated in patients with severe hepatic impairment (Child-Pugh score >9).

Monitor blood pressure and renal function periodically during therapy, especially after dose adjustments.

Adverse Reactions

Definition of frequency of adverse effects: very common (> 1/10); common (from > 1/100 to < 1/10); uncommon (from > 1/1000 to < 1/100); rare (from >1/10000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Lercanidipine + enalapril

From the blood and lymphatic system: uncommon – thrombocytopenia, decreased serum hemoglobin.

From the immune system: uncommon – hypersensitivity to one of the components of the drug, angioedema.

From the metabolism and nutrition: uncommon – hypertriglyceridemia.

Psychiatric disorders uncommon – anxiety.

From the nervous system common – dizziness; uncommon: headache.

From the ear and labyrinth disorders common – vertigo, including positional vertigo.

From the cardiovascular system: common – sensation of “flushing”; uncommon – pronounced decrease in blood pressure, vascular collapse, sensation of palpitations and tachycardia, decompensation of chronic heart failure.

From the respiratory system: common – cough, pharyngolaryngeal pain; uncommon – dry oral mucosa.

From the digestive system: uncommon – abdominal pain, nausea, constipation, dyspepsia, glossitis, increased ALT activity, AST activity.

From the skin and subcutaneous tissues uncommon – dermatitis, lip edema, erythema, urticaria, skin rash.

From the musculoskeletal system uncommon – arthralgia.

From the urinary system: uncommon – pollakiuria, polyuria, nocturia.

From the reproductive system: uncommon – erectile dysfunction.

General: common – peripheral edema; uncommon – asthenia, increased fatigue, feeling of heat.

Enalapril

From the hematopoietic system uncommon – anemia (including aplastic and hemolytic); rare – neutropenia, decreased serum hemoglobin and hematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune diseases.

From the immune system: common – hypersensitivity reactions/angioedema (angioedema of the face, extremities, lips, tongue, pharynx and/or larynx has been described).

From the endocrine system uncommon – hypoglycemia; frequency not known – syndrome of inappropriate ADH secretion.

Psychiatric disorders: common – depression; uncommon – confusion, drowsiness, insomnia, nervousness; rare – abnormal dreams, sleep disturbance.

From the nervous system: very common – dizziness; common – headache; uncommon – paresthesia.

From the organ of vision: very common – blurred vision.

From the ear and labyrinth disorders: uncommon – tinnitus, vertigo.

From the cardiovascular system: common – chest pain, cardiac arrhythmia, angina pectoris, tachycardia, myocardial infarction (possibly due to a sharp drop in blood pressure in high-risk patients), pronounced decrease in blood pressure (including orthostatic hypotension), syncope, stroke (possibly due to a sharp drop in blood pressure in high-risk patients); uncommon – sensation of palpitations, sensation of “flushing”; rare – Raynaud’s syndrome.

From the respiratory system: very common – cough; common – dyspnea, pharyngolaryngeal pain; uncommon – rhinorrhea, sore throat and hoarseness, bronchospasm/bronchial asthma; rare – pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.

From the digestive system very common – nausea; common – diarrhea, abdominal pain, flatulence, taste perversion; uncommon – ileitis, intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, dry oral mucosa, stomach pain, peptic ulcer; rare – stomatitis / aphthous ulcers, glossitis; very rare – intestinal angioedema.

From the liver and biliary tract: rare – hepatic failure, hepatitis (hepatocellular or cholestatic), including hepatic necrosis, cholestasis (including jaundice).

From the skin and subcutaneous tissues: common – skin rash; uncommon – increased sweating, pruritus, urticaria, alopecia; rare – erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma. A symptom complex has been described that may include: fever, myalgia/myositis, arthralgia/arthritis, serositis, vasculitis, increased ESR, leukocytosis and eosinophilia, positive test for antinuclear antibodies. Skin rash, photosensitivity reactions or other skin manifestations may also occur.

From the musculoskeletal system: uncommon – muscle cramps.

From the urinary system : impaired renal function, proteinuria, renal failure; rare – oliguria.

From the reproductive system: uncommon – erectile dysfunction; rare – gynecomastia.

General reactions: very common – asthenia; common – increased fatigue; uncommon – malaise.

Laboratory and instrumental data: common – hyperkalemia, increased serum creatinine concentration; uncommon – increased serum urea concentration, hyponatremia; rare – increased activity of liver enzymes, increased serum bilirubin concentration.

When using ACE inhibitors, including enalapril, in patients receiving intravenous gold preparation (sodium aurothiomalate), a symptom complex has been described, including: facial flushing, nausea, vomiting, and a pronounced decrease in blood pressure.

Lercanidipine

From the immune system: very rare – hypersensitivity reactions.

Psychiatric disorders: rare – drowsiness.

From the nervous system uncommon – dizziness, headache.

From the cardiovascular system: uncommon – tachycardia, sensation of palpitations, sensation of “flushing”; rare – angina pectoris, chest pain; very rare – in patients with angina pectoris, an increase in the frequency, duration and severity of attacks is possible, fainting.

From the digestive system: rare – nausea, dyspepsia, diarrhea, abdominal pain, vomiting.

From the skin and subcutaneous tissues rare – skin rash.

From the musculoskeletal system: rare – myalgia.

From the urinary system: rare – polyuria.

General reactions: uncommon – peripheral edema; rare – asthenia, increased fatigue.

There are reports of the following very rare adverse events: myocardial infarction, gingival hyperplasia, reversible increase in liver transaminase activity, pronounced decrease in blood pressure, pollakiuria (increased frequency of urination), chest pain.

Contraindications

Obstruction of the left ventricular outflow tract, including aortic stenosis; decompensated chronic heart failure; unstable angina; the first month after myocardial infarction (within 28 days); severe hepatic failure (more than 9 points on the Child-Pugh scale); simultaneous use with cyclosporine, potent inhibitors of the CYP3A4 isoenzyme (ketoconazole, itraconazole, erythromycin, ritonavir, troleandomycin), grapefruit juice; pregnancy, breastfeeding period; use in women of childbearing potential not using reliable methods of contraception; severe renal failure (creatinine clearance less than 30 ml/min), including patients on hemodialysis; history of angioedema associated with previous use of ACE inhibitors; history of episodes of angioedema (idiopathic, hereditary); simultaneous use with aliskiren in patients with diabetes mellitus or moderate or severe renal impairment (creatinine clearance less than 60 ml/min); age under 18 years; increased individual sensitivity to one of the components of the combination, any ACE inhibitors, dihydropyridine derivatives.

With caution

Renovascular hypertension (bilateral renal artery stenosis or stenosis of the artery of a single kidney), primary hyperaldosteronism, hyperkalemia, conditions with reduced circulating blood volume (including diarrhea, vomiting), systemic connective tissue diseases (including scleroderma, systemic lupus erythematosus), coronary artery disease, bone marrow depression, diabetes mellitus, renal failure (creatinine clearance more than 30 ml/min), mild and moderate hepatic failure, use in patients on a salt-restricted diet, simultaneous use with immunosuppressants, allopurinol, procainamide and diuretics, use in elderly patients, condition after kidney transplantation, sick sinus syndrome (without simultaneous use of an artificial pacemaker), left ventricular dysfunction, aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy, before LDL apheresis procedure with dextran sulfate, chronic heart failure, severe arterial hypotension (systolic blood pressure less than 90 mm Hg), simultaneous desensitizing therapy with hymenoptera venom (risk of anaphylactoid reactions), use in patients of the Black race, surgical intervention and general anesthesia.

Use in Pregnancy and Lactation

Use is contraindicated during pregnancy and lactation (breastfeeding).

Pediatric Use

Use is contraindicated in children and adolescents under the age of 18 years (lack of data on efficacy and safety).

Geriatric Use

The dose for elderly patients depends on the state of renal function.

Special Precautions

Should not be used in patients with cardiogenic shock and hemodynamically significant left ventricular obstruction.

In patients with mild or moderate renal impairment, therapy should be initiated with particular caution.

In patients with bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney, treatment with ACE inhibitors increases the risk of arterial hypotension and renal failure. Only minor changes in serum creatinine concentration may indicate a decrease in renal function. In such patients, treatment should be initiated with low doses of Enap L Combi under close medical supervision. Dose titration should be performed cautiously and renal function should be monitored.

Use in patients who have recently undergone kidney transplantation is not recommended.

The antihypertensive effect of lercanidipine may be enhanced in patients with impaired liver function.

In rare cases, treatment with ACE inhibitors has been associated with a syndrome starting with cholestatic jaundice and progressing to fulminant hepatocyte necrosis (sometimes fatal). The mechanism of development of this syndrome has not been established. If jaundice develops or liver enzyme activity increases significantly, the ACE inhibitor should be discontinued immediately and appropriate treatment instituted.

Use with extreme caution in patients with connective tissue diseases (including systemic lupus erythematosus, scleroderma) who are simultaneously receiving immunosuppressive therapy, allopurinol or procainamide, as well as with a combination of these factors, especially in the presence of existing renal impairment. In such patients, severe infections that do not respond to intensive antibiotic therapy may develop. If patients are still taking drugs containing this combination, periodic monitoring of the white blood cell count is recommended.

In patients taking ACE inhibitors during desensitization with hymenoptera venom, life-threatening anaphylactoid reactions have developed in rare cases. To prevent such reactions, it is necessary to temporarily discontinue the combined medication during desensitization procedures.

In patients taking ACE inhibitors during LDL apheresis with dextran sulfate, life-threatening anaphylactoid reactions have developed in rare cases. It should be temporarily replaced with drugs of another group.

Due to the increased risk of anaphylactoid reactions, this combination should not be used in patients on hemodialysis using high-flux polyacrylonitrile membranes (AN69^®) undergoing LDL apheresis with dextran sulfate. If hemodialysis is necessary, it is advisable to use dialysis membranes of a different type or antihypertensive drugs of another group.

In patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentrations should be carefully monitored during the first month of treatment with an ACE inhibitor.

Cough during the use of an ACE inhibitor should be considered in the differential diagnosis.

This combination, like other drugs containing ACE inhibitors, has a less pronounced antihypertensive effect in patients of the Black race compared with representatives of other races.

In patients treated with ACE inhibitors, including enalapril, reports of the development of angioedema of the face, extremities, lips, vocal folds, and/or larynx have been registered at any time after starting treatment. Even in the case of swelling of the tongue only, when only difficulty swallowing without respiratory distress syndrome is present, patients may require prolonged observation, as the use of antihistamines and glucocorticosteroids may be insufficient.

Angioedema of the larynx or tongue can be fatal in very rare cases. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction, especially in patients with a history of airway surgery.

Among Black patients receiving ACE inhibitor therapy, the frequency of angioedema is higher than among patients of other races.

Patients with a history of angioedema not associated with the use of ACE inhibitors have an increased risk of developing angioedema when using any ACE inhibitor.

Before surgical intervention (including dental procedures), the surgeon/anesthesiologist must be informed about the use of this combination.

During extensive surgical interventions or general anesthesia using agents that cause arterial hypotension, ACE inhibitors can block the formation of angiotensin II in response to compensatory renin release. If a pronounced decrease in blood pressure develops, explained by such a mechanism, it can be corrected by the administration of plasma substitutes.

Hyperkalemia may develop during treatment with ACE inhibitors, including this combination. Risk factors for the development of hyperkalemia are: renal failure, old age (over 70 years), diabetes mellitus, some concomitant conditions (decreased blood volume, acute decompensated heart failure, metabolic acidosis), simultaneous use of potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), as well as potassium preparations or potassium-containing substitutes and the use of other drugs that contribute to an increase in plasma potassium levels (for example, heparin). The use of potassium preparations, potassium-sparing diuretics and potassium-containing substitutes can lead to a significant increase in serum potassium levels, especially in patients with impaired renal function. Hyperkalemia can lead to serious cardiac arrhythmias, sometimes fatal. Simultaneous use of the above-mentioned drugs should be carried out with caution under the control of serum potassium levels.

During treatment, alcohol consumption should be avoided, as it may enhance the antihypertensive effect.

During in vitro fertilization, in some cases, the use of slow calcium channel blockers caused changes in the head of spermatozoa, which may lead to impaired sperm function. In cases where repeated in vitro fertilization failed for an unclear reason, the use of CCBs is considered a possible cause of failure.

Effect on the ability to drive vehicles and mechanisms

The possibility of dizziness, asthenia, weakness, increased fatigue, and in rare cases, drowsiness should be taken into account. Therefore, caution should be exercised when driving vehicles and performing work requiring increased attention, especially at the beginning of treatment and when increasing the dose of the combination components.

Drug Interactions

The antihypertensive effect may be enhanced with simultaneous use with other antihypertensive drugs, such as: diuretics, beta-blockers, alpha-blockers and others.

Enalapril

The risk of developing arterial hypotension, hyperkalemia and impaired renal function (including acute renal failure) is higher in the case of dual blockade of the RAAS, i.e., with simultaneous use of angiotensin II receptor antagonists (ARBs), ACE inhibitors or aliskiren, compared with the use of a drug from one of the listed groups.

ACE inhibitors reduce potassium loss caused by diuretics. Simultaneous use of enalapril and potassium-sparing diuretics (such as: spironolactone, eplerenone, triamterene, amiloride), potassium preparations or potassium-containing substitutes, as well as the use of other drugs that contribute to an increase in plasma potassium levels (for example, heparin) can lead to hyperkalemia.

Prior therapy with high doses of diuretics can lead to a decrease in blood volume and an increased risk of arterial hypotension during the initiation of enalapril therapy. Excessive antihypertensive effect can be reduced by discontinuing the diuretic, increasing fluid or salt intake, and by initiating enalapril treatment at a low dose.

Simultaneous use of beta-blockers, alpha-blockers, ganglion-blocking agents, methyldopa, CCBs, nitroglycerin or other nitrates with enalapril may further reduce blood pressure.

When ACE inhibitors are used simultaneously with lithium preparations, a transient increase in serum lithium concentration and the development of lithium intoxication have been observed. The use of thiazide diuretics can lead to an additional increase in serum lithium concentration and the risk of lithium intoxication when used simultaneously with ACE inhibitors. Simultaneous use of enalapril with lithium is not recommended. If it is necessary to use such a combination, serum lithium concentrations should be carefully monitored.

Simultaneous use of some analgesic agents, tricyclic antidepressants and antipsychotic agents (neuroleptics) with ACE inhibitors may lead to an additional decrease in blood pressure.

Simultaneous use of NSAIDs (including selective COX-2 inhibitors) may weaken the antihypertensive effect of ACE inhibitors. NSAIDs and ACE inhibitors have an additive effect on increasing serum potassium levels, which can lead to worsening renal function, especially in patients with impaired renal function. This effect is reversible. In rare cases, acute renal failure may develop, especially in patients with pre-existing impaired renal function (for example, elderly patients or patients with severe hypovolemia, including due to the use of diuretics).

Epidemiological studies suggest that simultaneous use of ACE inhibitors and hypoglycemic agents (insulin and oral hypoglycemic agents) may lead to an enhancement of the hypoglycemic effect with a risk of hypoglycemia. Hypoglycemia occurs more often in the first weeks of therapy in patients with impaired renal function.

Ethanol enhances the antihypertensive effect of ACE inhibitors.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Weakens the effect of medicinal products containing theophylline.

Allopurinol, cytostatics and immunosuppressants (including methotrexate, cyclophosphamide): simultaneous use with ACE inhibitors may increase the risk of leukopenia. When used simultaneously with allopurinol, the risk of an allergic reaction increases, especially in patients with impaired renal function.

Cyclosporine: simultaneous use with ACE inhibitors may increase the risk of hyperkalemia.

Antacids may reduce the bioavailability of ACE inhibitors.

When ACE inhibitors, including enalapril, were used by patients receiving intravenous gold preparation (sodium aurothiomalate), a symptom complex was described, including: facial skin flushing, nausea, vomiting, pronounced decrease in blood pressure.

Lercanidipine

Lercanidipine can be used simultaneously with beta-blockers, diuretics, ACE inhibitors.

When used simultaneously with metoprolol, the bioavailability of lercanidipine decreases by 50%. This effect may also occur with simultaneous use with other beta-blockers, so dose adjustment of lercanidipine may be required to achieve a therapeutic effect in this combination.

Lercanidipine is metabolized with the participation of the CYP3A4 isoenzyme, therefore inhibitors and inducers of the CYP3A4 isoenzyme may affect the metabolism and excretion of lercanidipine when used simultaneously. Simultaneous use of lercanidipine with inhibitors of the CYP3A4 isoenzyme (ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) is not recommended.

Simultaneous use of cyclosporine and lercanidipine is not recommended, as an increase in the plasma concentration of both substances is observed.

Caution should be exercised when lercanidipine is used simultaneously with other substrates of the CYP3A4 isoenzyme (terfenadine, astemizole, class III antiarrhythmic drugs, for example, amiodarone, quinidine).

When lercanidipine 20 mg is used simultaneously with midazolam, the bioavailability of lercanidipine in elderly patients may increase by approximately 40%.

Lercanidipine should be used with caution simultaneously with inducers of the CYP3A4 isoenzyme, for example anticonvulsants (phenytoin, carbamazepine) and rifampicin, since a decrease in the antihypertensive effect of lercanidipine is possible. Regular blood pressure monitoring is necessary.

In patients continuously taking digoxin, no pharmacokinetic interaction was noted with the simultaneous use of lercanidipine 20 mg. However, in healthy volunteers who took digoxin, an increase in the C_max of digoxin in plasma was noted, on average, by 33% after oral administration of 20 mg lercanidipine on an empty stomach, while the AUC and renal clearance of digoxin changed insignificantly. It is necessary to monitor for signs of digoxin intoxication in patients taking digoxin and lercanidipine simultaneously.

Simultaneous use of lercanidipine with cimetidine (up to 800 mg) does not cause significant changes in the plasma concentration of lercanidipine. When using high doses of cimetidine, the bioavailability of lercanidipine and its antihypertensive effect may increase.

With simultaneous use of lercanidipine (20 mg) and simvastatin (40 mg), the AUC value for simvastatin increased by 56%, and for its active metabolite (beta-hydroxy acid) – by 28%. When taking the drugs at different times of the day (lercanidipine – in the morning, simvastatin – in the evening), unwanted interaction can be avoided.

No changes in the pharmacokinetics of warfarin were observed with the simultaneous use of 20 mg lercanidipine and warfarin in healthy volunteers.

With simultaneous use with fluoxetine {an inhibitor of CYP2D6 and CYP3A4 isoenzymes) in elderly patients, no clinically significant changes in the pharmacokinetics of lercanidipine were detected.

Enhancement of the antihypertensive effect is possible with simultaneous use of grapefruit juice and lercanidipine.

Ethanol may potentiate the antihypertensive effect of lercanidipine.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.