Enap^® L Combi (Tablets) Instructions for Use

Marketing Authorization Holder

Krka-Rus, LLC (Russia)

ATC Code

C09BB02 (Enalapril and Lercanidipine)

Active Substances

Enalapril (Rec.INN registered by WHO)

Lercanidipine (Rec.INN registered by WHO)

Dosage Forms

	Enap^® L Combi	Film-coated tablets, 10 mg+10 mg: 7, 10, 28, 30, 56, 60, 84 or 90 pcs.
		Film-coated tablets, 10 mg+20 mg: 7, 10, 28, 30, 56, 60, 84 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, slightly biconvex, with beveled edges; the fracture view: a rough mass of yellowish-white color, with a white film coating.

	1 tab.
Lercanidipine hydrochloride	10 mg
Enalapril maleate	10 mg

Excipients: povidone K-30 – 10 mg, maleic acid – 5 mg, sodium carboxymethyl starch (type A) – 40 mg, lactose monohydrate – 317 mg, sodium stearyl fumarate – 8 mg.

Film coating composition Opadry white 00F280002 – 10 mg, including hypromellose – 65%, titanium dioxide – 20%, talc – 5%, macrogol – 10%.

7 pcs. – blister packs (1) – cardboard packs.
7 pcs. – blister packs (4) – cardboard packs.
7 pcs. – blister packs (8) – cardboard packs.
7 pcs. – blister packs (12) – cardboard packs.
10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.
14 pcs. – blister packs (2) – cardboard packs.
14 pcs. – blister packs (4) – cardboard packs.
14 pcs. – blister packs (6) – cardboard packs.

Film-coated tablets yellow, round, slightly biconvex, with beveled edges; the fracture view: a rough mass of yellowish-white color, with a yellow film coating.

	1 tab.
Lercanidipine hydrochloride	10 mg
Enalapril maleate	20 mg

Excipients: povidone K-30 – 10 mg, maleic acid – 5 mg, sodium carboxymethyl starch (type A) – 40 mg, lactose monohydrate – 307 mg, sodium stearyl fumarate – 8 mg.

Film coating composition Opadry white 00F220000 – 10 mg, including hypromellose – 64.36%, iron oxide yellow 0.66%, titanium dioxide – 19.8%, talc – 4.95%, quinoline yellow 0.33%, macrogol – 9.9%.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Combined antihypertensive agent (CCB + ACE inhibitor)

Pharmacological Action

The drug Enap^® L Combi is a fixed combination of the ACE inhibitor enalapril and the calcium channel blocker (CCB) lercanidipine.

Lercanidipine

Lercanidipine is a selective CCB, a dihydropyridine derivative, it inhibits the transmembrane influx 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 (TPR). Despite the relatively short half-life (T_1/2) from plasma, 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.

A pronounced decrease in blood pressure (BP) 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

Enalapril is an ACE inhibitor, it suppresses the formation of angiotensin II and eliminates its vasoconstrictive effect. It lowers BP without causing an increase in heart rate (HR) and cardiac output. It reduces TPR, 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 found with the simultaneous use of lercanidipine and enalapril.

Lercanidipine

Absorption

Lercanidipine is completely absorbed after oral administration, and its maximum concentration (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 the area under the concentration-time curve (AUC) of the S-enantiomer of lercanidipine are, on average, 1.2 times higher than those of the R-enantiomer. There is no interconversion of the two enantiomers in vivo.

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

The bioavailability of lercanidipine when taken orally increases 4 times 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 range of therapeutic doses is non-linear. When lercanidipine was taken at 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 the AUC in a ratio of 1:4:18, suggesting progressive saturation during the first pass through the liver. Accordingly, bioavailability increases with increasing dose taken.

Distribution

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

Metabolism

Lercanidipine is actively metabolized by the isoenzyme CYP3A4, mainly turning into inactive metabolites.

Excretion

Lercanidipine is eliminated primarily by 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.

Pharmacokinetics in special patient groups

Elderly patients

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, since Lercanidipine is metabolized primarily in the liver.

Enalapril

Absorption

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.

Distribution

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 in the range of therapeutic doses does not exceed 60%.

Metabolism

Apart from conversion to enalaprilat, no other metabolic changes of enalapril have been identified.

Excretion

Enalapril is excreted by the kidneys: about 40% as enalaprilat and about 20% as unchanged enalapril.

Pharmacokinetics in special patient groups

Renal impairment

The exposure of enalapril and enalaprilat increases in patients with renal failure. In patients with mild and moderate renal impairment (CrCl 40-60 ml/min) after taking enalapril at a dose of 5 mg once a day, the AUC of enalaprilat is approximately 2 times greater than in patients with normal renal function. In severe renal impairment (CrCl < 30 ml/min), the AUC increases approximately 8 times, and the T_1/2 of enalaprilat is also prolonged.

Enalaprilat can be removed from the systemic circulation by hemodialysis. The dialysis clearance is 62 ml/min.

Indications

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

ICD codes

Open the list of ICD codes

ICD-10 code	Indication
I10	Essential [primary] hypertension

ICD-11 code	Indication
BA00.Z	Essential hypertension, unspecified

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

Orally, once a day, take at least 15 minutes before meals, preferably in the morning, without chewing, with a sufficient amount of water. Do not take with grapefruit juice.

Recommended dose: 1 tablet of Enap^® L Combi (Lercanidipine 10 mg/Enalapril 10 mg) per day.

Depending on the clinical effect and individual patient tolerance of therapy with Enap^® L Combi, its dose can be increased to Lercanidipine 10 mg/Enalapril 20 mg once a day.

Elderly patients

The dose depends on the state of renal function.

Patients with renal impairment

Caution should be exercised when using Enap^® L Combi in patients with mild or moderate renal impairment.

Patients with hepatic impairment

Caution should be exercised when using Enap^® L Combi in patients with mild or moderate hepatic impairment (less than 9 points on the Child-Pugh scale).

Adverse Reactions

Classification of the 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 (< 1/10000); frequency not known (cannot be estimated from the available data).

When using the combination Lercanidipine /Enalapril

Blood and lymphatic system disorders

Uncommon: thrombocytopenia, decreased serum hemoglobin.

Immune system disorders

Uncommon: hypersensitivity to one of the components of the drug, angioedema.

Metabolism and nutrition disorders

Uncommon: hypertriglyceridemia.

Psychiatric disorders

Uncommon: anxiety.

Nervous system disorders

Common: dizziness; uncommon: headache.

Ear and labyrinth disorders

Common: vertigo, including positional.

Cardiac disorders:

Uncommon: palpitations and tachycardia, decompensation of CHF.

Vascular disorders:

Common: feeling of “flushing”; uncommon: pronounced decrease in BP, vascular collapse.

Respiratory, thoracic and mediastinal disorders:

Common: cough, pharyngolaryngeal pain;

Uncommon: dry oral mucosa.

Gastrointestinal disorders:

Uncommon: abdominal pain, nausea, constipation, dyspepsia, glossitis.

Skin and subcutaneous tissue disorders

Uncommon: dermatitis, lip edema, erythema, urticaria, skin rash.

Musculoskeletal and connective tissue disorders

Uncommon: arthralgia.

Renal and urinary disorders:

Uncommon: pollakiuria, polyuria, nocturia.

Reproductive system and breast disorders:

Uncommon: erectile dysfunction.

General disorders and administration site conditions:

Common: peripheral edema;

Uncommon: asthenia, increased fatigue, feeling of heat.

Laboratory and instrumental data

Uncommon: increased ALT activity, AST.

When using enalapril

Blood and lymphatic system disorders

Uncommon: anemia (including aplastic and hemolytic);

Rare: neutropenia, decreased serum hemoglobin and hematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune diseases.

Immune system disorders

Common: hypersensitivity reactions/angioedema (angioedema of the face, extremities, lips, tongue, pharynx and/or larynx has been described).

Endocrine disorders

Uncommon: hypoglycemia;

Frequency not known: syndrome of inappropriate antidiuretic hormone secretion.

Psychiatric disorders:

Common: depression;

Uncommon: confusion, drowsiness, insomnia, nervousness;

Rare: abnormal dreams, sleep disorder.

Nervous system disorders

Very common: dizziness;

Common: headache;

Uncommon: paresthesia.

Eye disorders

Very common: blurred vision.

Ear and labyrinth disorders

Uncommon: tinnitus, vertigo.

Cardiac disorders

Common: chest pain, cardiac arrhythmia, angina pectoris, tachycardia, myocardial infarction (possibly due to a sharp drop in BP in high-risk patients);

Uncommon: palpitations.

Vascular disorders

Common: pronounced decrease in BP (including orthostatic hypotension), syncope, stroke (possibly due to a sharp drop in BP in high-risk patients);

Uncommon: feeling of “flushing”;

Rare: Raynaud’s syndrome.

Respiratory, thoracic and mediastinal disorders

Very common: cough;

Common: dyspnea, pharyngolaryngeal pain;

Uncommon: rhinorrhea, sore throat and hoarseness, bronchospasm/bronchial asthma;

Rare: pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.

Gastrointestinal disorders

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.

Hepatobiliary disorders

Rare: hepatic failure, hepatitis (hepatocellular or cholestatic), including hepatic necrosis, cholestasis (including jaundice).

Skin and subcutaneous tissue disorders:

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 erythrocyte sedimentation rate (ESR), leukocytosis and eosinophilia, positive test for antinuclear antibodies. There may be: skin rash, photosensitivity reactions or other skin manifestations.

Musculoskeletal and connective tissue disorders

Uncommon: muscle cramps.

Renal and urinary disorders

Uncommon: renal function impairment, proteinuria, renal failure;

Rare: oliguria;

Reproductive system and breast disorders

Uncommon: erectile dysfunction;

Rare: gynecomastia.

General disorders and administration site conditions

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 BP.

When using lercanidipine

Immune system disorders

Very rare: hypersensitivity reactions.

Psychiatric disorders

Rare: drowsiness.

Nervous system disorders

Uncommon: dizziness, headache.

Cardiac disorders

Uncommon: tachycardia, palpitations;

Rare: angina pectoris, chest pain;

Very rarely: in patients with angina, an increase in the frequency, duration, and severity of attacks is possible.

Vascular disorders

Infrequently: sensation of facial flushing;

Very rarely: syncope.

Gastrointestinal disorders :

Rarely: nausea, dyspepsia, diarrhea, abdominal pain, vomiting.

Skin and subcutaneous tissue disorders

Rarely: skin rash.

Musculoskeletal and connective tissue disorders

Rarely: myalgia.

Renal and urinary disorders:

Rarely: polyuria.

General disorders and administration site conditions

Infrequently: peripheral edema;

Rarely: asthenia, increased fatigue.

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

Contraindications

Hypersensitivity to any component of the drug, any ACE inhibitors, dihydropyridine derivatives;
Left ventricular outflow tract obstruction, including aortic stenosis;
Chronic heart failure (CHF) in the stage of decompensation;
Unstable angina;
First month after myocardial infarction (within 28 days);
Severe hepatic impairment (more than 9 points on the Child-Pugh scale).
Concomitant 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 impairment (creatinine clearance less than 30 ml/min), including patients on hemodialysis;
History of angioedema associated with previous use of ACE inhibitors;
History of angioedema episodes (idiopathic, hereditary);
Concomitant use with aliskiren in patients with diabetes mellitus or moderate or severe renal impairment (creatinine clearance less than 60 ml/min);
Children and adolescents under 18 years of age (lack of data on efficacy and safety);
Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

With caution renovascular hypertension (bilateral renal artery stenosis or stenosis of the artery to a single kidney), primary hyperaldosteronism, hyperkalemia, conditions with reduced circulating blood volume (including diarrhea, vomiting), systemic connective tissue diseases (scleroderma, systemic lupus erythematosus, etc.), coronary artery disease (CAD), bone marrow depression, diabetes mellitus, renal impairment (creatinine clearance greater than 30 ml/min), mild to moderate hepatic impairment, use in patients on a salt-restricted diet, concomitant use with immunosuppressants, allopurinol, procainamide and diuretics, use in elderly patients, status after kidney transplantation, sick sinus syndrome (SSS) (without concomitant use of an artificial pacemaker), left ventricular dysfunction, aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy (HOCM), prior to low-density lipoprotein (LDL) apheresis with dextran sulfate, CHF, severe arterial hypotension (systolic BP less than 90 mm Hg), concomitant desensitizing therapy with hymenoptera venom (risk of anaphylactoid reactions), use in Black patients, surgical intervention and general anesthesia.

Use in Pregnancy and Lactation

Pregnancy

Enap^® L Combi

Use of Enap^® L Combi is not recommended in the first trimester of pregnancy and is contraindicated in the second and third trimesters.

Enalapril

Use of ACE inhibitors, including enalapril, is not recommended during the first trimester of pregnancy.

Use of ACE inhibitors, including enalapril, is contraindicated during the second and third trimesters of pregnancy.

Epidemiological data on the risk of teratogenic effects following the use of ACE inhibitors during pregnancy do not allow definitive conclusions. However, the possibility of risk cannot be excluded. If it is necessary to use ACE inhibitors, the patient should be switched to therapy with another antihypertensive drug approved for use during pregnancy with a proven safety profile.

If pregnancy is confirmed, the drug should be discontinued as soon as possible. Use during the second and third trimesters of pregnancy may cause fetotoxic effects (impaired renal function, oligohydramnios, delayed ossification of the fetal skull bones) and neonatal toxic effects (renal failure, arterial hypotension, hyperkalemia).

If an ACE inhibitor was used during the second and third trimesters of pregnancy, an ultrasound examination of the fetal kidneys and skull bones is recommended. Newborns whose mothers took ACE inhibitors during pregnancy should be closely observed due to the risk of arterial hypotension. In those rare cases where the use of an ACE inhibitor during pregnancy is considered necessary, periodic ultrasound examinations should be performed to assess the amniotic fluid index. If oligohydramnios is detected on ultrasound, the drug should be discontinued. The patient and physician should be aware that oligohydramnios develops with irreversible fetal damage. If ACE inhibitors are used during pregnancy and oligohydramnios develops, depending on the week of pregnancy, stress testing, non-stress testing, or determination of the biophysical profile may be necessary to assess the functional state of the fetus. Enalapril, which crosses the placenta, can be partially removed from the newborn’s circulation by peritoneal dialysis; theoretically, it could be removed by exchange transfusion.

Lercanidipine

In animal studies, Lercanidipine did not have a teratogenic effect; however, teratogenic effects were noted with the use of other dihydropyridine derivatives.

There is no experience with the use of lercanidipine in pregnant women, therefore it is not recommended for use during pregnancy or in women planning pregnancy.

Breastfeeding period

Enap^® L Combi

Use of Enap^® L Combi during breastfeeding is not recommended.

Enalapril

Enalapril and enalaprilat are detected in breast milk in trace concentrations, therefore, if it is necessary to use enalapril, breastfeeding should be discontinued.

Lercanidipine

There are no data on the excretion of lercanidipine in breast milk.

Use in Hepatic Impairment

Caution should be exercised when using Enap^® L Combi in patients with mild or moderate hepatic impairment (less than 9 points on the Child-Pugh scale).

Use in Renal Impairment

Caution should be exercised when using Enap^® L Combi in patients with mild or moderate renal impairment.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age (lack of data on efficacy and safety).

Geriatric Use

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

Special Precautions

Symptomatic arterial hypotension

Particular caution should be exercised in patients with:

Severe arterial hypotension with systolic BP less than 90 mm Hg;
CHF in the stage of decompensation.

Transient arterial hypotension is not a contraindication to further treatment, as an adequate response to the drug can be expected after replenishment of circulating blood volume.

Aortic or mitral stenosis, HOCM

Like all vasodilators, ACE inhibitors should be used with caution in patients with valvular obstruction and left ventricular outflow tract hypertrophy. Should not be used in patients with cardiogenic shock and hemodynamically significant left ventricular obstruction.

Renal impairment

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

Renovascular hypertension

In patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney, there is an increased risk of arterial hypotension and renal failure during treatment with ACE inhibitors. A decrease in renal function may be indicated by only minor changes in serum creatinine concentration. In such patients, treatment should be started with low doses of Enap^® L Combi under close medical supervision. Dose titration should be performed carefully and renal function should be monitored.

Kidney transplantation

There is no experience with the use of Enap^® L Combi in patients who have recently undergone kidney transplantation. Therefore, use in such patients is not recommended.

Hepatic impairment

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

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

Neutropenia/agranulocytosis

Cases of neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported in patients treated with ACE inhibitors. In patients with normal renal function and no other complications, neutropenia is rare. Enap^® L Combi should be used with extreme caution in patients with connective tissue diseases (including systemic lupus erythematosus, scleroderma) receiving concomitant immunosuppressive therapy, allopurinol or procainamide, or a combination of these factors, especially if there is pre-existing renal impairment. Such patients may develop severe infections that do not respond to intensive antibiotic therapy. If patients are still taking Enap^® L Combi, periodic monitoring of white blood cell counts is recommended. The patient should be warned to consult a doctor immediately if any signs of infection appear.

Anaphylactoid reactions during desensitization with hymenoptera venom

In patients receiving ACE inhibitors during desensitization with hymenoptera venom, life-threatening anaphylactoid reactions have occurred in rare cases. To prevent such reactions, Enap^® L Combi should be temporarily discontinued during desensitization procedures.

Anaphylactoid reactions during LDL apheresis

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

Hemodialysis

Due to the increased risk of anaphylactoid reactions, Enap^® L Combi should not be used in patients undergoing hemodialysis using high-flux polyacrylonitrile membranes (AN69^®) or 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.

Hypoglycemia

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

Cough

A “dry,” non-productive, persistent cough may occur with the use of Enap^® L Combi, which disappears after discontinuation of ACE inhibitors.

This should be considered in the differential diagnosis of cough during ACE inhibitor use.

Lithium

Concomitant use of lithium salts and Enap^® L Combi is not recommended.

Ethnic differences

Enap^® L Combi, like other drugs containing ACE inhibitors, has a less pronounced antihypertensive effect in Black patients compared to representatives of other races.

Hypersensitivity/angioedema

Cases of angioedema of the face, extremities, lips, vocal folds and/or larynx have been reported in patients receiving ACE inhibitors, including Enalapril, at any time after starting treatment. Enap^® L Combi should be discontinued immediately and the patient observed until symptoms completely resolve. Even in cases of swelling only of the tongue, where only difficulty swallowing without respiratory distress syndrome occurs, 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. If swelling of the tongue, vocal folds, or larynx occurs, the following therapy should be administered immediately: subcutaneous injection of 0.1% epinephrine (adrenaline) solution (0.3 ml-0.5 ml) and/or measures aimed at restoring airway patency (intubation or tracheostomy).

The incidence of angioedema is higher among Black patients receiving ACE inhibitor therapy than among patients of other races.

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

Surgery/general anesthesia

Before surgery (including dental procedures), the surgeon/anesthesiologist should be informed about the use of Enap^® L Combi.

During major surgery or general anesthesia with agents that cause arterial hypotension, ACE inhibitors may block the formation of angiotensin II in response to compensatory renin release. If a marked decrease in BP develops, explained by this mechanism, it can be corrected by the administration of plasma substitutes.

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors, including Enap^® L Combi. Risk factors for hyperkalemia are: renal failure, old age (over 70 years), diabetes mellitus, some concomitant conditions (decreased circulating blood volume, acute decompensated heart failure, metabolic acidosis), concomitant 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 (e.g., heparin). The use of potassium preparations, potassium-sparing diuretics and potassium-containing substitutes may lead to a significant increase in serum potassium, especially in patients with impaired renal function. Hyperkalemia can lead to serious cardiac arrhythmias, sometimes fatal. Concomitant use of the above drugs should be carried out with caution under the control of serum potassium levels.

Alcohol

Alcohol consumption should be avoided during therapy with Enap^® L Combi, as it may enhance the antihypertensive effect.

Other

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

Special information about excipients

Enap^® L Combi is contraindicated in patients with lactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome, as the drug contains lactose.

Effect on the ability to perform potentially hazardous activities requiring special attention and quick reactions (e.g., driving vehicles, operating machinery)

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 drug.

Overdose

There is no information on overdose with Enap^® L Combi. In case of overdose, conditions caused by overdose of the active substances (enalapril and lercanidipine) are possible.

Enalapril

Symptoms approximately 6 hours after oral administration – marked decrease in BP, up to collapse, water-electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough, convulsions, stupor. After oral administration of 300 mg and 440 mg of enalapril, serum concentrations of enalaprilat exceeded the usual therapeutic concentrations by 100 and 200 times, respectively.

Treatment the patient should be placed in a horizontal position with the head lowered.

In mild cases, gastric lavage and oral administration of activated charcoal are indicated; in more severe cases – intravenous infusion of 0.9% sodium chloride solution, plasma substitutes, if necessary – intravenous administration of catecholamines. Enalaprilat can be removed by hemodialysis, with a clearance rate of 62 ml/min. Patients with bradycardia resistant to drug therapy are indicated for implantation of an artificial pacemaker. Serum electrolyte levels and creatinine concentration should be carefully monitored.

Lercanidipine

Symptoms presumably, in case of lercanidipine overdose, symptoms similar to those of an overdose of other dihydropyridine derivatives (peripheral vasodilation with marked decrease in BP and reflex tachycardia) will be observed.

There are data on 3 cases of overdose with lercanidipine at doses of 150 mg, 280 mg and 800 mg

1. In the case of concomitant use of 150 mg lercanidipine with ethanol (undetermined amount), drowsiness was observed.

Treatment gastric lavage, oral administration of activated charcoal.

2. In the case of concomitant use of 280 mg lercanidipine with 5.6 mg moxonidine, the following symptoms were observed: cardiogenic shock, marked myocardial ischemia; mild renal failure.

Treatment cardiac glycosides, diuretics (furosemide), high doses of catecholamines, plasma substitutes.

3. In case of administration of 800 mg of lercanidipine, the following were observed: nausea and a pronounced decrease in blood pressure.

Treatment: oral administration of activated charcoal and laxatives, intravenous administration of dopamine.

In all cases of overdose, the patients survived. Information on the effectiveness of hemodialysis is not available. Given the high degree of plasma protein binding, dialysis may be ineffective.

Drug Interactions

The antihypertensive effect of Enap^® L Combi may be enhanced when used concomitantly with other antihypertensive drugs, such as: diuretics, beta-blockers, alpha-blockers and others.

Enalapril

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

The risk of 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 the simultaneous use of angiotensin II receptor antagonists (ARBs), ACE inhibitors, or aliskiren, compared to the use of a drug from one of the listed groups.

If simultaneous use of these drugs is necessary, it is recommended to monitor blood pressure, renal function, and water-electrolyte balance.

The simultaneous use of enalapril with aliskiren in patients with diabetes mellitus or moderate or severe renal impairment (creatinine clearance less than 60 ml/min) is contraindicated.

Potassium-sparing diuretics and potassium preparations

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.

If simultaneous use is necessary, caution should be exercised and serum potassium levels should be regularly monitored.

Diuretics (thiazide or “loop”)

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

Other antihypertensive drugs

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

Lithium

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

Tricyclic antidepressants/antipsychotic agents (neuroleptics)/anesthetics/narcotic agents

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

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Simultaneous use of NSAIDs (including selective cyclooxygenase-2 inhibitors) may weaken the antihypertensive effect of ACE inhibitors. NSAIDs and ACE inhibitors have an additive effect in increasing serum potassium levels, which may lead to worsening of 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, in elderly patients or in patients with severe hypovolemia, including due to the use of diuretics).

Circulating blood volume should be replenished before starting therapy. Renal function should be monitored during treatment.

Oral hypoglycemic agents and insulin

Epidemiological studies suggest that the 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 frequently in the first weeks of therapy in patients with impaired renal function.

Ethanol

Ethanol enhances the antihypertensive effect of ACE inhibitors.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics and beta-blockers

Simultaneous use of enalapril with acetylsalicylic acid (as an antiplatelet agent), thrombolytics, and beta-blockers is safe.

It reduces 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 concomitantly 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

Antacids may reduce the bioavailability of ACE inhibitors.

Gold preparations

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

No clinically significant pharmacokinetic interaction of enalapril with hydrochlorothiazide, furosemide, digoxin, timolol, methyldopa, warfarin, indomethacin, sulindac and cimetidine was observed. When used concomitantly with propranolol, the serum concentration of enalaprilat decreases, but this effect is clinically insignificant.

Lercanidipine

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

When used concomitantly 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 concomitantly. Simultaneous use of lercanidipine with inhibitors of the CYP3A4 isoenzyme (ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) is not recommended (see section “Contraindications”).

Simultaneous use of cyclosporine and lercanidipine is not recommended, as an increase in the plasma concentration of both substances is observed (see section “Contraindications”).

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

With simultaneous use of lercanidipine at a dose of 20 mg 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 at a dose of 20 mg. However, in healthy volunteers taking 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%. Undesirable interaction can be avoided by taking the drugs at different times of the day (Lercanidipine – in the morning, simvastatin – in the evening).

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

When used concomitantly 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 the simultaneous use of grapefruit juice and lercanidipine (see section “Contraindications”).

Ethanol may potentiate the antihypertensive effect of lercanidipine.

Storage Conditions

At a temperature not exceeding 25°C (77°F), in the original packaging. Keep out of reach of children.

Shelf Life

The shelf life is 2 years.

Dispensing Status

Dispensed by prescription.

Important Safety Information

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

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