Enap L Kombi - instructions for use, dose, side effects, contraindications

Active substanceLercanidipine + EnalaprilLercanidipine + Enalapril

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Coripren®

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RECORDATA Ireland Co., Ltd. Ireland

Enap® L Combi

pills inwards

KRKA-RUS, LLC Russia

Dosage form: & nbspfilm coated tablets

Composition:

Composition per 1 tablet 10 mg + 10 mg

Core:

Lercanidipine + Enalapril substance-mixture 392.00 mg

[Active ingredients of the substance-mixture: lercanidipine hydrochloride 10.00 mg, enalapril maleate 10.00 mg

Additives of substance-mixture: povidone K-30 10.00 mg, maleic acid 5.00 mg, sodium carboxymethyl starch (type A) 40.00 mg, lactose monohydrate 317,0 mg]

Excipients:

Sodium fumarate 8.00 mg

Film sheath: Drop off white 00F280002 10.00 mg

Composition per 1 tablet 10 mg + 20 mg

Core:

Lercanidipine + Enalapril substance-mixture 392.00 mg

[Active ingredients of the substance-mixture: lercanidipine hydrochloride 10.00 mg, enalapril maleate 20.00 mg

Additives of substance-mixture: povidone K-30 10.00 mg, maleic acid 5.00 mg, sodium carboxymethyl starch (type A) 40.00 mg, lactose monohydrate 307,0 mg]

Excipients:

Sodium fumarate 8.00 mg

Film sheath: Fell yellow 00F220000 10.00 mg

Composition lousy:

Fell yellow 00F220000:

hypromellose 64.36%, iron dye oxide yellow 0.66 %, titanium dioxide 19.80%, talc 4.95%, dye quinoline yellow 0.33%, macrogol 9.90%

Drop off white 00F280002:

hypromellose 65.00%, titanium dioxide 20.00%, talc 5.00%, macrogol 10.00%

Description:

Tablets 10 mg + 10 mg:

Round, slightly biconcave tablets, covered with a film shell of white color, with bevelled edges. View of the fracture: a rough mass of yellowish-white color, with a film shell of white color.

Tablets 10 mg + 20 mg:

Round, slightly biconvex tablets, covered with a film membrane of yellow color, with bevelled edges. View of the fracture: a rough mass of yellowish-white color, with a film coating of yellow color.

Pharmacotherapeutic group:The hypotensive agent combined (angiotensin-converting enzyme inhibitor + blocker of "slow" calcium channels)

ATX: & nbsp

C.09.B.B ACE inhibitors in combination with calcium channel blockers

C.09.B.B.02 Lercanidipine and enalapril

Pharmacodynamics:

The drug Enap® L Combi is a fixed combination of an angiotensin converting enzyme (ACE) inhibitor of enalapril and a lercanidipine "slow" calcium channel blocker (BCC) blocker.

Lercanidipine

Lercanidipine is a selective BCCC derived from dihydropyridine, inhibits the transmembrane current of calcium ions into myocardial cells and smooth vascular musculature. The mechanism of antihypertensive action is caused by a direct relaxing action on the smooth muscle cells of the vessels, as a result of which the overall peripheral vascular resistance (OPSS) decreases. Despite a relatively short half-life (T1/2) from the blood plasma, lercanidipine has a long-term antihypertensive effect due to a high coefficient membrane distribution. Due to high vascular selectivity, lercanidipine does not have a negative inotropic effect.

A marked decrease in blood pressure (AD) with reflex tachycardia occurs rarely due to the gradual development of vasodilation with lercanidipine.

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

Enalapril

Enalapril - ACE inhibitor, inhibits the formation of angiotensin II and eliminates its vasoconstrictive effect. Reduces blood pressure without causing an increase in the heart rate (heart rate) and the minute volume. Reduces OPSS, reduces afterload and preload on the heart. Reduces pressure in the right atrium and a small circle of blood circulation. Does not affect the metabolism of glucose, lipoproteins, as well as the functions of the reproductive system.

Pharmacokinetics:

With the simultaneous use of lercanidipine and enalapril, no pharmacokinetic interaction was detected.

Lercanidipine

Suction

Lercanidipine is completely absorbed after ingestion, and its maximum concentration (C_m_Oh) in the blood plasma is achieved after about 1.5-3 hours. Enantiomers of lercanidipine show a similar pharmacokinetic profile: they have the same time to reach the maximum concentration (TC_m_Oh), the same T1 / 2. FROM_m_Ohin the blood plasma and the area under the curve "concentration-time" (AUC) SThe enantiomer of lercanidipine, on average, is 1.2 times higher than Renantiomer. Interconversion of two enantiomers in vivo absent.

Due to the high metabolism at the "primary passage" through the liver, the absolute bioavailability of lercanidipine after ingestion is about 10%.When ingested on an empty stomach - bioavailability in healthy volunteers was 1/3 of the bioavailability after eating.

Bioavailability of lercanidipine when ingested increases 4-fold, if taken within 2 hours after eating high-fat foods, therefore, the drug should be taken at least 15 minutes before eating. The pharmacokinetics of lercanidipine in the range of therapeutic doses is non-linear. Upon admission lercanidipine in doses of 10 mg, 20 mg or 40 mg of C_m_Oh in blood plasma was determined in a ratio of 1: 3: 8, respectively, and AUC - in a ratio of 1: 4: 18, which suggests a progressive saturation in the "primary passage" through the liver. Accordingly, bioavailability increases with increasing dose.

Distribution

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

Metabolism

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

Excretion

Lercanidipine excretion occurs primarily through biotransformation. About 50% of the dose is excreted by the kidneys. The mean value of T1/2 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. Do not cumulate with repeated use.

Elderly patients

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

Enalapril

Suction

After ingestion enalapril quickly absorbed. FROM_m_Oh Enalapril in the blood plasma is observed within 1 hour after ingestion. Absorption of enalapril after ingestion is about 60% and does not depend on the time of eating.

Distribution

After suction enalapril It is rapidly and actively hydrolyzed to enalaprilat, a potent ACE inhibitor. FROM_m_Oh Enalaprilata in blood plasma is achieved 3-4 hours after ingestion. The binding of enalaprilat to plasma proteins in the therapeutic dose range does not exceed 60%.

Metabolism

In addition to turning into enalaprilate, other metabolic changes enalaprila not revealed.

Excretion

Enalapril is excreted by the kidneys: about 40% in the form of enalaprilat and about 20% in the form of unaltered enalapril.

Pharmacokinetics of special groups of patients

Impaired renal function

The exposure of enalapril and enalaprilat is increased in patients with renal insufficiency. In patients with mild to moderate renal impairment (creatinine clearance 40 to 60 mL / min) after enalapril 5 mg once daily AUC Enalaprilat is approximately 2 times greater than in patients with normal renal function. With severe renal dysfunction (CK <30 ml / min) AUC increases about 8 times, it also lengthens T1/2 enalaprilata.

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

Indications:

Essential hypertension (with ineffectiveness of monotherapy with enalapril or lercanidipine).

Contraindications:

- Increased individual sensitivity to one of the components of the drug, any ACE inhibitor, dihydropyridine derivative.

- Obstruction of the outflow tract of the left ventricle, including aortic stenosis.

- Chronic heart failure (CHF) in the stage of decompensation.

- Unstable angina.

- The first month after myocardial infarction (within 28 days).

- Severe liver failure (more than 9 points on the Child-Pugh scale).

- Simultaneous use with cyclosporine, potent inhibitors of isoenzyme CYP3A4 (ketoconazole, itraconazole, erythromycin, ritonavir, troleandomycin), grapefruit juice.

- Pregnancy, the period of breastfeeding.

- The use of women of childbearing age who do not use reliable methods of contraception.

- Severe renal failure (QC less than 30 ml / min), including patients on hemodialysis.

- Angioedema in history, associated with previous use of ACE inhibitors.

- Presence in the anamnesis of episodes of angioneurotic edema (idiopathic, hereditary).

- Simultaneous use with aliskiren in patients with diabetes mellitus or moderate or severe renal dysfunction (CC less than 60 mL / min).

- Children and adolescence under 18 years (lack of data on effectiveness and safety).

- Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

Carefully:R(bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney), primary hyperaldosteronism, hyperkalemia, conditions with reduced circulating blood volume (bcc) (including diarrhea, vomiting), systemic connective tissue diseases (scleroderma, systemic lupus erythematosus, etc.) ), ischemic heart disease (IHD), oppression of bone marrow hematopoiesis, diabetes mellitus, renal insufficiency (QC more than 30 ml / min), hepatic insufficiency of mild and moderate degree, use in patients s on a diet with restriction of salt intake,simultaneous use with immunosuppressants, allopurinol, procainamide and diuretics, use in patients of advanced age, condition after kidney transplantation, sinus node syndrome (SSCS) syndrome (without simultaneous application of an artificial pacemaker), left ventricular dysfunction, aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy (GOKMP), before the procedure of apheresis of low density lipoproteins (LDL) with dextran sulfate, CHF, severe arterial hypotension (systolic Blood pressure less than 90 mm Hg), concomitant desensitizing therapy with Hepaticoptera venom (risk of anaphylactoid reactions), use of Negroid race in patients, surgical intervention and general anesthesia.

Pregnancy and lactation:

Pregnancy

The drug Enap® L Combi

Application of the drug Enap® L Combi It is not recommended in the first trimester of pregnancy and is contraindicated in the second and third trimesters.

Enalapril

The use of ACE inhibitors, including enalapril, in the first trimester of pregnancy is not recommended.

The use of ACE inhibitors, including enalapril, in the second and third trimesters of pregnancy is contraindicated.

Epidemiological data on the risk of developing teratogenic effects with the use of ACE inhibitors during pregnancy do not provide an opportunity to draw definitive conclusions. Nevertheless, one can not exclude the likelihood of risk of their development. If it is necessary to use ACE inhibitors, the patient must be transferred to therapy with another, authorized antihypertensive drug with a proven safety profile for pregnant women.

When confirming pregnancy, the drug must be canceled as soon as possible. Application in the second and third trimesters of pregnancy can cause fetotoxic effects (renal dysfunction, oligohydramnios, deceleration of the fossil skull bones) and neonatal toxic effects (renal failure, arterial hypotension, hyperkalemia).

If the ACE inhibitor was taken in the second and third trimesters of pregnancy, it is recommended to perform ultrasound examination of the kidneys and bones of the fetal skull. Newborns whose mothers took ACE inhibitors during pregnancy should be monitored, given the risk of developing arterial hypotension.In those rare cases when the use of an ACE inhibitor during pregnancy is considered necessary, periodic ultrasound (ultrasound) should be performed to assess the amniotic fluid index. In case of detection during an ultrasound of oligohydramnion, it is necessary to stop taking the drug. Patients and the physician should be aware that the oligohydramnion develops with irreversible damage to the fetus. If ACE inhibitors are used during pregnancy and the development of oligohydramnion is observed, depending on the week of pregnancy, it may be necessary to perform a stress test, a stress test, or a biophysical profile of the fetus to assess the functional state of the fetus. Enalapril, which penetrates the placenta, can be partially removed from the circulation a newborn with peritoneal dialysis, in theory it can be removed by means of an exchange blood transfusion.

Lercanidipine

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

Experience with lercanidipine in pregnant women is not available, so it is not recommended for use during pregnancy or for women planning a pregnancy.

Breastfeeding period

The drug Enap® L Combi

The use of Enap® L Combine in the period of breastfeeding is not recommended.

Enalapril

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

Lercanidipine

There is no data on excretion of lercanidipine with breast milk.

Dosing and Administration:

Inside, once a day, take at least 15 minutes before eating, preferably in the morning, without chewing, drink plenty of water. You can not drink grapefruit juice.

Recommended dose: one tablet of Enap® L Combine (lercanidipine 10 mg / enalapril 10 mg) per day.

Depending on the clinical effect and individual patient's tolerance to the drug Enap ® L Combi, its dose may be increased to lercanidipine 10 mg / enalapril 20 mg once a day.

Elderly patients

The dose depends on the state of the kidney function.

Patients with impaired renal function

Care should be taken in patients with mild to moderate renal impairment when using Enap® L Combi.

Patients with impaired hepatic function

In patients with mild or moderate impairment of liver function (less than 9 on the Child-Pugh scale), care should be taken when using Enap® L Combi.

Side effects:

Classification of the incidence of side effects:

very often ≥ 1/10

often from ≥ 1/100 to <1/10

infrequently from ≥ 1/1000 to <1/100

rarely from ≥ 1/10000 to <1/1000

very rarely <1/10000

the frequency of the unknown can not be estimated from the available data.

When applying the combination lercanidipine / enalapril

Violations from the blood and lymphatic system:

infrequently: thrombocytopenia, reduction of hemoglobin in blood serum.

Immune system disorders:

infrequently: hypersensitivity to one of the components of the drug, edema Quincke.

Disorders from the metabolism and nutrition:

infrequently: hypertriglyceridemia.

Disorders of the psyche:

infrequently: anxiety.

Impaired nervous system:

often: dizziness; infrequently: headache.

Hearing disorders and labyrinthine disturbances:

often: vertical, including positional.

Heart Disease:

infrequent: a feeling of palpitations and tachycardia, decompensation of CHF.

Vascular disorders:

often: sensation of "tides" of blood to the skin of the face;

infrequent: marked decrease in blood pressure, vascular collapse.

Disturbances from the respiratory system, chest and mediastinal organs:

often: cough, pharyngeal-laryngeal pain;

infrequent: dryness of the oral mucosa.

Disorders from the gastrointestinal tract:

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

Disturbances from the skin and subcutaneous tissues:

infrequently: dermatitis, edema of the lips, erythema, urticaria, skin rash.

Disturbances from the musculoskeletal and connective tissue:

infrequently: arthralgia.

Disorders from the kidneys and urinary tract:

infrequently: pollakiuria, polyuria, nocturia.

Violations of the genitals and breast:

infrequently: erectile dysfunction.

General disorders and disorders at the site of administration:

often: peripheral edema;

infrequently: asthenia, increased fatigue, a feeling of heat.

Laboratory and instrumental data:

infrequently: increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT).

When using enalapril

Violations from the blood and lymphatic system:

infrequently: anemia (including aplastic and hemolytic);

rarely: neutropenia, a decrease in hemoglobin and hematocrit in the blood serum, thrombocytopenia, agranulocytosis, oppression of bone marrow hematopoiesis, pancytopenia, lymphadenopathy, autoimmune diseases;

Immune system disorders:

often: hypersensitivity reactions / angioedema (described angioedema, edema of the face, extremities, lips, tongue, throat and / or larynx).

Disorders from the endocrine system:

infrequently: hypoglycemia;

frequency unknown: syndrome of inadequate secretion of antidiuretic hormone.

Disorders of the psyche:

often: depression;

infrequently: confusion, drowsiness, insomnia, nervousness;

rarely: pathological dreams, sleep disturbance.

Impaired nervous system:

very often: dizziness;

often: headache;

infrequently: paresthesia.

Disorders from the side of the organ of vision:

very often: blurred vision.

Hearing disorders and labyrinthine disturbances:

infrequently: noise in the ears, vertigo.

Heart Disease:

often: chest pain, heart rhythm disorder, angina pectoris, tachycardia, myocardial infarction (possibly due to a sharp drop in blood pressure in patients at high risk);

infrequent: a feeling of palpitations.

Vascular disorders:

often: marked decrease in blood pressure (including orthostatic hypotension), syncope, stroke (possibly due to a sharp drop in blood pressure in patients at high risk);

infrequently: sensation of "tides" of blood to the skin of the face;

rarely: Raynaud's syndrome.

Disturbances from the respiratory system, organs of the thorax and mediastinum:

very often: cough;

often: dyspnea, pharyngeal-laryngeal pain;

infrequently: rhinorrhea, sore throat and hoarseness of the voice, bronchospasm / bronchial asthma;

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

Disorders from the gastrointestinal tract:

very often: nausea;

often: diarrhea, abdominal pain, flatulence, change in taste perception;

infrequently: ileitis, intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, dryness of the oral mucosa, stomach pain, peptic ulcer;

rarely: stomatitis / aphthous ulcers, glossitis;

very rarely: angioedema, intestinal edema.

Disorders from the liver and bile ducts:

rarely: hepatic insufficiency, hepatitis (hepatocellular or cholestatic), including hepatic necrosis, cholestasis (including jaundice).

Disturbances from the skin and subcutaneous tissues:

hasto: skin rash;

infrequently: increased sweating, itching, hives, alopecia;

rarely: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus (pemphigus), erythroderma.

A symptom complex is described, which may include: fever, myalgia / myositis, arthralgia / arthritis, serositis, vasculitis, erythrocyte sedimentation rate (ESR), leukocytosis and eosinophilia, positive antinuclear antibody test. There may be: skin rash, photosensitivity reactions or other skin manifestations.

Disturbances from the musculoskeletal and connective tissue:

infrequently: muscle cramps.

Disorders from the kidneys and urinary tract:

infrequently: impaired renal function, proteinuria, renal insufficiency;

rarely: oliguria;

Violations of the genitals and breast:

infrequently: erectile dysfunction;

rarely: gynecomastia.

General disorders and disorders at the site of administration:

very often: asthenia;

often: increased fatigue;

infrequently: malaise.

Laboratory and instrumental data:

often: hyperkalemia, increased serum creatinine concentration; infrequently: increased urea concentration in blood serum, hyponatremia; rarely: increased activity of "liver" enzymes, increased serum bilirubin concentration.

With the use of ACE inhibitors, including enalapril, in patients receiving an intravenous preparation of gold (sodium aurotomy malate), a symptom complex was described, which included: flushing of the facial skin, nausea, vomiting, and a marked decrease in blood pressure.

When lercanidipine is used

Immune system disorders:

very rarely: hypersensitivity reactions.

Disorders of the psyche:

rarely: drowsy.

Impaired nervous system:

infrequently: dizziness, headache.

Heart Disease:

infrequently: tachycardia, palpitation;

rarely: stenocardia, chest pain;

rarely: in patients with angina pectoris, an increase in frequency is possible, duration and severity of seizures.

Vascular disorders:

infrequently: sensation of "tides" of blood to the skin of the face;

very rarely: faint.

Disorders from the gastrointestinal tract:

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

Disturbances from the skin and subcutaneous tissues:

rarely: skin rash.

Disturbances from the musculoskeletal and connective tissues:

rarely: myalgia.

Disorders from the kidneys and urinary tract:

rarely: polyuria.

General disorders and disorders at the site of administration:

infrequent: peripheral edema;

rarely: asthenia, increased fatigue.

There are reports of the following very rare side effects: myocardial infarction, gingival hyperplasia, reversible increase in the activity of "hepatic" transaminases, marked decrease in blood pressure, pollakiuria (increased frequency of urination), pain in the chest.

Overdose:

There is no information about an overdose of Enap® L Combine. In the case of an overdose, conditions due to overdose of active substances (enalapril and lercanidipine) are possible.

Enalapril

Symptoms: approximately 6 hours after ingestion - marked decrease in blood pressure, up to the development of collapse, disturbance of water-electrolyte balance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough, convulsions, stupor. After ingesting 300 mg and 440 mg of enalapril, the serum concentrations of enalaprilat exceeded the usual therapeutic concentrations of 100 and 200 times, respectively.

Treatment: the patient should be moved to a horizontal position with a low headboard.

In mild cases, gastric lavage and ingestion of activated charcoal are shown, in more severe cases, intravenous infusion of 0.9% sodium chloride solution, plasma substitutes, if necessary intravenous catecholamines. It is possible to excrete enalaprilate by hemodialysis, the rate of excretion is 62 ml / min. Patients with bradycardia, resistant to drug therapy, are shown implantation of an artificial pacemaker.Care should be taken to monitor the electrolyte content and serum creatinine concentration.

Lercanidipine

Symptoms: presumably, in the case of an overdose of lercanidipine, Symptoms similar to those seen with an overdose of other dihydropyridine derivatives (peripheral vasodilation with marked lowering of blood pressure and reflex tachycardia) are observed.

There are data on 3 cases of overdose with the use of lercanidipine in doses of 150 mg, 280 mg and 800 mg:

1. In the case of simultaneous application of 150 mg of lercanidipine with ethanol (an unspecified amount), drowsiness was observed.

Treatment: gastric lavage, intake of activated charcoal.

2. In the case of simultaneous application of 280 mg of lercanidipine with 5.6 mg of moxonidine, the following symptoms were observed: cardiogenic shock. severe myocardial ischemia; renal failure of mild degree.

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

In the case of 800 mg of lercanidipine, nausea and a marked decrease in blood pressure were observed.

Treatment: intake of activated carbon and laxatives, intravenously - dopamine.

In all cases of overdose, patients remained alive. Information on the effectiveness of hemodialysis is absent. Given the high degree of association with plasma proteins, dialysis may be ineffective.

Interaction:

The antihypertensive effect of the Enap® L Combine can be enhanced with simultaneous use with other antihypertensive drugs, such as: diuretics, beta-blockers, alpha-blockers, and others.

Enalapril

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

The risk of developing arterial hypotension, hyperkalemia and renal dysfunction (including acute renal insufficiency) is higher in the case of double blockade of RAAS, that is, with simultaneous use of angiotensin II receptor antagonists (APA II), ACE inhibitors or aliskiren, in comparison with the use of the preparation of one from the listed groups.

If it is necessary to simultaneously use drugs, it is recommended to monitor blood pressure, kidney function and water-electrolyte balance.

Simultaneous use of enalapril with aliskiren in patients with diabetes mellitus or moderate or severe renal dysfunction (CC less than 60 ml / min) is contraindicated.

Potassium-sparing diuretics and potassium preparations

ACE inhibitors reduce potassium loss by diuretics.

Simultaneous use of enalapril and potassium-sparing diuretics (such as: spironolactone, eplerenone, triamterene, amiloride), potassium or potassium substitute preparations, and the use of other drugs that increase the potassium level in the blood plasma (eg, heparin) can lead to hyperkalemia.

If simultaneous application is necessary, care should be taken and the serum potassium content is regularly monitored.

Diuretics (thiazide or "loop")

Prior therapy with high doses of diuretics can lead to a decrease in BCC and an increased risk of developing arterial hypotension during the initiation of enalapril therapy. Excessive antihypertensive effects can be reduced by eliminating the diuretic, increasing fluid intake or table salt, as well as starting treatment with enalapril at a low dose.

Other antihypertensive drugs

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

Lithium

With simultaneous use of ACE inhibitors with lithium preparations, a transient increase in serum lithium concentration and the development of lithium intoxication were observed. The use of thiazide diuretics can lead to an additional increase in serum lithium concentration and the risk of lithium intoxication with simultaneous use of ACE inhibitors. Simultaneous use of enalapril with lithium is not recommended. If this combination is necessary, the serum concentrations of lithium should be carefully monitored.

Tricyclic antidepressants / antipsychotics (antipsychotics) / anesthetics / drugs

The simultaneous use of certain analgesics, tricyclic antidepressants and antipsychotics (antipsychotics) with ACE inhibitors may lead to an additional reduction in blood pressure.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Simultaneous application of NSAIDs (including selective inhibitors of cyclooxygenase-2) can weaken the antihypertensive effect of ACE inhibitors. NSAIDs and ACE inhibitors have an additive effect on the increase in serum potassium,which can lead to impaired renal function, especially in patients with impaired renal function. This effect is reversible.

In rare cases, the development of acute renal failure is possible, especially in patients with already impaired renal function (for example, in elderly patients or in patients with severe hypovolemia, including diuretics).

Before the start of therapy, it is necessary to replenish the BCC. During treatment, it is recommended to monitor kidney function.

Hypoglycemic agents for ingestion and insulin

Epidemiological studies suggest that simultaneous use of ACE inhibitors and hypoglycemic agents (insulin and hypoglycemic agents for ingestion) can lead to an increase in hypoglycemic effect with a risk of hypoglycemia. More often, hypoglycemia develops in the first weeks of therapy in patients with impaired renal function.

Ethanol

Ethanol enhances the antihypertensive effect of ACE inhibitors.

Sympathomimetics can reduce the antihypertensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics and beta-blockers Safe simultaneous use of enalapril with acetylsalicylic acid (as an antiplatelet agent), thrombolytics and beta-blockers. Relieves the effect of medications containing theophylline.

Allopurinol, cytostatics and immunosuppressants (including methotrexate, cyclophosphamide)

Simultaneous use with ACE inhibitors may increase the risk of developing leukopenia. With simultaneous application with allopurinol, the risk of developing an allergic reaction increases, especially in patients with impaired renal function.

Cyclosporin

Simultaneous use with ACE inhibitors may increase the risk of developing hyperkalemia.

Antacids

Antacids can reduce the bioavailability of ACE inhibitors.

Preparations of gold

With the use of ACE inhibitors, including enalapril, patients receiving intravenously the preparation of gold (sodium aurotomy malate), a symptom complex was described, which included: flushing of the facial skin, nausea, vomiting, marked decrease in blood pressure.

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

Lercanidipine

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

When used simultaneously with metoprolol the bioavailability of lercanidipine is reduced by 50%. This effect can also occur when applied simultaneously with other beta-blockers, therefore, a dose adjustment of lercanidipine may be required to achieve a therapeutic effect in this combination. Lercanidipine metabolized with the participation of isoenzyme CYP3A4, so inhibitors and inducers of isoenzyme CYP3A4 with simultaneous application can affect the metabolism and excretion of lercanidipine. It is not recommended simultaneous application of lercanidipine with inhibitors of isoenzyme CYP3A4 (ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) (see the section "Contraindications"),

Do not use concurrently cyclosporine and lercanidipine, as there is an increase in the concentration of both substances in the blood plasma (see the section "Contraindications"),

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

With the simultaneous use of lercanidipine at a dose of 20 mg s midazolam The bioavailability of lercanidipine in elderly patients may increase by approximately 40%.

Lercanidipine should be used with caution at the same time as inducers of isoenzyme CYP3A4, eg anticonvulsants (phenytoin, carbamazepine) and rifampicin, since it is possible to reduce the antihypertensive action of lercanidipine. Regular monitoring of blood pressure is necessary.

In patients who are constantly taking digoxin, with the simultaneous use of lercanidipine in a dose of 20 mg, no pharmacokinetic interaction was observed. However, in healthy volunteers who took digoxin, an increase in the value of C_m_Oh digoxin in blood plasma, on average, by 33% after ingestion of 20 mg of lercanidipine on an empty stomach, AUC and renal clearance digoxin changed insignificantly.It is necessary to monitor the presence of signs of intoxication digoxin in patients taking both digoxin and lercanidipine.

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

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

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

When used simultaneously with fluoxetine (inhibitor of isoenzymes CYP2D6 and CYP3A4) in elderly patients no clinically significant changes in the pharmacokinetics of lercanidipine were detected.

It is possible to increase the antihypertensive effect with simultaneous application grapefruit juice and lercanidipine (see the section "Contraindications"),

Ethanol can potentiate the antihypertensive effect of lercanidipine.

Special instructions:

Symptomatic arterial hypotension

Special care should be taken when patients have:

severe arterial hypotension with systolic blood pressure less than 90 mm Hg. p.
CHF in the stage of decompensation.

Transient arterial hypotension is not a contraindication to further treatment, since after replenishment of bcc it is possible to expect an adequate response to taking the drug.

Aortic oozeand mitral stenosis, GOKMP

Like all vasodilators, ACE inhibitors should be used with caution in patients with valvular obstruction and hypertrophy of the outflow tract of the left ventricle. Do not use in patients with cardiogenic shock and hemodynamically significant obstruction of the left ventricle.

Impaired renal function

In patients with mild to moderate renal impairment, therapy should be initiated with extreme caution.

Renovascular hypertension

In patients with bilateral renal artery stenosis or stenosis of the artery only functioning kidney during treatment with ACE inhibitors increased risk of hypotension and renal insufficiency.To reduce the function of the kidneys can indicate only minor changes in serum creatinine concentration. In such patients, treatment should begin with small doses of Enap®L Combi under the close supervision of a doctor. It is necessary to carefully titrate the dose and monitor the function of the kidneys.

Kidney Transplantation

The experience of using the drug Enap® L Combi in patients who have recently transferred kidney transplantation is absent. Therefore, the use in such patients is not recommended.

Impaired liver function

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

In rare cases, with the treatment with ACE inhibitors, a syndrome begins with cholestatic jaundice and ends with fulminant hepatocyte necrosis (sometimes fatal). The mechanism of this syndrome is not established. If jaundice develops and the activity of "hepatic" enzymes increases, an ACE inhibitor should be immediately discontinued and proper treatment should be prescribed.

Neutropenia / agranulocytosis

Patients using ACE inhibitors described cases of neutropenia / agranulocytosis, thrombocytopenia and anemia.In patients with normal renal function in the absence of other complications, neutropenia develops rarely. The drug Enap® L Combi should be used with great care in patients with connective tissue diseases (including systemic lupus erythematosus, scleroderma), simultaneously receiving immunosuppressive therapy, allopurinol or procainamide, as well as a combination of these factors, especially with the existing impairment of kidney function. These patients can develop severe infections that are not amenable to intensive antibiotic therapy. If patients still take the drug Enap® L Combi, it is recommended to periodically monitor the number of white blood cells in the blood. The patient should be warned that if there are any signs of infection, you should immediately consult a doctor.

Anaphylactoid reactions during desensitization with Hymenoptera

In patients who took ACE inhibitors during desensitization with Hepaticoptera, rare life-threatening anaphylactoid reactions developed. To prevent such reactions, it is necessary to temporarily stop taking Enap® L Combine during desensitization procedures.

Anaphylactoid reactions during apheresis of LDL

Patients taking ACE inhibitors during LDL apheresis using dextran sulfate, in rare cases, develop life-threatening anaphylactoid reactions. It should be temporarily replaced with drugs from another group.

Hemodialysis

Because of the increased risk of anaphylactoid reactions should not be used Enap® A Combination drug patients on hemodialysis using polyacrylonitrile membranes vysokoprotochnyh (AN69®), undergoing apheresis of LDL with dextran sulfate. If hemodialysis is necessary, it is advisable to use dialysis membranes of another type, or hypotensive drugs of another group.

Hypoglycaemia

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

Cough

When using Enap® L Combi, a "dry", unproductive, prolonged cough may occur, which disappears after the cessation of the use of ACE inhibitors. It is necessary to take into account in the differential diagnosis of cough with the use of an ACE inhibitor.

Lithium

Simultaneous use of lithium salts and Enap® L Combine is not recommended.

Ethnic Features

The drug Enap® L Combi, like other preparations containing ACE inhibitors, has a less pronounced antihypertensive effect in patients of the Negroid race compared with representatives of other races.

Hypersensitivity / angioedema

In patients who received ACE inhibitors, including enalapril, there have been reports of the development of angioedema, edema, limbs, lips, vocal folds and / or larynx at any time after initiation of treatment. It is necessary to immediately cancel the drug Enap® L Combi and monitor the patient until the symptoms disappear completely. Even if there is only edema in the tongue, when there is only difficulty swallowing without respiratory distress syndrome, patients may need long-term follow-up, since the use of antihistamines and glucocorticosteroids may not be sufficient.

Angioedema, edema of the larynx or tongue can be lethal in very rare cases. Swelling of the tongue, vocal cords, or larynx can lead to airway obstruction, especially after an operation on the airway in an anamnesis.In the presence of edema of the tongue, vocal folds or larynx, the following therapy should be performed immediately: subcutaneous administration of 0.1% epinephrine (epinephrine) solution (0.3 ml-0.5 ml) and / or measures aimed at restoring airway patency (intubation or tracheostomy).

Among patients of the Negroid race receiving ACE inhibitor therapy, the incidence of angioedema is higher than among patients of other race.

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

Surgery / general anesthesia

Before surgery (including dental procedures), it is necessary to alert the surgeon / anesthesiologist about the use of Enap® L Combine.

With extensive surgical interventions or general anesthesia with arterial hypotension, ACE inhibitors can block the formation of angiotensin II in response to compensatory release of renin.If this results in a pronounced decrease in blood pressure, explained by a similar mechanism, it can be corrected by introducing plasma substitutes.

Hyperkalemia

Hyperkalemia can develop during treatment with ACE inhibitors, including Enap®L Combi. Risk factors for hyperkalemia include renal failure, advanced age (over 70 years), diabetes mellitus, certain concomitant conditions (decreased BCC, acute heart failure during decompensation, metabolic acidosis), simultaneous use of potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), as well as preparations of potassium or potassium-containing substitutes and the use of other drugs that increase the potassium content in the blood plasma (for example, heparin). The use of potassium preparations, potassium-sparing diuretics and potassium-containing substitutes can lead to a significant increase in serum potassium content, especially in patients with impaired renal function. Hyperkalemia can lead to serious heart rhythm disturbances, sometimes with a fatal outcome.Simultaneous use of the above drugs should be done with caution under the control of potassium in the blood serum.

Alcohol

Avoid alcohol during therapy with the Enap® L Combine drug, as it is possible to increase the antihypertensive effect.

Other

With in vitro fertilization in some cases, the use of BCCI caused changes in the head of the spermatozoa, which may lead to a disruption in the function of spermatozoa. In cases in which repeated in vitro fertilization has not been carried out for an unclear reason, the use of BCCC is considered a possible cause of failure.

Special information on excipients

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

Effect on the ability to drive transp. cf. and fur:

It should be borne in mind the possibility of dizziness, asthenia, weakness, increased fatigue, in rare cases, drowsiness. Therefore, care must be taken when driving vehicles and performing works requiring increased attention,especially at the beginning of treatment and with an increase in the dose of the drug.

Form release / dosage:Tablets, film-coated, 10 mg + 10 mg, 10 mg + 20 mg.

Packaging:

For 7, 10 or 14 tablets in a contour acheikova packing of the combined material OPA / Al / PVC and aluminum foil.

1, 4, 8, 12 contour cell packs (7 tablets each), or 1, 3, 6, 9 contour cell packs (10 tablets each), or 2, 4, 6 contour cell packs (14 tablets each) together with the instructions for use are placed in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C, in the original packaging.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002583

Date of registration:14.08.2014

Date of cancellation:2018-02-09

The owner of the registration certificate:KRKA-RUS, LLC KRKA-RUS, LLC Russia

Manufacturer: & nbsp

KRKA-RUS, LLC Russia

Information update date: & nbsp09.02.2018

Illustrated instructions

Instructions

Enap® L Combi (Enap® L Combi)