Amlodipine + Lysinopril - instructions for use, dose, side effects, contraindications

Excipients: cellulose microcrystalline - 124.62 mg; sodium carboxymethyl starch 5.0 mg; magnesium stearate - 1.5 mg; silicon dioxide colloidal anhydrous (aerosil anhydrous) - 1.0 mg.

dosage of 10 mg + 20 mg:

active substance:

Amlodipine besylate - 13.90 mg in terms of amlodipine - 10 mg, lisinopril dihydrate - 21.86 mg in terms of lisinopril - 20 mg;

Excipients: cellulose microcrystalline - 249.24 mg; sodium carboxymethyl starch - 10.0 mg; magnesium stearate - 3.0 mg; silicon dioxide colloidal anhydrous (aerosil anhydrous) 2.0 mg.

dosage of 5 mg + 20 mg:

active substance:

Amlodipine besylate - 6.95 mg in terms of amlodipine - 5 mg, lisinopril dihydrate - 21.86 mg in terms of lisinopril - 20 mg;

Excipients: microcrystalline cellulose - 160.19 mg; sodium carboxymethyl starch - 7.0 mg; magnesium stearate - 2.0 mg; silicon dioxide colloidal anhydrous (aerosil anhydrous) 2.0 mg.

Description:

Dosages of 5 mg + 10 mg and 10 mg + 20 mg: tablets of white or almost white color, round, planocylindrical with a facet and a risk.

Dosage of 5 mg + 20 mg: tablets white or almost white, round, flat-cylindrical with a bevel.

Pharmacotherapeutic group:Hypotensive complex agent (angiotensin-converting enzyme inhibitor and blocker of "slow" calcium channels)

ATX: & nbsp

C.09.A.A.03 Lisinopril

C.08.C.A.01 Amlodipine

Pharmacodynamics:

Combined drug containing active ingredients: lisinopril and amlodipine.

Lisinopril - inhibitor of angiotensin-converting enzyme (ACE), reduces the formation of angiotensin II from angiotensin I.Reduction of angiotensin II leads to a direct decrease in the release of aldosterone. Reduces the degradation of bradykinin and increases the synthesis of prostaglandins. Reduces the overall peripheral vascular resistance (OPSS), arterial pressure (BP), preload, pressure in the pulmonary capillaries, causes an increase in the minute volume of blood and increased tolerance of the myocardium to loads in patients with chronic heart failure. Expands arteries more than veins. Some of the effects are explained by exposure to tissue renin-angiotensin-aldosterone system (RAAS).

With prolonged use, myocardial hypertrophy and the walls of arteries of resistive type decrease. Improves the blood supply of the ischemic myocardium.

ACE inhibitors prolong life expectancy in patients with chronic heart failure, slow the progression of left ventricular dysfunction in patients who underwent myocardial infarction without clinical manifestations of heart failure.

The onset of action is 1 hour after ingestion. The maximum antihypertensive effect is determined after 6 hours and persists for 24 hours.With arterial hypertension, the effect is observed in the first days after the start of treatment, stable action develops after 1-2 months. With a sharp withdrawal of the drug, there was no pronounced increase in blood pressure.

Despite the primary effect, which manifests itself in the effect on RAAS, it is also effective in hypertension with low renin activity. In addition to reducing blood pressure lisinopril reduces albuminuria. Lisinopril does not affect the concentration of glucose in the blood in patients with diabetes mellitus and does not increase the incidence of hypoglycemia.

Amlodipine - a dihydropyridine derivative, a blocker of "slow" calcium channels (BCCC), has antianginal and antihypertensive effect. Blocking calcium channels, reduces the transmembrane passage of calcium ions into the cell (mainly in vascular smooth muscle cells than cardiac myocytes). Antianginal action is due to the expansion of coronary and peripheral arteries and arterioles: with angina reduces severity of myocardial ischemia; expanding peripheral arterioles, reduces OPSS, reduces afterload on the heart, reduces the need for myocardium in oxygen.Expanding coronary arteries and arterioles in unchanged and ischemic zones of the myocardium, increases the flow of oxygen into the myocardium (especially with vasospastic angina); prevents spasm of the coronary arteries (including caused by smoking). In patients with stable angina, a single daily dose increases exercise tolerance, slows the development of angina pectoris and the "ischemic" depression of the segment ST, reduces the incidence of angina attacks and consumption of nitroglycerin and other nitrates. Has a long-term dose-dependent antihypertensive effect. Antihypertensive action is due to direct vasodilating effect on smooth muscle vessels. With arterial hypertension, a single dose provides a clinically significant reduction in blood pressure for 24 hours (in the patient's "lying" and "standing" position). Orthostatic hypotension in the appointment of amlodipine is rare. Does not cause a decrease in exercise tolerance, a fraction of the ejection of the left ventricle. Reduces the degree of myocardial hypertrophy of the left ventricle. Does not affect the contractility and conductivity of the myocardium,does not cause a reflex increase in the heart rate (HR), inhibits platelet aggregation, increases the rate of glomerular filtration, has a weak natriuretic effect. When diabetic nephropathy does not increase the severity of microalbuminuria. Does not have any adverse effect on the metabolism and concentration of plasma lipids and can be used in the treatment of patients with bronchial asthma, diabetes and gout. A significant reduction in blood pressure is observed after 6-10 hours, the duration of the effect is 24 hours.

Amlodipine + lisinopril

The combination of lisinopril with amlodipine in a single medicine can prevent the development of possible undesirable effects caused by one of the active substances. So, BCCC, directly expanding the arterioles, can lead to a delay in sodium and fluid in the body, and therefore can activate RAAS. The ACE inhibitor blocks this process.

Pharmacokinetics:

Lisinopril

Suction

After oral administration lisinopril absorbed from the gastrointestinal tract (GIT), its absorption can vary from 6 to 60%. Bioavailability is 29%.Eating does not affect the absorption of lisinopril.

Distribution

Almost does not bind to blood plasma proteins. The maximum concentration (Cmah) in the plasma of 90 ng / ml is reached after 6-7 hours. Permeability through the blood-brain and placental barrier is low.

Metabolism

Lizinopril is not biotransformed in the body.

Excretion

It is excreted by the kidneys unchanged. The half-life (T1 / 2) is 12.6 hours.

Pharmacokinetics in selected patient groups

In elderly patients, the concentration of lisinopril in the blood plasma and the area under the concentration-time curve (AUC) in 2 times more, than at patients of young age.

In patients with chronic heart failure, the absorption and clearance of lisinopril are reduced.

In patients with renal insufficiency, the concentration of lisinopril is several times higher than the concentration in the blood plasma in healthy volunteers, with an increase in the time to reach the maximum concentration in the blood plasma and an increase in the half-life.

Lizinopril is excreted from the body by hemodialysis.

Amlodipine

Suction

After oral administration amlodipine slowly and almost completely (90%) is absorbed from the digestive tract. Bioavailability of amlodipine is 64% - 80%. Food intake does not affect the absorption of amlodipine.

Distribution

Most of the amlodipine, which is in the blood (95% - 98%), binds to blood plasma proteins. FROMmah in the serum is observed after 6 to 10 hours. Equilibrium concentrations (Css) are achieved after 7-8 days of therapy. The average volume of distribution is 20 l / kg body weight, indicating that most of the amlodipine is in the tissues, and the smaller is in the blood.

Metabolism

Amlodipine undergoes a slow but active metabolism in the liver in the absence of a significant "first pass" effect. Metabolites do not have significant pharmacological activity.

Excretion

The elimination consists of two phases, the final phase of 30-50 hours. About 60% of the ingested dose is excreted by the kidney mainly in the form of metabolites, 10% in unchanged form, and 20-25% in the form of metabolites through the intestine with bile. The total clearance of amlodipine is 0.116 ml / s / kg (7 ml / min / kg, 0.42 l / h / kg).

Pharmacokinetics in selected patient groups

In elderly patients (over 65 years), amlodipine withdrawal is slowed (T1 / 2 - 65 h) compared with young patients, but this difference has no clinical significance.

In patients with hepatic insufficiency, prolongation of T1 / 2 suggests that, with prolonged use, cumulation of amlodipine in the body will be higher (T1/2 - up to 60 hours).

Renal failure does not significantly affect the kinetics of amlodipine. Amlodipine penetrates the blood-brain barrier. When hemodialysis is not removed.

Amlodipine + Lysinopril

Interaction between the active substances in the formulation Amlodipine + Lysinopril, it is unlikely. AUC, the time of reaching and the value of the maximum concentration, the half-lives do not undergo changes in comparison with the indices of each individual active substance. Eating does not affect the absorption of active ingredients.

Indications:

Arterial hypertension (patients who are shown combined therapy).

Contraindications:

- Hypersensitivity to lisinopril or other ACE inhibitors;

- Hypersensitivity to amlodipine or other dihydropyridine derivatives;

- Hypersensitivity to other components of the drug;

- Angioedema (edema of Quincke);

- Hereditary or idiopathic angioedema;

- Hemodynamically significant stenosis of the aorta or mitral valve;

- Hypertrophic obstructive cardiomyopathy;

- Severe arterial hypotension (systolic blood pressure less than 90 mm Hg);

- Shock (including cardiogenic);

- Unstable angina (with the exception of Prinzmetal angina);

- Hemodynamically unstable heart failure after acute myocardial infarction;

- Simultaneous use with aliskiren and preparations containing aliskiren, in patients with diabetes mellitus and / or moderate or severe renal dysfunction (glomerular rate filtration (GFR) of less than 60 ml / min / 1.73 m² surface area of the body);

- Pregnancy and the period of breastfeeding;

- Age to 18 years (effectiveness and safety not established).

Carefully:

Severe renal dysfunction, bilateral renal artery stenosis or arterial stenosis of a single kidney with progressive azotemia, condition after kidney transplantation, azotemia, hyperkalemia, primary hyperaldosteronism, liver dysfunction, arterial hypotension, cerebrovascular diseases (including cerebral circulatory insufficiency),ischemic heart disease, coronary insufficiency, sinus node weakness syndrome (severe bradycardia, tachycardia), chronic heart failure (CHF) of non-ischemic etiology III-IV functional class by classification NYHA, aortic stenosis, mitral stenosis, acute myocardial infarction (and within 1 month after myocardial infarction), autoimmune systemic connective tissue diseases (including scleroderma, systemic lupus erythematosus), oppression of bone marrow hematopoiesis, diabetes mellitus, diet with restriction of table salt, hypovolemic conditions (including as a result of diarrhea, vomiting), hemodialysis with the use of high-flow dialysis membranes with high permeability (AN69®), old age, with simultaneous application with inhibitors or inducers of isoenzyme CYP3A4, simultaneous use with preparations containing aliskiren, or angiotensin receptor antagonists II (APA II) (increased risk of developing arterial hypotension, hyperkalemia and renal failure with a double blockade of RAAS).

Pregnancy and lactation:

Application of the drug Amlodipine + Lysinopril during pregnancy and during breastfeeding is contraindicated.

Pregnancy

When diagnosing pregnancy, taking the drug Amlodipine + Lysinopril should be stopped immediately.

Admission of ACE inhibitors in II and III trimester of pregnancy has an adverse effect on the fetus (there may be a marked decrease in blood pressure, renal failure, hyperkalemia, hypoplasia of the skull bones, intrauterine death). Data on the negative effects of the drug on the fetus in the case of use during the first trimester of pregnancy is not.

For newborns and infants who have undergone intrauterine effect of ACE inhibitors, it is recommended to carefully monitor for the timely detection of a marked decrease in blood pressure, oliguria, and hyperkalemia.

The safety of amlodipine during pregnancy is not established, so the use of amlodipine is not recommended during pregnancy.

Breastfeeding period

Lizinopril penetrates the placenta and can be excreted in breast milk. There is no evidence that amlodipine is excreted in breast milk.However, it is known that other BCCC - dihydropyridine derivatives are excreted in breast milk. Application of the drug Amlodipine + Lysinopril during lactation is not recommended.

If the drug is needed during breastfeeding, then breastfeeding should be discontinued.

Dosing and Administration:

A drug Amlodipine + Lysinopril is indicated only for those patients in whom the optimal maintenance dose of lisinopril and amlodipine is titrated to 10 mg and 5 mg, respectively, or to 10 mg and 20 mg, respectively, or up to 20 mg and 5 mg, respectively.

Inside, regardless of food intake. The recommended dose is one tablet of the drug Amlodipine + Lysinopril daily.

The maximum daily dose is one tablet of the drug Amlodipine + Lysinopril.

At the beginning of drug therapy Amlodipine + Lysinopril may develop symptomatic arterial hypotension, which is more likely to occur in patients with impaired water-electrolyte balance, due to previous therapy with diuretics. Admission diuretikov should be discontinued 2-3 days before the start of therapy with the drug Amlodipine + Lysinopril. In cases where the cancellation of diuretics is not possible, the initial dose of the drug Amlodipine + Lysinopril is ½ tablets (5 mg amlodipine + 10 mg lisinopril) once a day, after which the patient should be monitored for several hours because of the possible development of symptomatic arterial hypotension.

Patients with renal insufficiency

To determine the optimal initial and maintenance dose for patients with renal insufficiency, the dose should be titrated and determined individually, using separately lisinopril and amlodipine. During treatment with the drug Amlodipine + Lysinopril it is necessary to monitor the kidney function, the content of potassium and sodium in the blood serum. In case of impaired renal function, taking the drug Amlodipine + Lysinopril It is necessary to cancel and replace it with lisinopril and amlodipine in adequate doses.

Patients with hepatic insufficiency

Excretion of amlodipine may be delayed in patients with impaired hepatic function. Clear recommendations on the dosing regimen in such cases are not established, so the drug Amlodipine + Lysinopril should be administered with caution in patients with hepatic insufficiency.

Elderly patients (over 65 years of age)

In clinical studies, age-related changes in efficacy or safety profile for amlodipine and lisinopril have not been observed. To determine the optimal maintenance dose, it is necessary to determine the dosing regimen individually, using separately lisinopril and amlodipine.

Side effects:

The incidence of adverse reactions in patients receiving the combined drug was not higher than in patients receiving one of the active substances. Adverse reactions corresponded to the previously obtained data on amlodipine and / or lisinopril. Adverse reactions were mild, transient and rarely required the withdrawal of treatment. The most common adverse reactions with the combination of drugs were: headache (8%), cough (5%), dizziness (3%).

The frequency of adverse reactions is given separately for lisinopril and amlodipine.

The data are presented according to the system-organ classes in accordance with the classification MedDRA and with the following frequency: 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); frequency is unknown (can not be established based on available data).

Class of organ system MedDRA	Frequency	Unwanted Effects lisinopril	The undesirable effects of amlodipine
Disturbances from the hematopoietic and lymphatic system	Rarely	Inhibition of bone marrow hemopoiesis, agranulocytosis, leukopenia, neutropenia, thrombocytopenia, hemolytic anemia, anemia, lymphadenopathy	Thrombocytopenia
Immune system disorders	Rarely	Vasculitis, positive test for antinuclear antibodies	Hypersensitivity
Disorders from the metabolism and nutrition	Rarely	Hypoglycaemia	Hyperglycaemia
Mental disorders	Infrequently	Change in mood, sleep disorders	Insomnia, unusual dreams, mood changes, increased excitability, depression, anxiety
Mental disorders	Rarely	Disorders of the psyche	Apathy, agitation
Disturbances from the nervous system	Often	Dizziness, headache, drowsiness	Drowsiness, dizziness, headache
	Infrequently	Systemic dizziness, paresthesia, dysgeusia, convulsive twitching of the muscles of the extremities and lips	Syncope, tremor, dysgeusia, hypoesthesia, paresthesia
	Rarely	Confusion of consciousness	Migraine
	Rarely		Peripheral neuropathy, ataxia, amnesia, parosmia
Disturbances on the part of the organ of sight	Infrequently		Visual disturbances (diplopia, accommodation disorder), xerophthalmia, conjunctivitis, pain in the eyes
Violations from the organ of hearing and labyrinth	Infrequently		Noise in ears
Heart Disease	Often		Cardiopalmus
	Infrequently	Myocardial infarction, violation of atrioventricular conduction, bradycardia, tachycardia, heart palpitations, worsening of CHF, chest pain
	Rarely		Exacerbation of CHF flow
	Rarely		Myocardial infarction, ventricular tachycardia, atrial fibrillation, arrhythmia
Disorders from the vascular system	Often	Severe BP reduction, orthostatic hypotension	Hyperemia of the skin
	Infrequently	Violation of cerebral circulation, Raynaud's syndrome	Severe BP reduction, orthostatic hypotension
	Rarely		Vasculitis
Disturbances from the respiratory system, chest and mediastinal organs	Often	Dry cough
	Infrequently	Rhinitis	Disnea, rhinitis, nosebleeds
	Rarely	Dyspnea
	Rarely	Bronchospasm, allergic alveolitis / eosinophilic pneumonia, sinusitis	Cough
Disorders from the digestive system	Often	Diarrhea, vomiting	Abdominal pain, nausea
	Infrequently	Abdominal pain, nausea, digestive disorders	Vomiting, indigestion, constipation or diarrhea, dry mouth, anorexia, thirst
	Rarely	Dry mouth	Increased appetite
	Rarely	Pancreatitis, intestinal angioedema	Pancreatitis, gastritis, gingival hyperplasia
Disturbances from the liver and bile ducts	Rarely	Hepatic insufficiency, hepatitis, cholestatic jaundice	Hepatitis, jaundice, cholestasis
Disturbances from the skin and subcutaneous fat	Infrequently	Allergic reactions / angioedema, swelling of the face, extremities, lips, tongue, vocal cords and / or larynx, skin rash, skin itching, photosensitivity	Skin rash, purpura, itchy skin, xeroderma
	Rarely	Psoriasis, urticaria rash, alopecia	Dermatitis
	Rarely	Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme. Vulgar pemphigus, increased sweating, pseudolymphoma of the skin *	Multiform erythema, angioedema, urticaria rash, increased sweating, "cold sweat", alopecia, skin discoloration
Disturbances from the musculoskeletal system and connective tissue	Infrequently		Arthralgia, myalgia, muscle cramps, back pain, arthrosis
	Rarely	Arthralgia, myalgia, arthritis	Myasthenia gravis
Disorders from the kidneys and urinary tract	Often	Impaired renal function
	Infrequently		Upset, nocturia, increased frequency of urination
	Rarely	Acute renal failure, uremia
	Rarely	Oliguria / anuria
Disorders from the reproductive system and mammary glands	Infrequently	Impotence	Impotence, gynecomastia
Disorders from the reproductive system and mammary glands	Rarely	Gynecomastia
General (systemic) and local reactions	Often		Peripheral edema, increased fatigue
General (systemic) and local reactions	Infrequently	Increased fatigue, asthenia	Pain in the chest, pain, malaise, asthenia
Violations from laboratory indicators	Infrequently	Increase in the concentration of urea and serum creatinine, hyperkalemia, increased activity of "liver" enzymes	Weight gain, weight loss
	Rarely	Reduction of hemoglobin and hematocrit, erythropenia, hyperbilirubinemia, hyponatremia
	Rarely		Increased activity of "liver enzymes"

* The development of a complex symptom complex that may include all or some of the following symptoms has been reported: fever, vasculitis, myalgia, arthralgia / arthritis, positive antinuclear antibody test, increased erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitivity or other changes from the skin.

Overdose:

Amlodipine

Symptoms: marked decrease in blood pressure with possible development of reflex tachycardia and excessive peripheral vasodilation (risk of development severe and persistent arterial hypotension, including, with the development of shock and death).

Treatment: gastric lavage, the appointment of activated charcoal, maintenance of cardiovascular function, control of cardiovascular and respiratory functions systems, giving to the patient horizontal position with raised legs, control of the volume of circulating blood (BCC) and diuresis. To restore the vascular tone, the use of vasoconstrictors (in the absence contraindications to their use); with the purpose of elimination of consequences of blockade of calcium channels - intravenous introduction of calcium gluconate. Hemodialysis is ineffective.

Lisinopril

Symptoms: marked decrease in blood pressure, dry mouth, drowsiness, urinary retention, constipation, anxiety, increased irritability.

Treatment: gastric lavage, taking activated carbon, giving the patient a horizontal position with raised legs, replenishment of BCC - intravenous administration of plasma-substituting solutions, symptomatic therapy, control of cardiovascular and respiratory systems, bcc, urea, creatinine and electrolytes in blood serum, and diuresis. Lisinopril can be removed from the body by hemodialysis.

Interaction:

Contraindicated medicinal combinations

Dantrolene (for intravenous administration): in cases of laboratory animals fibrillation of ventricles with a lethal outcome was noted against the background of verapamil and intravenous administration of dantrolene. Extrapolating available data, simultaneous application of dantrolen and verapamil.

Simultaneous administration of ACE inhibitors with aliskiren and aliskiren-containing preparations in patients with diabetes mellitus and / or moderate or severe renal dysfunction (GFR less than 60 mL / min / 1.73 m² body surface area) increases the risk hyperkalemia, impaired renal function, and increased rates of cardiovascular morbidity and mortality.

Combinations of medicines, requiring special care when applying

Inhibitor inhibitors CYP3A4: with simultaneous application diltiazem in a dose of 180 mg and amlodipine in a dose of 5 mg in patients aged 69 to 87 years with arterial hypertension, there was an increase in system exposure of amlodipine by 57%. At the same time, amlodipine and erythromycin in healthy volunteers (18 to 43 years) does not lead to significant changes in exposure to amlodipine (an increase AUC on 22%). Despite the fact that the clinical significance of these effects to the end it is unclear whether they can be more pronounced in elderly patients.

Powerful inhibitors of isoenzyme CYP3A4 (eg, ketoconazole. itraconazole) can lead to an increase in the concentration of amlodipine in the blood plasma to a greater extent than diltiazem. It should be used with caution amlodipine and isoenzyme inhibitors CYP3A4.

Clarithromycin: isoenzyme inhibitor CYP3A4. In patients taking both clarithromycin and amlodipine, increased risk of lowering blood pressure. Patients who take this combination are recommended to be under close medical supervision.

Inductors of isoenzyme CYP3A4: data on the influence of inducers isoenzyme CYP3A4 there is no pharmacokinetics of amlodipine. It is necessary to carefully monitor blood pressure while using amlodipine and isoenzyme inducers CYP3A4.

Tacrolimus: with simultaneous use with amlodipine there is a risk of increasing tacrolimus concentration in the blood plasma. In order to avoid the toxicity of tacrolimus when used simultaneously with amlodipine, the concentration of tacrolimus in the blood plasma should be monitored and the dose of tacrolimus should be adjusted if necessary.

Baclofen enhances the antihypertensive effect of ACE inhibitors, requires monitoring of blood pressure and, if necessary, correction of doses of antihypertensive drugs.

Combinations of medicines, requiring caution when applying

Caution should be applied lisinopril at the same time with potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium preparations, salt substitutes, containing potassium, cyclosporin - the risk of hyperkalemia increases, especially with impaired renal function. Therefore, these combinations should be used only on the basis of the individual solutions at regular physician monitoring the potassium content in blood serum and renal function.

May increase antianginal and antihypertensive action of BCCI when combined with thiazide and "loop" diuretics, ACE inhibitors and nitrates, beta-blockers, as well as strengthening their antihypertensive effects when combined with alpha 1-blockers, neuroleptics. Beta-blockers while the use of amlodipine may cause worsening CHF flow.

Simultaneous prolonged use of simvastatin 80 mg per day of amlodipine and 10 mg per day leads to 77% increase in exposure of simvastatin. It is recommended to reduce the dose of simvastatin in patients taking amlodipine, up to 20 mg per day.

Although no negative inotropic effects were usually observed in the study of amlodipine, nevertheless, some BCCCs can enhance the expression of negative inotropic action antiarrhythmic drugs, causing lengthening of the interval QT (eg, amiodarone and quinidine).

With the simultaneous use of lisinopril with vasodilators, barbiturates, antipsychotic agents (antipsychotics), tricyclic antidepressants, general anesthetic agents, muscle relaxants, BCCC, beta-blockers possibly increased antihypertensive effect.

Antiviral drugs (ritonavir) increases plasma concentrations of BCCC, including amlodipine.

Neuroleptics and isoflurane - increased antihypertensive effect of dihydropyridine derivatives.

Grapefruit juice: simultaneous single administration of 240 mg grapefruit juice and 10 mg of amlodipine inside is not accompanied by a significant change in the pharmacokinetics of amlodipine. Nevertheless, it is not recommended to use grapefruit juice and amlodipine At the same time, as in the genetic polymorphism of the isoenzyme CYP3A4 it is possible to increase the bioavailability of amlodipine and, as a result, enhance antihypertensive action.

Ethanol strengthens the action of lisinopril.

Calcium preparations can reduce the effect of BCCI.

In the joint application of BCCI with lithium preparations (there are no data for amlodipine), it is possible to intensify the manifestation of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

Studies of simultaneous use of amlodipine and cyclosporine in healthy volunteers and all patient groups, except for patients after kidney transplantation, were not performed. Various studies of amlodipine with cyclosporine in patients after kidney transplantation show that the use of this combination may not lead to any effect, or increase the minimum concentration of cyclosporin to varying degrees to 40%. These data should be taken into account and the concentration of cyclosporine in this group of patients should be monitored while cyclosporine and amlodipine are used simultaneously.

With simultaneous application amlodipine can increase the system exposure tasononemine in the blood plasma.In such cases, regular monitoring of the tasononemine in the blood and a dose adjustment if necessary.

When used simultaneously with non-steroidal anti-inflammatory drugs (NSAIDs) (including selective inhibitors of cyclooxygenase-2 (COX-2)), acetylsalicylic acid at a dose of more than 3 g / day, estrogens, as well as sympathomimetics, decreases the antihypertensive effect of lisinopril. NSAIDs, including COX-2, and ACE inhibitors increase serum potassium levels and can worsen renal function. This effect is usually reversible.

Lizinopril slows the withdrawal of drugs lithium, therefore, with simultaneous application, a reversible increase in its concentration in the blood plasma occurs, which may increase the likelihood of development undesirable phenomena, therefore, the maintenance of lithium in blood serum should be regularly monitored.

When used simultaneously with antacids and colestyramine the absorption of lisinopril from the digestive tract decreases.

In elderly patients and patients with impaired renal function, simultaneous administration of ACE inhibitors with sulfamethoxazole / trimethoprim accompanied by severe hyperkalemia, which is believed to be caused by trimethoprim, so the drug should be used with caution with preparations containing trimethoprim, regularly monitoring the potassium content in the blood plasma.

With the simultaneous use of lisinopril with heparin it is possible to increase the potassium content in the blood serum.

When combined with lisinopril with selective serotonin reuptake inhibitors can lead to severe hyponatraemia.

Simultaneous use of ACE inhibitors with drugs containing aliskiren or ARA II, patients can lead to a double blockade of RAAS (risk of arterial hypotension, hyperkalemia and kidney failure), so care must be taken.

Other drug interactions

Amlodipine

Amlodipine can be safely used for the therapy of arterial hypertension along with thiazide diuretics, alpha-adrenoblockers or ACE inhibitors.

In patients with stable angina pectoris amlodipine can be used with other antianginal agents, for example, with prolonged or short-acting nitrates, beta-blockers.

Unlike other BCCC, clinically significant interaction of amlodipine was not found when combined with NSAIDs, including indomethacin. Amlodipine can be safely used with antibiotics and hypoglycemic agents for oral administration. A single dose of 100 mg sildenafil in patients with hypertension does not affect the pharmacokinetics parameters of amlodipine.

With simultaneous application with sildenafil, it is necessary to control blood pressure (the risk of developing arterial hypotension).

Repeated use of amlodipine in a dose of 10 mg and atorvastatin in a dose of 80 mg is not accompanied by significant changes in the pharmacokinetics of atorvastatin.

Ethanol (drinks containing alcohol): amlodipine at a single and repeated application in a dose of 10 mg does not affect the pharmacokinetics of ethanol. Does not affect serum concentration digoxin and its renal clearance.

Has no significant effect on the action warfarin (prothrombin time).

Cimetidine does not affect the pharmacokinetics of amlodipine.

In studies in vitro Amlodipine does not affect the binding to plasma proteins digoxin, phenytoin, warfarin and indomethacin ..

Aluminum - or magnesium-containing antacids: their single administration does not have a significant effect on the pharmacokinetics of amlodipine.

Corticosteroids (mineral and glucocorticosteroids), tetracosactide

Reduction of antihypertensive action (fluid retention and sodium ions due to the action of corticosteroids).

Amifostine

It is possible to increase the antihypertensive effect of amlodipine.

Lisinopril

When used simultaneously with insulin and hypoglycemic agents for oral administration increases the risk of developing hypoglycemia.

With simultaneous use of ACE inhibitors and preparations of gold intravenously (sodium aurotomy malate) describes a symptom complex, which includes facial flushing, nausea, vomiting and lowering blood pressure.

Joint application with Allopurinol, procainamide, cytostatics can lead to leukopenia.

Estramustine

Simultaneous application can lead to an increased risk of side effects, such as angioedema.

Inhibitors mTOR (mammalion Target of Rapamycin - a target of rapamycin in mammalian cells) (for example, tessirolimus, sirolimus, everolimus) In patients taking both ACE inhibitors and inhibitors mTOR, there was an increased risk of angioedema.

Glyptins (linaglyptin, saxagliptin, sitagliptin, vildagliptin)

Co-administration with ACE inhibitors may increase the risk of developing angioedema due to inhibition of dipeptidyl peptidase IV (DAP-IV) glyptins.

Inhibitors of neutral endopeptidase

Due to the action of neutral endopeptidase (NEP) inhibitors, the activity of endogenous vasodilating substances increases, therefore, with the simultaneous use of lisinopril with vasodilators (omapatrilat, ilepatril), an increase in the antihypertensive effect is possible.

Special instructions:

Arterial hypotension

A marked decrease in blood pressure with the development of clinical symptoms can be observed in patients with a decrease in the volume of circulating blood and / or sodium content due to diuretics, fluid loss or other reasons, for example, increased perspiration, prolonged vomiting and / or diarrhea. It is necessary that the restoration of fluid loss and / or sodium be carried out before the drug therapy begins Amlodipine + Lysinopril. It is necessary to monitor BP after taking the initial dose. Similar conditions apply to patients with coronary heart disease or cerebrovascular disease, in whom a marked decrease in blood pressure can lead to myocardial infarction or stroke.

Aortic and mitral stenosis

Like all vasodilator drugs, the drug Amlodipine + Lysinopril should be administered with caution to patients with obstruction of the left ventricular outflow tract and stenosis of the mitral valve.

Impaired renal function

In some patients with arterial hypertension without pronounced manifestations of renovascular diseases, an increase in the concentration of serum creatinine and urea was observed, in most cases minimal or transient, more pronounced with concurrent administration of an ACE inhibitor and a diuretic. This is most typical for patients with a history of kidney disease.

To determine the optimal maintenance dose, it is necessary to determine the dosage regimen individually, using separately lisinopril and amlodipine, with simultaneous monitoring of kidney function. A drug Amlodipine + Lysinopril is indicated only for those patients in whom the optimal maintenance dose of lisinopril and amlodipine is titrated to 10 mg and 5 mg, respectively, or to 10 mg and 20 mg, respectively, or up to 20 mg and 5 mg, respectively.

In the case of a decrease in kidney function, taking the drug Amlodipine + Lysinopril should be discontinued and replaced by monotherapy with drugs in adequate doses. In addition, a dose reduction or elimination of diuretics may be required.

Angioedema

Angioedema of the face, extremities, lips, tongue, vocal folds and / or larynx was recorded in patients taking ACE inhibitors, including lisinopril. In these cases, taking the drug Amlodipine + Lysinopril should immediately stop and the patient to conduct a thorough medical observation until the symptoms disappear completely. Edema of the face, lips and extremities usually passes independently, however, to reduce the severity of symptoms should use antihistamines.

Angioedema, accompanied by swelling of the larynx, can lead to death. If you detect edema of the tongue, pharynx or larynx, which are the cause of airway obstruction, emergency measures should be urgently started.The proper measures include: the use of 0.1% epinephrine (adrenaline) solution subcutaneously in a dose of 0.3-0.5 mg or 0.1 mg intravenously slowly, followed by the use of glucocorticosteroids (intravenously) and antihistamines and simultaneous monitoring of vital functions.

Patients who took ACE inhibitors were rarely seen intestinal angioedema. These patients complained of abdominal pain (with or without nausea and vomiting); in some cases of the previous angioedema, the face was not observed and the activity of C-1 esterase was within the normal range. Intestinal angioedema has been diagnosed by computed tomography of the gastrointestinal tract, or after ultrasound, or in surgical intervention; symptoms disappeared after discontinuation of the ACE inhibitor. When performing differential diagnosis of abdominal pain in patients taking ACE inhibitors, you should also consider intestinal angioedema.

Anaphylactic reactions in patients on hemodialysis

In patients who underwent hemodialysis through polyacrylonitrile membranes (for example, AN 69) and who simultaneously received ACE inhibitors, cases of anaphylactic shock have been recorded, so this combination should be avoided. Patients are recommended to use either another type of dialysis membrane, or an antihypertensive drug of another pharmacotherapeutic group.

Anaphylactic reactions in patients during apheresis of low-density lipoproteins (LDL)

Rarely in patients who received ACE inhibitors during the apheresis of LDL with dextran sulfate, life-threatening anaphylactic reactions developed. Such reactions were prevented by withdrawal of an ACE inhibitor before each apheresis procedure.

Desensitization from aspen or bee venom

Sometimes anaphylactic reactions developed in patients taking ACE inhibitors when desiccating the venom of Hymenoptera (eg, wasps or bees). Such life-threatening situations can be avoided with the abolition of the ACE inhibitor before the desensitization procedure.

Effects on the liver

In rare cases, the administration of ACE inhibitors was accompanied by a syndrome that began with cholestatic jaundice or hepatitis and grew into fulminant liver necrosis and in a few cases resultedto a lethal outcome. The mechanism of this syndrome is unclear. Patients receiving the drug Amlodipine + Lysinopril, and in which jaundice develops or the activity of "liver" enzymes is increased, it is necessary to cancel the drug with subsequent monitoring of their condition.

Liver failure

In patients with impaired hepatic function, the half-life of amlodipine is longer. At the moment, recommendations on the dosage regimen have not been developed, and therefore this drug should be administered with caution, having previously estimated the expected benefit and the potential risk of treatment.

Neutropenia / agranulocytosis

In rare cases, neutropenia, agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and in the absence of other aggravating factors, neutropenia is rare. Neutropenia and agranulocytosis are reversible and disappear after the withdrawal of the ACE inhibitor. A drug Amlodipine + Lysinopril should be used with extreme caution in patients with systemic connective tissue diseases, with immunosuppressive therapy,during treatment with allopurinol or procainamide or a combination of these aggravating factors, especially in the presence of a previous impairment of kidney function. Some of these patients developed serious infectious diseases, in which a response to antibiotic treatment was not received in several cases. During treatment with the drug Amlodipine + Lysinopril periodic monitoring of leukocytes (blood count with counting of the leukocyte formula) in such patients is necessary, as well as to warn them about the need to report the appearance of the first signs of an infectious disease.

Cough

Cough was often recorded during the use of ACE inhibitors. As a rule, cough is unproductive, persistent and stopped after the drug was discontinued. With a differential diagnosis of cough, one must also consider the cough caused by the use of ACE inhibitors.

Surgery / general anesthesia

In patients who undergo extensive surgery or during general anesthesia with drugs leading to hypotension, lisinopril can block the formation of angiotensin II after compensatory release of renin.If arterial hypotension develops, probably as a result of the above mechanism, it is possible to correct the increase in the volume of circulating blood.

Elderly patients

Older patients with impaired renal function should undergo a dose adjustment, applying separately lisinopril and amlodipine.

Hyperkalemia

In some patients who received ACE inhibitors, an increase in serum potassium was observed. Risk group for the development of hyperkalemia consists of patients with renal failure, diabetes, congestive heart failure, dehydration, metabolic acidosis or while receiving potassium-sparing diuretics, potassium-containing food additives, potassium-based salt substitutes or any other medications, leading to an increase of potassium in blood serum (e.g., heparin). If it is necessary to simultaneously take the above drugs, you need to monitor the potassium content in the blood serum.

Patients with reduced body weight, patients of low growth and patients with a marked impairment of liver function may need to reduce the dose.

A drug Amlodipine + Lysinopril does not have any adverse effects on the metabolism and lipids of blood plasma and can be used to treat patients with bronchial asthma, diabetes and gout.

During treatment, weight control is necessary.

It is necessary to maintain oral hygiene and supervision at the dentist (to prevent soreness, bleeding and gingival hyperplasia).

Acute myocardial infarction

Treatment for acute myocardial infarction is carried out against the background of standard therapy (thrombolytics, acetylsalicylic acid (as antiplatelet agents), beta-blockers).

Lizinopril can be used together with intravenous nitroglycerin or with the use of transdermal nitroglycerin systems.

CHF of non-ischemic etiology III-IV functional class by classification NYHA

Against the background of the use of amlodipine in patients with CHF of non-ischemic etiology III-IV functional class by classification NYHA There was an increase in the incidence of pulmonary edema, despite the absence of signs of worsening heart failure.

Double blockade of RAAS

Arterial hypotension, fainting, stroke, hyperkalemia and renal dysfunction (including acute renal failure) have been reported in susceptible patients, especially when used with medications that affect this system. Therefore, a double blockade of RAAS due to a combination of an ACE inhibitor with ARA II or aliskiren is not recommended.

Patients with diabetes mellitus

When prescribing a drug for patients with diabetes mellitus receiving hypoglycemic agents for ingestion or insulin, during the first month of therapy it is necessary to regularly monitor the concentration of glucose in the blood.

Ethnic differences

It should be borne in mind that in patients of the Negroid race the risk of angioedema development is higher. Like other ACE inhibitors, lisinopril It is less effective in reducing blood pressure in patients of the Negroid race. This effect is probably associated with a marked predominance of low-grade status in patients of the Negroid race with arterial hypertension.

In Vitro Fertilization (IVF)

In isolated cases with IVF on the background of BCCC, reversible biochemical changes in the head of spermatozoa were noted, which led to a disruption of their functions.

With unsuccessful attempts of IVF and with the exclusion of other causes of infertility, one should take into account the probability of influence on spermatozoa BCCC, provided they are used.

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

Apply the drug Amlodipine + Lysinopril it is necessary with caution (the risk of a pronounced decrease in blood pressure and dizziness). Therefore, at the beginning of treatment, it is recommended to avoid driving vehicles, working with mechanisms and performing other work requiring increased concentration of attention.

Form release / dosage:

Tablets 5 mg + 10 mg, 10 mg + 20 mg, 5 mg + 20 mg.

Packaging:

For 10 tablets in a planar cell packaging made of a polyvinylchloride film and aluminum foil printed aluminum foil or aluminum foil with a heat-sealable coating.

For 30 tablets in a polymer type BP bottle made of low pressure polyethylene with a high-pressure polyethylene lid or in a low-pressure polyethylene polymer bottle with a high-pressure polyethylene lid.

Each bank or vial, 3, 5, 6 contour mesh packages together with instructions for use in a cardboard bundle.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004417

Date of registration:16.08.2017

Expiration Date:16.08.2022

The owner of the registration certificate:NORTH STAR, CJSC NORTH STAR, CJSC Russia

Manufacturer: & nbsp

NORTH STAR, CJSC Russia

Information update date: & nbsp11.09.2017

Illustrated instructions

Instructions

Amlodipine + Lysinopril (Amlodipine + Lisinopril)