Amlodipine, Valsartan, Hydrochlorothiazide

Pharmacological properties

Combisart N contains three antihypertensive drugs with complementary mechanisms for controlling hell in patients with essential hypertension: amlodipine belongs to the class of calcium antagonists, valsartan belongs to the class of angiotensin II antagonists, and hydrochlorothiazide belongs to the class of thiazide diuretics. a combination of these three components is characterized by a complementary antihypertensive effect.

Amlodipine

Amlodipine, which is part of Combisart N, inhibits the transmembrane entry of calcium ions into the muscles of the heart and vascular smooth muscles. The antihypertensive effect of amlodipine is carried out by a direct relaxing effect on the smooth muscles of blood vessels, which causes a decrease in the resistance of peripheral vessels and blood pressure.

Amlodipine in therapeutic doses in patients with hypertension causes vasodilation, which leads to a decrease in blood pressure in the patients supine position. Such a decrease in blood pressure is not accompanied by pronounced changes in heart rate or plasma catecholamines with prolonged use.

Plasma concentration is correlated with the effect in patients of both young and old age.

In patients with hypertension and normal renal function, amlodipine in therapeutic doses leads to a decrease in renal vascular resistance and an increase in glomerular filtration rate (GFR) and effective renal plasma flow without changing the filtration fraction or proteinuria.

Valsartan

Valsartan is an oral active, potent, and specific antagonist of angiotensin II receptors. Valsartan acts selectively on subtype AT₁receptors responsible for the known effects of angiotensin II.

Taking valsartan in patients with hypertension helps to lower blood pressure without affecting heart rate.

In most patients, after oral administration of a single dose, the onset of the hypotensive effect occurs within 2 hours, and the maximum decrease in blood pressure is achieved within 4-6 hours. The antihypertensive effect lasts for 24 hours after administration of the drug. With repeated use, the maximum decrease in blood pressure (with all dosage modes) is achieved, as a rule, within 2-4 weeks.

Hydrochlorothiazide

The site of action of thiazide diuretics is mainly the distal sinuous tubules of the kidneys. It has been confirmed that in the cortical layer of the kidneys there are highly related receptors, which are the main binding site for thiazide diuretics and inhibition of NaCl transport to the distal sinuous tubules. The mechanism of action of thiazides is the inhibition of Na carriers⁺Cl^–possibly by competing for Cl centers^–, which, in turn, acts on the mechanisms of electrolyte reabsorption: it directly enhances the excretion of sodium and chlorine to an approximately equivalent degree and indirectly (due to the diuretic effect) reduces blood plasma volume with a further increase in plasma renin activity, aldosterone secretion and potassium excretion in urine as well as a decrease in serum potassium levels.

Pharmacokinetics

Linearity

Amlodipine, valsartan, and hydrochlorothiazide demonstrate linear pharmacokinetics.

Amlodipine / Valsartan / Hydrochlorothiazide

After oral administration of the drug Combisart N C_max amlodipine, valsartan and hydrochlorothiazide in blood plasma are reached within 6–8; 3 and 2 hours, respectively. The rate and volume of absorption of amlodipine, valsartan and hydrochlorothiazide when using Combisart N are similar to those observed when using its components as separate preparations.

Amlodipine

Absorption. Following oral administration in therapeutic doses of amlodipine C alone_max in blood plasma is reached after 6-12 hours. Absolute bioavailability is from 64 to 80%. Eating does not affect the bioavailability of amlodipine.

Distribution. The distribution volume is approximately 21 l / kg body weight. About 97.5% of the drug, which is in the circulating blood, binds to plasma proteins.

Biotransformation. Amlodipine is actively (approximately 90%) metabolized in the liver to inactive metabolites.

Amlodipine is excreted from blood plasma in two stages, the final T_½ is approximately 30-50 hours. Levels of equilibrium in blood plasma are achieved after continuous use for 7-8 days. 10% of the initial amlodipine and 60% of amlodipine metabolites are excreted in the urine.

Valsartan

Absorption. Following oral administration of valsartan alone, its C_max achieved in 2–4 hours. The average absolute bioavailability is 23%. Eating reduces the exposure (as determined by AUC) of valsartan by approximately 40%, and C_max - approximately 50%, although approximately 8 hours after application, the concentration of valsartan is similar in the fasting and after meals groups. However, such a decrease in AUC is not accompanied by a clinically significant decrease in the therapeutic effect, so valsartan can be used regardless of food intake.

Distribution. The distribution volume of valsartan in equilibrium after iv administration is approximately 17 L, which indicates that valsartan is not distributed extensively in tissues. Valsartan is actively associated with plasma proteins (94–97%), mainly with serum albumin.

Biotransformation. Valsartan does not transform significantly, since only approximately 20% of the dose is excreted as metabolites. Hydroxymetabolite is identified in blood plasma at low concentrations (10% AUC of valsartan). This metabolite is pharmacologically inactive.

Valsartan is excreted primarily with feces (approximately 83% of the dose) and urine (approximately 13% of the dose), mainly as an unchanged drug. After iv administration, the plasma clearance of valsartan is about 2 l / h, and the renal clearance is 0.62 l / h (approximately 30% of the total clearance). T_½ valsartan - 6 hours

Hydrochlorothiazide

Absorption. The absorption of hydrochlorothiazide after oral administration occurs rapidly (T_max - approximately 2 hours). The increase in average AUC is linear and proportional to the dose when used in the therapeutic dose range. There is no change in the kinetics of hydrochlorothiazide with repeated use, and cumulation was minimal when taken once a day. When taken with food, there was an increase as well as a decrease in the systemic availability of hydrochlorothiazide compared with fasting. The severity of these effects is insignificant and has little clinical significance. The absolute bioavailability of hydrochlorothiazide is 60–80% after oral administration.

Distribution. The apparent volume of distribution is 4–8 l / kg. Hydrochlorothiazide in the circulating blood binds to plasma proteins (40–70%), mainly with albumin in the blood serum. Hydrochlorothiazide also accumulates in red blood cells in an amount 1.8 times higher than that in blood plasma.

Biotransformation. Hydrochlorothiazide is excreted unchanged.

More than 95% of the absorbed dose is excreted unchanged in the urine. Renal clearance consists of passive filtration and active secretion in the renal tubules. T_½ - 6-15 hours

Individual patient groups

Children (under 18 years old). No data on pharmacokinetics in children.

Elderly patients (≥65 years old). Time to reach C_max amlodipine is similar in young and old patients. In elderly patients, amlodipine clearance tends to decrease, causing an increase in AUC and T_½. The average systemic AUC of valsartan is 70% higher in elderly patients than in young patients; therefore, it is necessary to increase the dose of such patients with caution.

The systemic exposure of valsartan is slightly higher in elderly patients compared with younger patients, but this is not of clinical significance.

Limited data indicate that systemic clearance of hydrochlorothiazide is reduced in both healthy elderly volunteers and elderly patients with hypertension compared with younger healthy volunteers.

Since the three components of the drug are equally well tolerated by patients of young and old age, the usual dosage regimen is recommended.

Impaired renal function. Impaired renal function does not significantly affect the pharmacokinetics of amlodipine. As expected, for a drug whose renal clearance is only 30% of the total plasma clearance, there is no relationship between renal function and systemic exposure of valsartan. Therefore, patients with mild to moderate renal impairment can use the drug in the usual initial dose.

Impaired liver function. In patients with impaired liver function, amlodipine clearance is reduced, which leads to an increase in AUC by approximately 40-60%. On average, in patients with mild to moderate chronic diseases, exposure (determined by AUC) of valsartan is 2 times higher than in adult volunteers (grouped by age, gender and body weight). With caution, the drug should be prescribed to persons with liver diseases.

The combination of amlodipine / valsartan / hydrochlorothiazide was not tested for genotoxicity and carcinogenicity, since there were no signs of interaction between these drugs on the market for a long time. However, amlodipine, valsartan, and hydrochlorothiazide have been individually tested for genotoxicity and carcinogenicity; negative results were obtained.

Indications

Treatment of essential arg in adult patients with hell adequately controlled by a combination of amlodipine, valsartan and hydrochlorothiazide, which are used as three separate drugs or as two drugs, one of which is a combination.

Application

Mode of application

Combisart N can be used regardless of food intake. The tablets should be swallowed whole, washed down with water, at the same time of the day, preferably in the morning.

Dosage

The recommended dose of Combisart N is 1 tablet per day, preferably in the morning.

Before switching to the use of the drug Combisart N, the patients condition should be controlled by constant doses of single drugs that are taken simultaneously. The dose of Combisart N should depend on the doses of the individual components of the combination that are used at the time of drug change.

The maximum recommended dose of Combisart N is 10 mg / 320 mg / 25 mg.

Individual patient groups

Impaired renal function

Since the preparation contains hydrochlorothiazide, Combisart N is contraindicated in patients with anuria and severe renal impairment (creatinine clearance 30 ml / min).

The simultaneous use of the drug Combisart H with aliskiren is contraindicated in patients with impaired renal function (GFR 60 mg / min / 1.73 m²) There is no need for dose adjustment in patients with mild to moderate renal impairment.

Diabetes. The simultaneous use of the drug Combisart H with aliskiren is contraindicated in patients with diabetes mellitus.

Impaired liver function. Since the composition of the drug includes hydrochlorothiazide and valsartan, the drug Combisart N is contraindicated in patients with severe hepatic impairment. For persons with mild to moderate hepatic impairment who are not accompanied by cholestasis, the maximum recommended dose of valsartan is 80 mg, so Combisart N is not indicated for this group of patients. For patients with impaired hepatic function of mild to moderate degree, recommendations for dosing amlodipine have not been established.

Heart failure and coronary artery disease.The experience with the use of Combisart N, especially in the maximum doses, is limited for patients with heart failure and coronary artery disease. It is recommended to use the drug with caution in patients with heart failure and coronary artery disease, especially the maximum dose of Combisart N is 10 mg / 320 mg / 25 mg.

Elderly patients (≥65 years old). It is recommended with caution, often controlling blood pressure, to prescribe the drug to elderly patients, especially at the maximum doses of Combisart N - 10 mg / 320 mg / 25 mg, since data on the use of the drug by patients in this group are limited.

Contraindications

• Hypersensitivity to active substances, other sulfonamides, derivatives of dihydropyridine or to any excipient. pregnancy or pregnancy planning (see use during pregnancy or lactation). impaired liver function, biliary cirrhosis or cholestasis. severe renal impairment (SCF 30 ml / min / 1.73 m2), anuria, as well as being on dialysis. simultaneous use of angiotensin receptor antagonists, including valsartan, or angiotensin converting enzyme inhibitors (IAPP) with aliskiren in case of diabetes mellitus or renal impairment (SCF 60 mg / min / 1.73 m2). refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia. severe hypotension. shock (including cardiogenic shock). obstruction of the excretory tract of the left ventricle (for example, hypertrophic obstructive cardiomyopathy and severe aortic stenosis). hemodynamically unstable heart failure after acute myocardial infarction.

Side effects

Amlodipine / Valsartan / Hydrochlorothiazide

• From the side of metabolism and nutrition: anorexia, hypercalcemia, hyperlipidemia, hyperuricemia, hypokalemia, hyponatremia;
• from the psyche: insomnia / sleep disturbance;
• from the nervous system: impaired coordination, dizziness, postural dizziness, tension dizziness, dysgeusia, headache, lethargy, paresthesia, peripheral neuropathy, neuropathy, drowsiness, syncope;
• on the part of the organ of vision: visual impairment;
• on the part of the organ of hearing: vertigo;
• on the part of the heart: tachycardia;
• from the vascular system: arterial hypotension, orthostatic hypotension, phlebitis, thrombophlebitis;
• from the respiratory tract, mediastinal organs and chest: cough, dyspnea, throat irritation;
• from the digestive tract: abdominal discomfort, pain in the upper abdomen, bad breath, diarrhea, dry mouth, dyspepsia, nausea, vomiting;
• on the part of the skin and its derivatives: hyperhidrosis, itching;
• from the musculoskeletal system and connective tissue: back pain, swelling of the joints, muscle spasms, muscle weakness, myalgia, pain in the limbs;
• on the part of the kidneys and urinary system: increased creatinine in plasma, poliuria, acute renal failure;
• from the reproductive system: impotence;
• general disorders: abasia, gait disturbance, asthenia, discomfort, malaise, weakness, non-cardiac chest pain, edema;
• examination: an increase in the level of urea nitrogen, an increase in the level of uric acid in the blood, a decrease in the level of potassium in the blood plasma, an increase in body weight.

Amlodipine

• On the part of the blood system and lymphatic system: leukopenia, thrombocytopenia, sometimes with purpura;
• from the immune system: hypersensitivity;
• from the side of metabolism and nutrition: hyperglycemia;
• from the psyche: insomnia / sleep disturbance, mood changes, embarrassment;
• from the nervous system: dizziness, dysgeusia, extrapyramidal syndrome, headache, hypertension, paresthesia, peripheral neuropathy, neuropathy, drowsiness, syncope, tremor, hypoesthesia;
• on the part of the organ of vision: visual impairment;
• on the part of the organ of hearing: ringing in the ears;
• on the part of the heart: palpitation, arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation), myocardial infarction;
• from the vascular system: flushing, arterial hypotension, vasculitis;
• from the respiratory tract, mediastinal organs and chest: cough, dyspnea, rhinitis;
• from the digestive tract: abdominal discomfort, pain in the upper abdomen, changes in the frequency of bowel movements, diarrhea, dry mouth, dyspepsia, gastritis, gingival hyperplasia, nausea, pancreatitis, vomiting;
• on the part of the liver and biliary tract: an increase in the level of liver enzymes, including an increase in the level of bilirubin in the blood plasma (more associated with cholestasis), hepatitis, intrahepatic cholestasis, jaundice;
• on the part of the skin and its derivatives: alopecia, angioedema, erythema multiforme, exanthema, hyperhidrosis, photosensitivity reactions, itching, purpura, rash, skin discoloration, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke edema;
• from the musculoskeletal system and connective tissue: arthralgia, back pain, muscle spasms, myalgia, ankle edema;
• from the kidneys and urinary system: impaired urination, nocturia, poliakuria;
• from the reproductive system and mammary glands: impotence, gynecomastia;
• general disorders: asthenia, discomfort, malaise, weakness, non-cardiac chest pain, swelling, pain;
• examination: increase / decrease in body weight.

Valsartan

• On the part of the organ of hearing: vertigo;
• from the respiratory tract, mediastinal organs and chest: cough;
• from the digestive tract: abdominal discomfort, pain in the upper abdomen;
• general disorders: weakness.

Hydrochlorothiazide

• From the blood and lymphatic systems: agranulocytosis, bone marrow depression, hemolytic anemia, leukopenia, thrombocytopenia, sometimes with purpura;
• from the immune system: hypersensitivity;
• from the side of metabolism and nutrition: hypercalcemia, hyperglycemia, hyperuricemia, hyperchloremic alkalosis, hypokalemia, hypomagnesemia, hyponatremia, metabolic symptoms of diabetes;
• from the psyche: depression, insomnia / sleep disturbance;
• from the nervous system: dizziness, headache, paresthesia;
• on the part of the organ of vision: visual impairment;
• on the part of the heart: arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation);
• from the vascular system: orthostatic hypotension;
• from the respiratory tract, mediastinal organs and chest: respiratory distress, pulmonary edema, pneumonitis;
• from the digestive tract: abdominal discomfort, pain in the upper abdomen, constipation, decreased appetite, diarrhea, nausea, pancreatitis, vomiting;
• from the liver and biliary tract: intrahepatic cholestasis, jaundice;
• on the part of the skin and its derivatives: skin reactions similar to lupus erythematosus, reactivation of the skin form of lupus erythematosus, photosensitivity reactions, purpura, rash, urticaria, necrotizing vasculitis and toxic epidermal necrolysis;
• from the kidneys and urinary system: renal failure and impaired renal function;
• from the reproductive system: impotence;
• examination: increased lipid levels, glucosuria.

special instructions

The safety and effectiveness of amlodipine in hypertensive crisis have not been investigated.

Sodium deficient patients with dehydration

In patients with an activated renin-angiotensin system (patients with salt deficiency and / or dehydration who receive diuretics in high doses) using angiotensin II receptor antagonists, symptomatic arterial hypotension may occur. It is recommended to correct this condition before using Combisart N or to carefully observe patients at the beginning of treatment.

If pronounced arterial hypotension occurs during the use of Combisart N, the patient should take a horizontal position and raise his legs and, if necessary, inject a physiological solution into the IV infusion. Treatment can be continued after stabilization of blood pressure.

Changes in electrolyte levels in blood plasma

Amlodipine / valsartan / hydrochlorothiazide. It is necessary to periodically, at appropriate intervals, check the levels of electrolytes in the blood serum to determine a possible electrolyte imbalance. Periodic determination of serum electrolytes and potassium levels should be carried out through appropriate periods to prevent possible electrolyte imbalance, especially in patients with risk factors such as impaired renal function, treatment with other drugs and a history of electrolyte imbalance.

Valsartan. The simultaneous use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that can increase potassium levels (for example, with heparin) is not recommended. If necessary, potassium levels should be monitored.

Hydrochlorothiazide. The development of hypokalemia in the treatment of thiazide diuretics, including hydrochlorothiazide, has been reported. Treatment with thiazide diuretics, including hydrochlorothiazide, is associated with the development of hyponatremia and hypochloremic alkalosis. Thiazides, including hydrochlorothiazide, increase the excretion of magnesium in the urine, which can lead to hypomagnesemia. When thiazide diuretics are used, calcium excretion decreases, which can lead to hypercalcemia. All patients using thiazide diuretics, it is necessary to periodically monitor the level of electrolytes, especially potassium, sodium and magnesium.

Impaired renal function. There is no need for dose adjustment of Combisart N in patients with mild to moderate renal impairment (GFR 30 ml / min / 1.73 m²).

It is recommended to periodically monitor the level of potassium, creatinine and uric acid in the blood serum in patients with impaired renal function when using Combisart N.

The simultaneous use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with impaired renal function (GFR 60 mg / min / 1.73 m²).

Renal artery stenosis. Combisart H should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis or single kidney stenosis, as serum urea and creatinine levels may increase.

Kidney transplantation. To date, there is no information regarding the safety of the drug Combisart N in patients who have recently undergone a kidney transplant.

Impaired liver function. Valsartan is mainly excreted unchanged with bile. T_½ amlodipine increases and AUC is higher in patients with impaired liver function; dosage recommendations not established. For patients with mild to moderate hepatic impairment who are not accompanied by cholestasis, the maximum recommended dose of valsartan is 80 mg. For this reason, Combisart N is not indicated for patients in this group.

Angioneurotic edema. Quincke edema, including swelling of the larynx and glottis, which can lead to airway obstruction, and / or swelling of the face, lips, pharynx, and / or tongue was noted in patients receiving valsartan. Some of these patients had a history of Quincke edema when taking other drugs, including ACE inhibitors. The use of Combisart H should be stopped immediately if Quinckes edema occurs; repeated use is not recommended.

Heart failure and coronary artery disease / condition after myocardial infarction.Due to inhibition of the renin-angiotensin-aldosterone system (RAAS) in patients with hypersensitivity, changes in renal function are possible. In people with severe heart failure, in whom renal function may depend on RAAS activity, treatment with ACE inhibitors and angiotensin receptor antagonists leads to oliguria and / or progressive azotemia (rarely) with acute renal failure and / or death. Similar results have been reported for valsartan.

It is recommended to prescribe the drug with caution to patients with heart failure and coronary artery disease, especially at the maximum dose of Combisart N - 10 mg / 320 mg / 25 mg, since data on the use of the drug in patients of this group are limited.

Stenosis of the aortic and mitral valves. As with the use of other vasodilators, with extreme caution, the drug is prescribed to patients with aortic and mitral valve stenosis of a low degree.

Primary hyperaldosteronism. Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan, since the renin-angiotensin system is not activated. Therefore, Combisart N is not recommended for patients in this group.

Systemic lupus erythematosus. Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate the course of systemic lupus erythematosus.

Other metabolic disorders. Thiazide diuretics, including hydrochlorothiazide, can alter glucose tolerance and increase serum cholesterol, triglyceride, and uric acid levels. It may be necessary to adjust the dose of insulin or oral hypoglycemic agents in patients with diabetes mellitus.

Since Combisart N contains hydrochlorothiazide, it is contraindicated in systemic hyperuricemia. Hydrochlorothiazide can increase the level of uric acid in blood serum due to a decrease in the clearance of uric acid and can cause exacerbation of hyperuricemia, as well as sudden gout in sensitive patients.

Thiazides can weaken the excretion of calcium in the urine and cause a periodic and slight increase in the level of calcium in the blood plasma in the absence of known disorders of calcium metabolism. Severe hypercalcemia may indicate latent hyperparathyroidism. Thiazides should be discontinued before testing for parathyroid function.

Photosensitivity. Cases of photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reactions occur during the administration of Combisart N, it is recommended to discontinue treatment. If the resumption of the use of a diuretic is necessary, it is recommended to protect open areas of the body from sunlight or artificial ultraviolet radiation.

Angle-closure glaucoma. Hydrochlorothiazide, sulfonamide are associated with an allergic reaction that led to acute transient myopia and angle-closure glaucoma. Symptoms included an acute onset of decreased visual acuity or eye pain and usually appeared in the first hours or the first week after starting treatment. Untreated angle-closure glaucoma can lead to irreversible loss of vision.

First of all, it is necessary to stop the use of hydrochlorothiazide as soon as possible. If intraocular pressure remains uncontrolled, the need for immediate medical or surgical treatment should be considered. Risk factors for developing angle-closure glaucoma can be a history of allergic reactions to sulfonamide or penicillin.

Are common. With caution, the drug is prescribed for patients who have observed hypersensitivity to other angiotensin II receptor antagonists.Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies and asthma.

Elderly patients (≥65 years old). It is recommended with caution, in particular often controlling blood pressure, to prescribe the drug to elderly patients, especially at maximum doses of Combisart N - 10 mg / 320 mg / 25 mg, since data on the use of the drug in patients of this group are limited.

Double blockade of RAAS. The concomitant use of angiotensin receptor antagonists, including valsartan, with other agents acting as RAAS, can lead to increased cases of hypotension, hyperkalemia, and changes in kidney function compared with monotherapy. It is necessary to control blood pressure, kidney function and electrolyte levels in patients taking Combisart N and other agents acting as RAAS.

Angiotensin receptor antagonists, including valsartan, must be used with caution with other agents that block RAAS, such as ACE inhibitors or aliskiren.

Concomitant use of the drug Combisart H with angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with impaired renal function (GFR 60 mg / min / 1.73 m²) or with diabetes.

Use during pregnancy and lactation

Pregnancy

Amlodipine. Amlodipine safety studies during pregnancy have not been conducted.

Use during pregnancy is recommended only if there is no safer alternative drug and if the disease itself carries a high risk for the pregnant woman and the embryo.

Valsartan. The drug is contraindicated for pregnant women or women planning a pregnancy. If pregnancy is confirmed during treatment with the drug, its use should be stopped immediately and, if necessary, replaced with another drug approved for use in pregnant women.

Hydrochlorothiazide. The experience of using hydrochlorothiazide during pregnancy, especially in the first trimester, is limited. The data obtained during animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. The pharmacological mechanism of action of hydrochlorothiazide suggests that the use of this drug in the second and third trimester of pregnancy can disrupt fetoplacental perfusion and cause the occurrence of fetal and neonatal reactions, such as jaundice, electrolyte imbalance and thrombocytopenia, and can also be associated with other adverse reactions that are observed in adults.

Amlodipine / Valsartan / Hydrochlorothiazide

There is no experience with the use of Combisart N in pregnant women. Available data on the components of the drug suggest that the use of Combisart N is contraindicated.

The period of breastfeeding. There is no information regarding the use of valsartan and / or amlodipine during breastfeeding. Hydrochlorothiazide is excreted in breast milk, so the use of Combisart N during breastfeeding is contraindicated.

Children. Safety and efficacy of the drug to children have not been established, therefore, the drug is not used in patients of this age group.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Patients using Combisart N may experience dizziness or a feeling of weakness after taking the drug, so they should take this into account when driving vehicles and working with potentially dangerous mechanisms.

Amlodipine may slightly or moderately affect the ability to drive vehicles or work with other mechanisms. If patients experience dizziness, headache, fatigue, or nausea when using amlodipine, their reaction may be impaired.

Interactions

Studies of the interaction of the drug combisart n with other drugs have not been conducted. the table provides only information on the interaction with other drugs known for each individual active substance.

However, it is important to consider that Combisart N may enhance the hypotensive effect of other antihypertensive drugs.