Amlodipine + Valsartan + Hydrochlorothiazide - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Included in the formulation

Ko-Vamloset

pills inwards

KRKA-RUS, LLC Russia

Ko-Exforge®

pills inwards

Novartis Pharma AG Switzerland

Tritenzine

pills inwards

Teva Pharmaceutical Enterprises Co., Ltd. Israel

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

ONLS

АТХ:

C.09.D.A Angiotensin II antagonists in combination with diuretics

Pharmacodynamics:

The drug is a combination of 3 antihypertensive components with a complementary mechanism for monitoring blood pressure: amlodipine (a derivative of dihydropyridine) - BCCC, valsartan - an antagonist of angiotensin II receptors (ATII) and hydrochlorothiazide - a thiazide diuretic. The combination of these components leads to a more pronounced decrease in blood pressure compared to that of monotherapy with each drug alone.

Amlodipine included in the drug, inhibits transmembrannoe intake of calcium ions in cardiomyocytes and smooth muscle cells of blood vessels. The mechanism of antihypertensive action of amlodipine is associated with a direct relaxing effect on the smooth muscle of the vessels, which causes a reduction in OPSS and a decrease in blood pressure.With arterial hypertension in patients with normal renal function amlodipine in therapeutic doses leads to a decrease in the resistance of renal vessels, an increase in the glomerular filtration rate and effective renal blood flow of the plasma without changing the filtration fraction and the expression of proteinuria. As well as the use of other BCCI, in patients receiving amlodipine in patients with normal left ventricular (LV) function observed change in hemodynamic parameters of cardiac function at rest and during exercise: a small increase in cardiac index without significant influence on the maximum rate of pressure rise in the LV, on the final DAD and LV volume. Hemodynamic studies in intact animals and healthy volunteers showed that a decrease in blood pressure under the influence of amlodipine in the range of therapeutic doses is not accompanied by a negative inotropic effect even with simultaneous application with beta-blockers.

Valsartan is an active and specific antagonist of the ATII receptor, intended for oral administration. It acts selectively on the AT subtype receptors₁, which are responsible for the effects of ATII.Increase in plasma concentration of unbound ATII due to AT blockade₁-receptors under the influence of valsartan can stimulate unlocked AT₂-receptors that counteract the stimulation effects of AT₁receptors. Valsartan does not have any expressed agonistic activity against AT₁receptors. The affinity of valsartan for AT subtype receptors₁ approximately 20,000 times higher than to the AT subtype receptors₂.

Valsartan does not inhibit ACE which converts ATI to ATII and causes destruction of bradykinin. Because with the use of ATII antagonists there is no inhibition of ACE and the accumulation of bradykinin or substance P, the development of a dry cough is unlikely. In the treatment of valsartan in patients with arterial hypertension, a decrease in blood pressure is noted, not accompanied by a change in heart rate.

Hydrochlorothiazide. The point of application of the action of thiazide diuretics is distal convoluted renal tubules. When thiazide diuretics are applied to highly sensitive receptors of the distal tubules of the cortical layer of the kidneys, reabsorption of sodium ions (Na⁺) and chlorine (Cl^-). Suppression of the co-transport system Na⁺ and Cl^-, apparently, is due to competition for the bonding sites of Cl ions^- in this system. As a result, the removal of sodium and chlorine ions increases approximately equally. As a result of diuretic action, a decrease in the volume of circulating blood plasma is observed, as a result of which the activity of renin, the secretion of aldosterone, the excretion of potassium by the kidneys and, consequently, the decrease in the potassium content in serum are increased.

Amlodipine + valsartan + hydrochlorothiazide. When using triple combination therapy Amlodipine + valsartan + hydrochlorothiazide; there was a more pronounced decrease in SAD and DAD, compared with the use of double combinations: valsartan + hydrochlorothiazide, amlodipine + valsartan and amlodipine + hydrochlorothiazide.

The greatest antihypertensive effect of the drug is observed after 2 weeks after the start of the drug at the maximum individual dose inside. When the drug was used, reaching the target blood pressure (less than 140/90 mm Hg) was noted in 71% of patients, compared with 45-54% against the background of the use of double combinations.

After taking the drug, the antihypertensive effect persists for 24 hours.

Pharmacokinetics:

The pharmacokinetic parameters of amlodipine, valsartan and hydrochlorothiazide are characterized by linearity.

Amlodipine

After ingestion of amlodipine in therapeutic doses, Cmax in the blood plasma is reached after 6-12 hours. Absolute bioavailability averages 64-80%. Eating food does not affect the bioavailability of amlodipine.

VSS is approximately 21 l / kg. In patients with hypertension, approximately 97.5% of the circulating drug binds to plasma proteins.

Amlodipine is intensively (approximately 90%) metabolized in the liver with the formation of active metabolites.

Withdrawal of blood plasma is biphasic with a T1 / 2 of about 30 to 50 hours. The equilibrium plasma concentration achieved after prolonged use within 7-8 days. 10% is excreted unchanged, 60% - in the form of metabolites.

Valsartan

After ingestion of valsartan Cmax in the blood plasma is achieved after 2-4 hours. The average absolute bioavailability is 23%. Valsartan pharmacokinetic curve is downward multiexponential character (T1 / 2α <1 hour and T1 / 2β about 9 hours). When taken with food, there is a decrease in bioavailability (AUC) by 40% and Cmax in blood plasma by almost 50%although approximately 8 hours after taking the drug inside the concentration of valsartan in the blood plasma in people who took it with food, and in the group receiving the drug on an empty stomach, equalize. The decrease in AUC, however, is not accompanied by a clinically significant decrease in the therapeutic effect, so valsartan can be administered regardless of the time of ingestion.

VSS of valsartan in the equilibrium period after intravenous administration was about 17 liters, indicating a lack of extensive distribution of valsartan in the tissues. Valsartan is largely associated with serum proteins (94-97%), mainly with albumins.

Valsartan does not undergo a pronounced metabolism (about 20% of the dose is determined in the form of metabolites). The hydroxyl metabolite is determined in blood plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive.

Valsartan is excreted mainly unchanged through the intestine with feces (about 83% of the dose) and with the kidneys (about 13% of the dose). After intravenous administration, vasartan plasma Cl is about 2 l / h and its renal Cl is 0.62 l / h (about 30% total Cl).T1 / 2 - 6 hours.

Hydrochlorothiazide

Absorption of hydrochlorothiazide after ingestion is rapid (the time to reach Cmax is about 2 hours). On average, the increase in AUC is linear and proportional to the dose in the therapeutic range. With simultaneous intake of food, both the increase and decrease in the systemic bioavailability of hydrochlorothiazide were reported compared with the administration of the drug on an empty stomach. The magnitude of this effect is small and clinically insignificant. Absolute bioavailability of hydrochlorothiazide after oral administration is 60-80%.

The kinetics of distribution and elimination as a whole is described as a bi-exponential decreasing function, with T1 / 2 6-15 hours. With repeated use, the hydrochlorothiazide kinetics does not change and when used once a day, cumulation is minimal. The apparent VSS is 4-8 l / kg. 40-70% of the hydrochlorothiazide circulating in the blood plasma binds to blood plasma proteins, mainly with albumins. Hydrochlorothiazide also accumulates in erythrocytes in concentrations about 3 times higher than those in blood plasma.

Hydrochlorothiazide is excreted unchanged.

More than 95% of the absorbed dose of hydrochlorothiazide is excreted unchanged in kidneys with urine.

Amlodipine + valsartan + hydrochlorothiazide

After ingestion of Cmax preparation, amlodipine, valsartan and hydrochlorothiazide are achieved after 6-8, 3 and 2 hours, respectively. The speed and degree of absorption of the drug are equivalent to the bioavailability of amlodipine, valsartan and hydrochlorothiazide when taken in separate tablets.

Indications:

Hypertension II and III degree.

ICD-10

IX.I10-I15.I15 Secondary Hypertension

IX.I10-I15.I10 Essential [primary] hypertension

Contraindications:

Hypersensitivity to amlodipine, valsartan, hydrochlorothiazide, other derivatives of sulfonamide, dihydropyridine derivative and other auxiliary components of the drug; pregnancy and the period of breastfeeding; severe liver dysfunction; pronounced violations of the function of the nights (Cl creatinine less than 30 ml / min), anuria; refractory to adequate therapy hypokalemia, hyponatremia, hypercalcemia, as well as hyperuricemia with clinical manifestations; age to 18 years (efficacy and safety not established). With caution - Unilateral or bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney; state,accompanied by a decrease in BCC; violations of water-electrolyte balance (including hyponatremia, hyperkalemia); mitral or aortic stenosis, and hypertrophic obstructive cardiomyopathy; light and moderate violations of the liver, especially against the background of bile duct obstruction; diabetes; systemic lupus erythematosus.

The safety of the drug in patients after a recent transplantation of the kidney, as well as in patients with heart failure or ischemic heart disease is not established.

Carefully:

Unilateral or bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney; Conditions, accompanied by a decrease in BCC; violations of water-electrolyte balance (including hyponatremia, hyperkalemia); mitral or aortic stenosis, and hypertrophic obstructive cardiomyopathy; light and moderate violations of the liver, especially against the background of bile duct obstruction; diabetes; systemic lupus erythematosus.

The safety of the drug in patients after a recent transplantation of the kidney, as well as in patients with heart failure or ischemic heart disease is not established.

Pregnancy and lactation:

It is known that the appointment of ACE inhibitors that affect the renin-angiotensin-aldosterone system (RAAS), pregnant in the II and III trimesters, leads to damage or death of the developing fetus. Given the mechanism of action of ATII receptor antagonists, the risk to the fetus can not be ruled out. According to the retrospective analysis, the use of ACE inhibitors in the first trimester of pregnancy was accompanied by the development of fetal and newborn pathology. Hydrochlorothiazide penetrates the placenta. With the use of thiazide diuretics, including hydrochlorothiazide, pregnancy may develop embryonic or neonatal thrombocytopenia, as well as other unwanted reactions observed in adult patients. In case of unintended admission of valsartan in pregnant women, cases of spontaneous abortion, malignancy and renal dysfunction in newborns are described. The drug, like any other drug that directly affects RAAS, should not be prescribed in pregnancy and women planning a pregnancy. Patients of childbearing age should be informed of the possible risk to the fetus associated with the use of drugs,influencing RAAS. If pregnancy is diagnosed during drug treatment, the drug should be discontinued as soon as possible.

It is not known whether the valsartan and / or amlodipine in breast milk. In experimental studies, valsartan was isolated from breast milk. Hydrochlorothiazide excreted in breast milk. The drug should not be used during breastfeeding.

Dosing and Administration:

Inside (preferably in the morning), with a small amount of water, regardless of food intake. Recommended daily doses of the drug:

5 + 160 + 12.5 mg (1 table, containing Amlodipine + valsartan + hydrochlorothiazide in doses of 5 + 160 + 12.5 mg);

10 + 160 + 12.5 mg (1 table, containing Amlodipine + valsartan + hydrochlorothiazide doses of 5 + 160 + 12.5 mg);

10 + 320 + 25 mg (2 tablets containing Amlodipine + valsartan + hydrochlorothiazide in doses of 5 + 160 + 12.5 mg).

The maximum dose of the drug is 10 + 320 + 25 mg / day.

Patients over 65 years of age. Correction of the dose is not required.

Children and adolescents under the age of 18. Since the safety and efficacy of the drug in children and adolescents (under 18 years) have not yet been established, the drug is not recommended for use in this category of patients.

Patients with impaired renal or hepatic function.In patients with mild and moderate impairment of renal function (Cl creatinine more than 30 ml / min) and liver dosage adjustment is not required.

Side effects:

Amlodipine

From the blood and lymphatic system: very rarely - leukopenia, thrombocytopenia.

From the side of the immune system: very rarely - reactions of increased sensitivity.

Disorders from the metabolism and nutrition: very rarely - hyperglycemia.

Disorders of the psyche: infrequently - insomnia / sleep disorders, drowsiness, lability of mood.

From the nervous system: often - dizziness, headache; infrequently - flavors, paresthesia, fainting, tremor; very rarely - muscle hypertonia, peripheral neuropathy, neuropathy; frequency unknown - extrapyramidal disorders.

From the side of the organ of vision: infrequently - visual disturbances.

On the part of the hearing organs and labyrinthine disturbances: infrequently, noise in the ears.

From the side of the cardiovascular system: often - a feeling of strong palpitations, flushes of blood to the face; infrequent - marked decrease in blood pressure; Very rarely - vasculitis, arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation).

From the respiratory system, chest and mediastinum: infrequently - shortness of breath, rhinitis; very rarely - cough.

From the digestive system: often - discomfort in the abdomen, pain in the upper abdomen, nausea; infrequent - changes in the frequency of bowel movements, diarrhea, dry mouth, indigestion, vomiting; very rarely - gastritis, gingival hyperplasia, pancreatitis.

From the liver and bile ducts: very rarely - increased activity of liver enzymes, increased bilirubin concentration in blood plasma, hepatitis, intrahepatic cholestasis, jaundice.

From the skin and subcutaneous fat: rarely - alopecia, increased sweating, pruritus, rash, incl. exanthema, purpura, discoloration of the skin; very rarely - angioedema, erythema multiforme, urticaria.

From the musculoskeletal system and connective tissue: infrequently - arthralgia, back pain, muscle spasms, myalgia.

From the side of the kidneys and urinary tract: infrequently - disturbances of urination, nocturia, pollakiuria.

From the genitals and the breast: infrequently - erectile dysfunction, gynecomastia.

General disorders and disorders at the injection site: often - increased fatigue, swelling; infrequently - asthenia, discomfort, general weakness, pain in the chest,pain of different localization.

Laboratory and instrumental data: infrequent - increase or decrease in body weight.

Valsartan

On the part of the blood and lymphatic system: the frequency is unknown - a decrease in hemoglobin and hematocrit, leukopenia, thrombocytopenia.

On the part of the immune system: the frequency is unknown - hypersensitivity reactions.

On the part of the hearing organs and labyrinthine disturbances: infrequently - vertigo.

From the cardiovascular system: the frequency is unknown - vasculitis.

From the respiratory system, chest and mediastinum: infrequently - cough.

From the digestive system: infrequently - abdominal discomfort, pain in the upper abdomen.

From the liver and bile ducts: the frequency is unknown - increased activity of liver enzymes, increased bilirubin concentration in the blood plasma.

From the skin and subcutaneous fat: the frequency is unknown - angioedema, itching, rash.

From the musculoskeletal system and connective tissue: the frequency is unknown - myalgia.

From the side of the kidneys and urinary tract: the frequency is unknown - an increase in the concentration of creatinine in the blood plasma, impaired renal function, including acute renal failure.

General disorders and disorders at the site of administration: infrequently - increased fatigue.

Laboratory and instrumental data: the frequency is unknown - an increase in the potassium content in the blood plasma.

In clinical studies with valsartan in monotherapy, the following AEs were noted (regardless of their causal relationship with the study drug): viral infections, upper respiratory tract infections, sinusitis, rhinitis, neutropenia, insomnia.

Hydrochlorothiazide

From the blood and lymphatic system: rarely - thrombocytopenia; very rarely - agranulocytosis, oppression of bone marrow hematopoiesis, hemolytic anemia, leukopenia.

From the side of the immune system: very rarely - reactions of increased sensitivity.

Disorders from the metabolism and nutrition: often - hypokalemia; infrequently - hyperuricemia, hypomagnesemia, hyponatremia; rarely - hypercalcemia, hyperglycemia; very rarely - hypochloraemic alkalosis.

Disorders of the psyche: rarely - insomnia / sleep disorders, depression.

From the nervous system: rarely - dizziness, headache, inhibition.

From the side of the organ of vision: infrequently - visual disturbances.

From the cardiovascular system: infrequently - orthostatic hypotension; rarely - arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation).

From the respiratory system, chest and mediastinum: very rarely - respiratory distress syndrome, pulmonary edema and pneumonitis.

On the part of the digestive system: infrequently - decreased appetite, nausea, vomiting; rarely - discomfort in the abdomen, pain in the upper abdomen, constipation, diarrhea; very rarely - pancreatitis.

From the liver and bile ducts: rarely - hepatitis, intrahepatic cholestasis, jaundice.

From the skin and subcutaneous fat: rarely - rashes, hives; rarely - increased photosensitivity, purpura; very rarely - necrotizing vasculitis, toxic epidermal necrolysis, lupus-like reactions; exacerbation of cutaneous manifestations of systemic lupus erythematosus.

From the side of the kidneys and urinary tract: rarely - violations of kidney function, including acute renal failure.

From the genitals and the breast: infrequently - erectile dysfunction.

Laboratory and instrumental data: often - hyperlipidemia; rarely - glycosuria.

Overdose:

Data on cases of drug overdose are currently not available.

Symptoms: in case of an overdose of valsartan one can expect the development of a pronounced decrease in blood pressure and dizziness.

An overdose of amlodipine can lead to excessive peripheral vasodilation and possible reflex tachycardia. I also report the occurrence of a pronounced and prolonged BP reduction, up to the development of a fatal shock. The main clinical manifestations of an overdose of hydrochlorothiazide are symptoms associated with loss of electrolytes (hypokalemia, hypochloraemia) and dehydration due to diuresis stimulation. The most frequent symptoms of an overdose are nausea and drowsiness. Hypokalemia can be accompanied by muscle spasms. With the concomitant use of cardiac glycosides (or other antiarrhythmic drugs) hypokalemia can enhance cardiac arrhythmia.

Treatment: In case of accidental overdose, you should induce vomiting (if the drug was taken recently) or to wash the stomach. The use of activated carbon in healthy volunteers immediately or 2 hours after taking amlodipine significantly reduced its absorption.In case of a marked decrease in blood pressure, the patient should be placed with raised legs, take active measures to increase blood pressure, maintain cardiovascular system, including regular monitoring of heart and respiratory system function, BCC and the amount of urine released. In the absence of contraindications to restore vascular tone and blood pressure, it is possible to use (with caution) a vasoconstrictor. In / in the introduction of solutions of calcium salts can be effective in eliminating BCC. The excretion of valsartan and amlodipine during hemodialysis is unlikely. Hydrochlorothiazide can be removed from the systemic circulation by hemodialysis.

Interaction:

In monotherapy with amlodipine, there is no clinically significant interaction with thiazide diuretics, beta-blockers, ACE inhibitors, long-acting nitrates, nitroglycerin for sublingual use, digoxin, warfarin, atorvastatin, sildenafil, antacid drugs (magnesium hydroxide, aluminum hydroxide gel, simethicone), cimetidine, NSAIDs, antibiotics and hypoglycemic agents for oral administration.

Inhibitors of the isoenzyme CYP3A4.When amlodipine is used together with diltiazem, in elderly patients slowed metabolism of amlodipine, probably due to inhibition of the isoenzyme CYP3A4, which leads to an increase in the concentration of amlodipine in the blood plasma by approximately 50% and increase its systemic exposure. When using amlodipine together with powerful inhibitors of CYP3A4 (for example ketoconazole, itraconazole and ritonavir) a marked increase in the systemic exposure of amlodipine.

Inductors of isoenzyme CYP3A4. Since the use of amlodipine together with inducers of the isoenzyme CYP3A4 (for example carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidon, rifampicin, grapefruit juice, herbal preparations containing Hypericum perforated), can lead to a marked decrease in its concentration in the blood plasma, with the appointment of amlodipine with inducers CYP3A4, it should monitor its content in blood plasma.

Valsartan

It was found that with monotherapy valsartan there is no clinically significant interaction with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin, hydrochlorothiazide, amlodipine, glibenclamide.

When used simultaneously with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other drugs that can cause an increase in the potassium content in the blood (for example, with heparin), care should be taken and regular monitoring of potassium in the blood.

When valsartan is used together with NSAIDs, it is possible to reduce the antihypertensive effect of valsartan.

Hydrochlorothiazide

Lithium. With simultaneous use with ACE inhibitors and diuretics, cases of a reversible increase in the plasma concentration of lithium and its toxic effect were reported. Therefore, with the simultaneous use of hydrochlorothiazide and lithium preparations, it is recommended to monitor the concentration of lithium in the blood plasma.

Muscle relaxants of peripheral action. Thiazide diuretics, including hydrochlorothiazide, potentiate the action of muscle relaxants of peripheral action.

NSAIDs. It is possible to reduce the diuretic and antihypertensive effects of the thiazide component of the drug when used simultaneously with NSAIDs, for example, with acetylsalicylic acid (ASA), indomethacin.Concomitant hypovolemia can lead to the development of acute renal failure.

Drugs that can cause a decrease in potassium in the blood plasma. The risk of hypokalemia increases with simultaneous appointment of other diuretics, GCS, ACTH, amphotericin B, carbenoxolone and ASA (at a dose of more than 3 g).

Cardiac glycosides. Thiazide diuretics can cause such undesirable effects as hypokalemia or hypomagnesemia; these conditions increase the risk of arrhythmia with the simultaneous use of cardiac glycosides.

Hypoglycemic agents for oral administration and insulin. When using the drug in patients with diabetes mellitus, it may be necessary to adjust the dose of insulin or hypoglycemic agents for oral administration. Since the use of hydrochlorothiazide together with metformin may develop lactic acidosis (due to impaired function against hydrochlorothiazide therapy), caution should be exercised when using the drug in patients receiving metformin treatment.

Anticholinergics. It is possible to increase the bioavailability of the thiazide diuretic with simultaneous use of m-cholinoblockers (for example, atropine, biperidene), which, apparently, is associated with a decrease in gastrointestinal motility and slowing down the rate of gastric emptying.

Methyldopa. There have been reports of cases of hemolytic anemia with simultaneous administration of hydrochlorothiazide and methyldopa.

Kolestyramin reduces the absorption of thiazide diuretics, including hydrochlorothiazide.

Vitamin D and calcium salts. When combined use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts, an increase in the serum calcium content is possible.

Cyclosporine. Simultaneous administration of cyclosporine may increase the risk of hyperuricemia and the appearance of symptoms resembling an exacerbation of gout.

Carbamazepine. In patients receiving hydrochlorothiazide Simultaneously with carbamazepine, the development of hyponatremia is possible. Since patients receiving both hydrochlorothiazide and carbamazepine, it is possible to develop hyponatremia, when prescribing the drug along with carbamazepine, appropriate monitoring of the sodium content in the blood plasma should be carried out.

Other types of interaction. Simultaneous administration of thiazide diuretics, including hydrochlorothiazide, may lead to an increase in the frequency of development of hypersensitivity reactions to allopurinol; increased risk of side effects of amantadine; enhancing the hyperglycemic effect of diazoxide; cytotoxic agents (for example, cyclophosphamide, methotrexate), and to potentiation of their myelosuppressive effects.

Special instructions:

Impaired renal function. When using the drug, regular monitoring of creatinine and potassium in blood plasma should be carried out.

Abolition of beta-blockers. If it is necessary to cancel beta-blockers before starting therapy with the drug, the dose of beta-blockers should be reduced gradually. Since the drug does not include a beta-blocker, the use of the drug does not prevent the development of withdrawal syndrome, which occurs when the beta-blockers are abruptly discontinued.

Pronounced decrease in blood pressure. In controlled trials, when the drug was used in the maximum daily dose (10 mg + 320 mg + 25 mg) in patients with arterial hypertension of grade II and III, a marked decrease in blood pressure was observed in 1.7% of cases, including orthostatic hypotension (1.8,0,4 and 0,2% against the background of combined therapy valsartan + hydrochlorothiazide in a dose of 320 mg + 25 mg, amlodipine + valsartan in a dose of 10 mg + 320 mg and amlodipine + hydrochlorothiazide in a dose of 10 mg + 25 mg, respectively). In case of development of arterial hypotension, the patient should be laid with raised legs, if necessary, an intravenous infusion of 0.9% sodium chloride solution. After stabilization of blood pressure treatment with the drug can be continued.

Hyponatremia and / or decreased BCC. In patients with activated RAAS (eg, with a deficiency of bcc and / or hyponatremia, as well as in patients receiving high doses of diuretics), the development of symptomatic arterial hypotension is possible with angiotensin receptor antagonists. Before starting treatment, the drug should be corrected for sodium in the body and / or BCC, or begin therapy under close medical supervision. When using the drug, it is necessary to conduct regular monitoring of the content of plasma electrolytes.

Change in the concentration of potassium in the blood plasma. In controlled studies, the combination Amlodipine + valsartan + hydrochlorothiazide in the maximum daily dose of 10 mg + 320 mg + 25 mg in patients with moderate and severe degree of hypertension, the incidence of hypokalemia (the potassium content in the blood plasma was less than 3.5 mmol / l) was 9.9% compared to 24.5, 6.6 and 2.7% on the background of combination therapy amlodipine + hydrochlorothiazide in a dose of 10 mg + 25 mg, valsartan + hydrochlorothiazide in a dose of 320 mg + 25 mg and amlodipine + valsartan in a dose of 10 mg + 320 mg, respectively. The frequency of cancellation of therapy due to the development of hypokalemia was 0.2% (1 patient) in the drug groups and amlodipine + hydrochlorothiazide. In patients treated with the drug, hyperkalemia (the content of potassium in the blood plasma was more than 5.7 mmol / L) was observed in 0.4% of cases (compared to 0.20.7% when double combinations were used). When using the drug in a controlled trial, the opposing effects of valsartan at a dose of 320 mg per day and hydrochlorothiazide at a dose of 25 mg per day on serum potassium content practically balanced each other in many patients. In other cases, patients either had hypo- or hyperkalemia. When using the drug, regular monitoring of the potassium content in the blood plasma is necessary.

Other metabolic disorders.Thiazide diuretics can impair glucose tolerance and increase plasma concentrations of cholesterol, triglycerides and uric acid.

With the use of thiazide diuretics, a decrease in the excretion of calcium, leading to the development of moderate hypercalcemia, is possible. Expressed hypercalcemia on the background of drug therapy may indicate latent hyperparathyroidism.

Influence on ability to drive vehicles and work with mechanisms. Some side effects of the drug, incl. dizziness or visual disturbances, can adversely affect the ability to drive vehicles and carry out potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Instructions

Amlodipine + Valsartan + Hydrochlorothiazide (Amlodipinum + Valsartanum + Hydrochlorothiazidum)