Valz Combi, 10 mg+160 mg 28 pcs

Pharmacotherapeutic group: combined hypotensive agent (BMCC + angiotensin II receptor antagonist)

ATX code: C09DB01

Pharmacological Properties

.Pharmacological action

The pharmacological action is antihypertensive.

Pharmacodynamics

The drug Valz Combi is a combination of two antihypertensive components with a complementary mechanism of blood pressure (BP) control. Amlodipine, a dihydropyridine derivative, belongs to the class of “slow” calcium channel blockers (CMCBs), and valsartan belongs to the class of angiotensin II receptor antagonists (ARA II). The combination of these components has a mutually complementary antihypertensive effect, which leads to a more pronounced BP reduction compared to that when they are used separately.

Amlodipine

Amlodipine in the drug inhibits transmembrane entry of calcium ions into cardiomyocytes and vascular smooth muscle cells. Mechanism of antihypertensive action of amlodipine is related to direct relaxant effect on vascular smooth muscle which causes decrease of total peripheral vascular resistance (TPR) and blood pressure.

After therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation leading to a decrease in BP (in the patient “lying” and “standing” position). The BP reduction is not accompanied by significant changes in heart rate (HR) and catecholamine levels with long-term use.

In arterial hypertension patients with normal renal function, amlodipine at therapeutic doses decreases renal vascular resistance, increases glomerular filtration rate (GFR) and improves renal blood flow without changing filtration fraction and degree of proteinuria.

Amlodipine decreases BP in therapeutic dose range without negative inotropic effect even with concomitant use with beta-adrenoblockers.

Amlodipine does not alter sinoatrial node function or atrioventricular conduction. When using amlodipine in combination with beta-adrenoblockers in patients with arterial hypertension or angina pectoris, BP reduction is not accompanied by adverse electrocardiogram changes.

The clinical efficacy of amlodipine has been proven in patients with chronic stable angina pectoris, vasospastic angina pectoris, and angiographically confirmed coronary artery disease.

Valsartan

Valsartan is an active and specific angiotensin II receptor antagonist for oral administration. It acts selectively on AT₁ subtype receptors, which are responsible for pressor and several other effects of angiotensin II.

Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and causes bradykinin breakdown.

The use of angiotensin II antagonists does not inhibit ACE and accumulation of bradykinin or Substance P, so the development of dry cough is unlikely.

Valsartan does not interact with or block other hormone receptors or ion channels important to the regulation of cardiovascular function.

When treating patients with arterial hypertension with valsartan, there is a decrease in BP with no change in HR.

The antihypertensive effect of the drug is seen within 2 hours in most patients after a single dose of valsartan. Maximal BP decrease develops in 4-6 hours. The effect of the drug lasts more than 24 hours. With repeated use, maximum BP reduction, regardless of the dose taken, is usually achieved within 2-4 weeks and is maintained during prolonged therapy. Abrupt discontinuation of valsartan is not associated with withdrawal syndrome (severe increase in BP or other adverse clinical effects). The use of valsartan in patients with chronic heart failure (CHF) (NYHA class II-IV) leads to a significant reduction in hospitalizations for CHF. When taking valsartan in patients with left ventricular failure (stable clinical course) or with impaired LV function after myocardial infarction, there is a decrease in cardiovascular mortality.

Amlodipine + Valsartan

The combination of amlodipine and valsartan reduces BP in a dose-dependent manner over the therapeutic dose range. After a single dose of amlodipine + valsartan combination, the antihypertensive effect persists for 24 hours.

A sudden discontinuation of the drug is not accompanied by a sharp increase in BP (no withdrawal syndrome).

Therapeutic efficacy is independent of the patient’s age, sex, race and body mass index.

In combination therapy of amlodipine + valsartan, comparable BP control is achieved with lower likelihood of peripheral edema in patients with previously achieved BP control and significant peripheral edema on amlodipine therapy.

Pharmacokinetics

The pharmacokinetics of amlodipine + valsartan combination therapy are linear.

Amlodipine

Intake

. After oral administration of amlodipine at therapeutic doses, its maximum plasma concentration (C_max) is reached after 6-12 hours. The value of absolute bioavailability is on average 64-80%. Food intake does not affect the bioavailability of amlodipine.

Distribution

The volume of distribution (V_d) is approximately 21 l/kg. In vitro studies have shown that in patients with arterial hypertension approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Metabolism

Amlodipine is extensively (approximately 90%) metabolized in the liver to form active metabolites.

Elimation

Elimination of amlodipine from plasma is biphasic with a half-life (T_1/2) of approximately 30 to 50 hours. Equilibrium plasma concentrations are reached after 7-8 days of use. 10% of unchanged amlodipine and 60% of amlodipine as metabolites are excreted by the kidneys.

Valsartan

Absorption

. After oral administration, valsartan C_max in plasma is reached within 2-4 h. Mean absolute bioavailability is 23%. When valsartan is taken with food, there is a 40% decrease in bioavailability (as measured by the area under the pharmacokinetic concentration-time curve (AUC)) and C_max in plasma by almost 50%, although approximately 8 hours after taking the drug, plasma concentrations of valsartan in the dietary intake group and the fasting group equalize. Decrease of AUC however is not associated with clinically significant decrease of therapeutic effect, therefore, valsartan can be prescribed regardless of meal time.

Distribution

The V_d of valsartan in equilibrium after intravenous (IV) administration is approximately 17 liters, indicating that there is no extensive distribution of the drug in tissues. Valsartan is largely bound to serum proteins (94-97%), predominantly to albumin.

Metabolism

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

Elimation

The pharmacokinetic curve of valsartan has a descending multiexponential character (T1/2α < 1 h and T1/2β, about 9 h). Valsartan is mainly excreted unchanged via the intestine (about 83% of the dose) and the kidneys (about 13% of the dose). After intravenous administration, plasma clearance of valsartan is about 2 l/h, renal clearance is 0.62 l/h (about 30% of total clearance). T_1/2 valsartan is 6 h.

Amlodipine + Valsartan

After oral administration of Valz Combi (amlodipine + valsartan), C_max of valsartan and amlodipine are reached after 3 and 6-8 h, respectively. The rate and extent of drug absorption are equivalent to the bioavailability of valsartan and amlodipine when each is taken as separate tablets.

Pharmacokinetics in Special Clinical Cases

Childhood

Pharmacokinetic features of amlodipine + valsartan combination drug use in children under 18 years of age have not been established.

Elderly patients(>65 years)

. The time to reach C_max of amlodipine in plasma in young and elderly patients is the same. Amlodipine clearance is slightly decreased in elderly patients, resulting in increased AUC and T_1/2.

The systemic effects of valsartan were slightly more pronounced in elderly patients than in younger patients, but these rates were not clinically significant. Because tolerability of the drug components was equally good in elderly and younger patients, the usual dosing regimens are recommended.

Patients with impaired renal function

In patients with impaired renal function the pharmacokinetic parameters of amlodipine do not change significantly. No correlation has been found between renal function (creatinine clearance (CK)) and systemic exposure to valsartan (AUC) in patients with varying degrees of renal impairment. No change in starting dose is required in patients with initial and moderate renal dysfunction (CK 30-50 ml/min).

Patients with impaired hepatic function

Patients with impaired hepatic function have decreased clearance of amlodipine, resulting in an increase in AUC of approximately 40-60%. On average, patients with mild (5-6 Child-Pugh scores) and moderate (7-9 Child-Pugh scores) chronic liver disease have twice the bioavailability (according to AUC) of valsartan compared to healthy volunteers (corresponding age, sex, and body weight). The drug should be used with caution in patients with hepatic dysfunction, obstructive biliary tract disease.

Indications

Arterial hypertension (for patients for whom combination therapy is indicated).

Pharmacological effect

Pharmacotherapeutic group: combined antihypertensive drug (BMCC + angiotensin II receptor antagonist)

ATX code: C09DB01

PHARMACOLOGICAL PROPERTIES

Pharmacological action

Pharmacological action – antihypertensive.

Pharmacodynamics

The drug Valz Combi is a combination of two antihypertensive components with a complementary mechanism for controlling blood pressure (BP). Amlodipine, a dihydropyridine derivative, belongs to the class of “slow” calcium channel blockers (SCBCs), valsartan belongs to the class of angiotensin II receptor antagonists (ARA II). The combination of these components has a mutually complementary antihypertensive effect, which leads to a more pronounced decrease in blood pressure compared to that when they are used separately.

Amlodipine

Amlodipine, which is part of the drug, inhibits the transmembrane entry of calcium ions into cardiomyocytes and vascular smooth muscle cells. The mechanism of the antihypertensive effect of amlodipine is associated with a direct relaxing effect on vascular smooth muscle, causing a decrease in total peripheral vascular resistance (TPVR) and a decrease in blood pressure.

When taken in therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation, leading to a decrease in blood pressure (in the patient’s “lying” and “standing” position). The decrease in blood pressure is not accompanied by a significant change in heart rate (HR) and catecholamine levels with long-term use.

In arterial hypertension in patients with normal renal function, amlodipine in therapeutic doses causes a decrease in renal vascular resistance, an increase in glomerular filtration rate (GFR) and an improvement in renal blood flow without changing the filtration fraction and the degree of proteinuria.

The decrease in blood pressure under the influence of amlodipine in the range of therapeutic doses is not accompanied by a negative inotropic effect, even when used simultaneously with beta-blockers.

Amlodipine does not change sinoatrial node function or atrioventricular conduction. When amlodipine is used in combination with beta-blockers in patients with arterial hypertension or angina pectoris, a decrease in blood pressure is not accompanied by undesirable changes in the electrocardiogram.

The clinical effectiveness of amlodipine has been proven in patients with chronic stable angina, vasospastic angina and angiographically confirmed lesions of the coronary arteries.

Valsartan

Valsartan is an active and specific angiotensin II receptor antagonist intended for oral administration. It acts selectively on receptors of the AT1 subtype, which are responsible for the pressor and a number of other effects of angiotensin II.

Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and causes the destruction of bradykinin.

When using angiotensin II antagonists, there is no inhibition of ACE and accumulation of bradykinin or substance P, and therefore the development of a dry cough is unlikely.

Valsartan does not interact with or block other hormone receptors or ion channels that are important for regulating the functions of the cardiovascular system.

When treating patients with arterial hypertension with valsartan, a decrease in blood pressure is observed, not accompanied by a change in heart rate.

The antihypertensive effect of the drug appears within 2 hours in most patients after a single dose of valsartan. The maximum decrease in blood pressure develops after 4–6 hours. The effect of the drug lasts more than 24 hours. With repeated use, the maximum decrease in blood pressure, regardless of the dose taken, is usually achieved within 2–4 weeks and is maintained at the achieved level during long-term therapy. Abrupt cessation of valsartan is not accompanied by withdrawal syndrome (sharp increase in blood pressure or other undesirable clinical consequences). The use of valsartan in patients with chronic heart failure (CHF) (NYHA class II–IV) leads to a significant reduction in the number of hospitalizations for CHF. When taking valsartan in patients with left ventricular failure (stable clinical course) or with impaired LV function after myocardial infarction, a decrease in cardiovascular mortality is observed.

Amlodipine + Valsartan

The combination of amlodipine and valsartan reduces blood pressure in an additive dose-dependent manner over the therapeutic dose range. After taking one dose of the combination amlodipine + valsartan, the antihypertensive effect persists for 24 hours.

Sudden cessation of taking the drug is not accompanied by a sharp increase in blood pressure (there is no withdrawal syndrome).

Therapeutic effectiveness does not depend on the patient’s age, gender, race and body mass index.

When using combination therapy with amlodipine + valsartan, comparable blood pressure control is achieved with a lower likelihood of developing peripheral edema in patients with previously achieved blood pressure control and severe peripheral edema during amlodipine therapy.

Pharmacokinetics

The pharmacokinetics of the combination drug amlodipine + valsartan is characterized by linearity.

Amlodipine

Suction

After oral administration of amlodipine in therapeutic doses, its maximum plasma concentration (Cmax) is achieved within 6–12 hours. The absolute bioavailability averages 64–80%. Food intake does not affect the bioavailability of amlodipine.

Distribution

The volume of distribution (Vd) is approximately 21 l/kg. In vitro studies have shown that in patients with arterial hypertension, approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Metabolism

Amlodipine is extensively (approximately 90%) metabolized in the liver to form active metabolites.

Removal

The elimination of amlodipine from plasma is biphasic with a half-life (T1/2) of approximately 30 to 50 hours. Equilibrium plasma concentrations are achieved after use for 7–8 days. 10% of unchanged amlodipine and 60% of amlodipine in the form of metabolites are excreted by the kidneys.

Valsartan

Suction

After oral administration of valsartan, Cmax in blood plasma is achieved within 2–4 hours. The average absolute bioavailability is 23%. When taking valsartan with food, there is a decrease in bioavailability (measured by the area under the concentration-time pharmacokinetic curve (AUC)) by 40% and Cmax in the blood plasma by almost 50%, although approximately 8 hours after taking the drug, the concentrations of valsartan in the blood plasma in the group of patients taking it with food and in the group taking it on an empty stomach level out. The decrease in AUC, however, is not accompanied by a clinically significant decrease in the therapeutic effect, so valsartan can be prescribed regardless of the timing of meals.

Distribution

The Vd of valsartan at steady state after intravenous (IV) administration is about 17 L, indicating the absence of extensive distribution of the drug in tissues. Valsartan is highly bound to serum proteins (94–97%), mainly to albumin.

Metabolism

Valsartan is not subject to significant metabolism (about 20% of the dose taken is determined in the form of metabolites). The hydroxyl metabolite is detected in blood plasma in low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.

Removal

The pharmacokinetic curve of valsartan has a descending multi-exponential character (T1/2α < 1 hour and T1/2β - about 9 hours). Valsartan is excreted mainly unchanged through the intestines (about 83% of the dose) and by the kidneys (about 13% of the dose). After intravenous administration, plasma clearance of valsartan is about 2 l/h, renal clearance is 0.62 l/h (about 30% of total clearance). T1/2 of valsartan - 6 hours.

Amlodipine + Valsartan

After oral administration of the combination drug Valz Combi (amlodipine + valsartan), Cmax of valsartan and amlodipine is achieved after 3 and 6–8 hours, respectively. The rate and extent of absorption of the drug are equivalent to the bioavailability of valsartan and amlodipine when each of them is taken in the form of separate tablets.

Pharmacokinetics in special clinical situations

Childhood

The pharmacokinetic features of the use of the combination drug amlodipine + valsartan in children under 18 years of age have not been established.

Elderly patients (> 65 years)

The time to reach Cmax of amlodipine in blood plasma is the same in young and elderly patients. In elderly patients, the clearance of amlodipine is slightly reduced, which leads to an increase in AUC and T1/2.

In elderly patients, the systemic exposure to valsartan was slightly more pronounced than in younger patients, but these indicators were not clinically significant. Since the tolerability of the drug components in older and younger patients is equally good, it is recommended to use the usual dosage regimens.

Patients with impaired renal function

In patients with impaired renal function, the pharmacokinetic parameters of amlodipine do not change significantly. There was no correlation between renal function (creatinine clearance (CC)) and systemic exposure of valsartan (AUC) in patients with varying degrees of renal impairment. No change in the initial dose is required in patients with initial and moderate renal impairment (creatinine clearance 30–50 ml/min).

Patients with liver dysfunction

Patients with impaired liver function have reduced clearance of amlodipine, resulting in an increase in AUC of approximately 40–60%. On average, in patients with mild (Child-Pugh score 5-6) and moderate (Child-Pugh score 7-9) chronic liver disease, the bioavailability (according to AUC) of valsartan is doubled compared to healthy volunteers (matched age, gender and body weight). The drug should be used with caution in patients with impaired liver function and obstructive diseases of the biliary tract.

Special instructions

Aortic stenosis / mitral stenosis / hypertrophic obstructive cardiomyopathy

The combination drug amlodipine + valsartan has a vasodilating effect, the drug should be used with caution in patients with aortic stenosis, mitral stenosis or hypertrophic obstructive cardiomyopathy. In patients with left ventricular outflow tract obstruction (for example, severe aortic stenosis), the use of the drug is not recommended.

Amlodipine

Cardiovascular diseases

The effectiveness and safety of amlodipine in hypertensive crisis has not been established.

In acute myocardial infarction, the use of amlodipine is possible only after stabilization of hemodynamic parameters.

In rare cases, in patients with coronary heart disease (especially with severe obstructive lesions of the coronary arteries), an increase in the frequency, duration and/or severity of angina attacks was observed after starting the use of BMCC or after increasing their dosage.

Although in general BMCC should be used with caution in patients with CHF, amlodipine did not increase mortality or the incidence of cardiovascular events in patients with CHF in short- and long-term clinical studies. During the use of amlodipine in patients with CHF (III and IV functional class according to the NYHA classification) of non-ischemic origin, an increase in the incidence of pulmonary edema was observed, despite the absence of signs of progression of heart failure.

Withdrawal syndrome

Despite the absence of withdrawal syndrome in BMCC, it is advisable to discontinue treatment with amlodpine by gradually reducing the dose of the drug. Amlodipine does not prevent the development of withdrawal syndrome after abrupt cessation of beta-blockers.

Peripheral edema

Mild to moderate peripheral edema was the most common adverse event of amlodipine in clinical studies. The incidence of peripheral edema increases with increasing dose (when using amlodipine at a dose of 2.5 mg, 5 mg and 10 mg per day, edema occurred in 1.8%, 3% and 10.8% of patients, respectively). Peripheral edema associated with the use of amlodipine should be carefully differentiated from symptoms of progression of left ventricular heart failure.

Liver dysfunction

Controlled studies have not been conducted in patients with impaired liver function. In a small number of patients with mild to moderate liver failure, an increase in T1/2 of amlodipine was noted. Patients with liver failure, if it is necessary to use amlodipine, should be under medical supervision. In some cases (for example, with moderate liver failure), the use of a lower initial dose of amlodipine (2.5 mg per day) is recommended.

Old age

In elderly patients, T1/2 may increase and amlodipine clearance may decrease. In clinical studies, the incidence of adverse events in patients aged >65 years was approximately 6% higher than in younger patients. No changes in amlodipine doses are required, but more careful monitoring of patients in this category is necessary.

Other

During amlodipine therapy, it is necessary to monitor body weight and salt intake, and the appointment of an appropriate diet is indicated.

It is necessary to maintain dental hygiene and follow-up with a dentist (to prevent pain, bleeding and gum hyperplasia).

Valsartan

Renal dysfunction

There is no experience with the safe use of valsartan in patients with creatinine clearance less than 10 ml/min and in patients on hemodialysis, so valsartan should be used with caution in such patients. In patients with CC more than 10 ml/min, no dose adjustment is required.

Liver dysfunction

In patients with mild to moderate liver dysfunction without cholestasis, valsartan should be used with caution.

Hyperkalemia

When using valsartan concomitantly with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other drugs that may cause an increase in potassium concentrations in the blood (for example, heparin), caution should be exercised and regular monitoring of potassium levels in the blood should be performed.

Bilateral renal artery stenosis or stenosis of the artery of a solitary kidney

The use of valsartan in a short course in patients with renovascular hypertension, which developed secondary to unilateral stenosis of the artery of a single kidney, does not lead to any significant changes in renal hemodynamics, serum creatinine concentrations or blood urea nitrogen. However, given that other drugs that affect the RAAS may cause increases in serum urea and creatinine concentrations in patients with bilateral renal artery stenosis or solitary renal artery stenosis, monitoring these parameters is recommended as a precaution.

Primary hyperaldosteronism

Valsartan is not effective for the treatment of arterial hypertension in patients with primary hyperaldosteronism, since activation of the RAAS is not observed in this category of patients.

Kidney transplant

There are no data on the safety of valsartan in patients who have undergone kidney transplantation.

Sodium deficiency in the body and/or decreased blood volume

In patients with severe BCC deficiency, for example, those receiving high doses of diuretics, in rare cases, at the beginning of treatment with the drug, arterial hypotension may develop, accompanied by clinical manifestations. Before starting treatment with valsartan, sodium levels in the body should be corrected and/or BCC should be replenished, including by reducing the dose of the diuretic.

Angioedema, including angioedema

Angioedema, including swelling of the larynx and vocal cords leading to airway obstruction and/or swelling of the face, lips, pharynx and/or swelling of the tongue, has occurred in patients receiving valsartan, some of these patients having previously experienced angioedema while taking other drugs, including ACE inhibitors. If angioedema develops, taking valsartan should be immediately discontinued, and resumption of valsartan is prohibited.

CHF / period after myocardial infarction

In patients with CHF or after a myocardial infarction who begin treatment with valsartan, a slight decrease in blood pressure is often observed, and therefore, blood pressure control is recommended at the beginning of therapy. Provided that the dosage recommendations are followed, there is usually no need to discontinue valsartan due to arterial hypotension. Evaluation of patients with CHF should include assessment of renal function.

Due to inhibition of the RAAS system, renal dysfunction may occur in some patients. In patients with CHF of functional class III-IV according to the NYHA classification, whose renal function depends on the state of the RAAS, treatment with ACE inhibitors and ARA II may be accompanied by oliguria and/or an increase in azotemia and, in rare cases, the development of acute renal failure and/or death. Therefore, in these categories of patients, before using valsartan, as well as periodically during treatment with the drug, it is necessary to assess renal function.

Combination therapy for arterial hypertension

For arterial hypertension, valsartan can be used in monotherapy, as well as in combination with other antihypertensive drugs, in particular with diuretics.

Combination therapy in the period after myocardial infarction

It is possible to use valsartan in combination with other drugs used after myocardial infarction, namely thrombolytics, acetylsalicylic acid as an antiplatelet agent, beta-blockers and HMG-CoA reductase inhibitors. In this category of patients, it is not recommended to use valsartan concomitantly with ACE inhibitors, since this combination therapy does not have advantages over valsartan or ACE inhibitor monotherapy in terms of overall mortality from any cause.

Combination therapy for CHF

For CHF, valsartan can be used both in monotherapy and simultaneously with other drugs – diuretics, cardiac glycosides, as well as ACE inhibitors or beta-blockers.

In this category of patients, the use of triple combination therapy with ACE inhibitors, a beta-blocker and valsartan is not recommended.

Double blockade of the RAAS

When treated with drugs that affect the RAAS, especially when they are combined, a marked decrease in blood pressure, syncope, stroke, hyperkalemia and renal dysfunction (including acute renal failure) have been reported in sensitive patients. Caution is required when combining ARB II, including valsartan, with other drugs that block the RAAS, such as ACE inhibitors or aliskiren.

The simultaneous use of ARA II with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

Concomitant use of ARB II with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES AND MECHANISMS

There is no data on the effect of the drug Valz Combi on the ability to drive vehicles and machines.

Due to the possible occurrence of dizziness or increased fatigue, caution should be exercised when driving vehicles or operating machinery.

Active ingredient

Amlodipine, Valsartan

Composition

1 tablet 10 mg + 160 mg contains:

Pregnancy

Considering the mechanism of action of ARA II, the risk of their use for the fetus cannot be excluded. It is known that the administration of ACE inhibitors, which affect the RAAS, to pregnant women in the second and third trimesters leads to damage or death of the developing fetus. According to a retrospective analysis, the use of ACE inhibitors during the first trimester of pregnancy was accompanied by the development of pathology in the fetus and newborn. With the unintentional use of valsartan in pregnant women, cases of spontaneous abortion, oligohydramnios and renal dysfunction in newborns have been described.

The combination drug Valz Combi (amlodipine + valsartan), like any other drug that has a direct effect on the RAAS, should not be prescribed during pregnancy or to women wishing to become pregnant. Patients of childbearing age should be informed of the possible risk to the fetus associated with the use of drugs that affect the RAAS. If pregnancy is detected during treatment with the combination drug amlodipine + valsartan, the drug should be discontinued as soon as possible.

It is unknown whether valsartan and/or amlodipine passes into breast milk. Since experimental studies have shown that valsartan is excreted in breast milk, it is not recommended to use the combination drug Valz Combi during breastfeeding.

Contraindications

hypersensitivity to amlodipine, other dihydropyridine derivatives, valsartan, as well as auxiliary components of the drug;
hereditary angioedema, or edema in patients during previous therapy with ARA II;
severe (more than 9 points on the Child-Pugh scale) degree of liver dysfunction, biliary cirrhosis, cholestasis;
severe renal dysfunction (GFR < 30 ml/min/1.73 m2 body surface area), hemodialysis; pregnancy, pregnancy planning and breastfeeding; severe arterial hypotension (systolic blood pressure <90 mmHg), collapse; state of shock, including cardiogenic shock; hemodynamically unstable heart failure after acute myocardial infarction; simultaneous use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area); simultaneous use with ACE inhibitors in patients with diabetic nephropathy; children and adolescents under 18 years of age (safety of use has not been established).

With caution:

hereditary angioedema, or angioedema during therapy with ARA II or ACE inhibitors in history (special care should be taken);
chronic heart failure of non-ischemic etiology, functional class III-IV according to the NYHA classification;
coronary heart disease with severe obstructive lesions of the coronary arteries; patients with CHF II-IV functional class according to the NYHA classification, whose kidney function depends on the state of the renin-angiotensin-aldosterone system (RAAS);
acute myocardial infarction (and within 1 month after it); unstable angina;
aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy;
arterial hypotension;
sick sinus syndrome (severe tachycardia, bradycardia);
simultaneous use with inhibitors or inducers of the CYP3A4 isoenzyme;
old age;
impaired renal function with CC less than 10 ml/min (no clinical data);
bilateral renal artery stenosis or stenosis of the artery of a single kidney;
following a diet with limited salt intake;
conditions accompanied by a decrease in circulating blood volume (including diarrhea, vomiting, treatment with large doses of diuretics); hyponatremia;
liver failure; liver dysfunction of mild to moderate severity (< 9 points on the Child-Pugh scale) of non-biliary origin without cholestasis; simultaneous use with other drugs that inhibit the RAAS, such as ACE inhibitors or aliskiren.

Side Effects

The safety of the combination of amlodipine + valsartan has been assessed in more than 2613 patients.

Undesirable adverse reactions are presented by system-organ classes in accordance with the MedDRA classification and with the frequency of occurrence: very often (≥ 1/10); often (≥ 1/100 < 1/10); uncommon (≥ 1/1000 < 1/100); rare (≥ 1/10000 < 1/1000); very rare (< 1/10000), frequency unknown (cannot be estimated based on available data).

Within each group, identified by frequency of occurrence, adverse reactions are distributed in decreasing order of their importance.

Amlodipine + valsartan

Infectious and parasitic diseases: often – nasopharyngitis, influenza.

Immune system disorders: rarely – hypersensitivity.

Metabolic and nutritional disorders: often – hypokalemia; uncommon – anorexia, hypercalcemia, hyperlipidemia, hyperuricemia, hyponatremia.

Mental disorders: rarely – anxiety.

Nervous system disorders: often – headache; uncommon – impaired coordination, dizziness, drowsiness, postural dizziness, paresthesia.

Violations of the organ of vision: infrequently – visual impairment; rarely – visual impairment.

Hearing and labyrinthine disorders: uncommon – vertigo; rarely – tinnitus.

Cardiac disorders: uncommon – tachycardia, palpitations; rarely – syncope.

Vascular disorders: uncommon – orthostatic hypotension; rarely – a pronounced decrease in blood pressure.

Disorders of the respiratory system, chest and mediastinal organs: infrequently – cough, pain in the pharynx and larynx.

Digestive system disorders: uncommon – diarrhea, nausea, abdominal pain, constipation, dry oral mucosa.

Disorders of the skin and subcutaneous tissues: infrequently – erythema, skin rash; rarely – exanthema, hyperhidrosis, itching.

Musculoskeletal and connective tissue disorders: uncommon – joint swelling, back pain, arthralgia; rarely – muscle spasms, a feeling of heaviness throughout the body.

Renal and urinary tract disorders: rarely – pollakiuria, polyuria.

Disorders of the genital organs and breast: rarely – erectile dysfunction.

General disorders: often – pastosity, facial swelling, asthenia, peripheral edema, increased fatigue, flushing of the face, asthenia, feeling of heat.

In comparative and placebo-controlled clinical studies, the incidence of peripheral edema was lower in patients receiving the combination of amlodipine with valsartan (5.8%) than in patients receiving amlodipine monotherapy (9%).

Laboratory and instrumental data: an increase in the concentration of urea nitrogen in the blood (more than 3.1 mmol/l) was observed slightly more often in the groups receiving amlodipine + valsartan (5.5%) and valsartan as monotherapy (5.5%), compared with the group receiving placebo (4.5%).

Adverse events (AEs) specific to each of the components may occur when using Valz Combi, even if they were not observed in clinical studies.

Amlodipine

Disorders of the blood and lymphatic system: very rarely – leukopenia, thrombocytopenia.

Immune system disorders: very rarely – hypersensitivity.

Metabolic and nutritional disorders: very rarely – hyperglycemia.

Mental disorders: uncommon – depression, insomnia/sleep disorders, mood lability; rarely – confusion.

Nervous system disorders: often – dizziness, headache, drowsiness; uncommon – taste disturbance, paresthesia, fainting, tremor, hypoesthesia; very rarely – muscle hypertonicity, peripheral neuropathy, neuropathy; frequency unknown – extrapyramidal symptoms.

Visual disturbances: infrequently – visual impairment, visual impairment.

Cardiac disorders: often – palpitations; very rarely – arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation), myocardial infarction.

Vascular disorders: often – “flushes” of blood to the facial skin; infrequently – pronounced decrease in blood pressure; very rarely – vasculitis.

Disorders of the respiratory system, chest and mediastinal organs: infrequently – shortness of breath, rhinitis; very rarely – cough.

Disorders of the digestive system: often – a feeling of discomfort in the abdomen, pain in the upper abdomen, nausea; uncommon – changes in stool, diarrhea, dry oral mucosa, dyspepsia, vomiting; very rarely – gastritis, gingival hyperplasia, pancreatitis.

Disorders of the liver and biliary tract: very rarely – increased activity of liver enzymes, including increased concentrations of bilirubin in the blood serum (usually associated with cholestasis), hepatitis, intrahepatic cholestasis, jaundice.

Disorders of the skin and subcutaneous tissues: uncommon – alopecia, exanthema, hyperhidrosis, purpura, skin discoloration, photosensitivity, itching, skin rash; very rarely – angioedema (Quincke’s edema), urticaria, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome.

Disorders of the musculoskeletal system and connective tissue: often – swelling of the ankles; uncommon – arthralgia, back pain, muscle spasms, myalgia.

Renal and urinary tract disorders: uncommon – urinary disorders, nocturia, pollakiuria.

Disorders of the genital organs and mammary gland: infrequently – impotence, gynecomastia.

General disorders: often – increased fatigue, swelling; uncommon – asthenia, discomfort, malaise, non-cardiogenic heart pain, pain of various localizations.

Laboratory and instrumental data: infrequently – increase or decrease in body weight.

Valsartan

The following are AEs identified in patients with arterial hypertension during clinical trials, as well as in clinical practice and laboratory studies. For AEs identified in clinical practice and laboratory studies, it is impossible to establish the frequency of occurrence, therefore for these AEs it is indicated: “frequency unknown.”

Blood and lymphatic system disorders: frequency unknown – decreased hemoglobin and hematocrit, neutropenia, thrombocytopenia.

Immune system disorders: frequency unknown – hypersensitivity reactions, including serum sickness.

Hearing and labyrinthine disorders: uncommon – vertigo.

Vascular disorders: frequency unknown – vasculitis.

Disorders of the respiratory system, chest and mediastinal organs: uncommon – cough.

Digestive system disorders: uncommon – abdominal discomfort, pain in the upper abdomen.

Disorders of the liver and biliary tract: frequency unknown – impaired liver function, increased activity of liver enzymes, increased concentration of bilirubin in the blood plasma.

Skin and subcutaneous tissue disorders: frequency unknown – angioedema, bullous dermatitis, pruritus, skin rash.

Musculoskeletal and connective tissue disorders: frequency unknown – myalgia.

Renal and urinary tract disorders: frequency unknown – increased serum creatinine concentrations, impaired renal function, including acute renal failure.

General disorders: uncommon – increased fatigue, asthenia.

Laboratory and instrumental data: frequency unknown – increased potassium content in blood plasma.

If any of the side effects indicated in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.

Interaction

Amlodipine

Other antihypertensive and antianginal drugs

Amlodipine can be safely used for the treatment of hypertension together with thiazide diuretics, beta-blockers or ACE inhibitors.

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

It is possible to enhance the antianginal and antihypertensive effects of BMCC when used together with thiazide and loop diuretics, ACE inhibitors, beta-blockers and nitrates.

Ethanol, barbiturates, antipsychotics, antidepressants, narcotic analgesics, general anesthesia

It is possible to enhance the antihypertensive effect of dihydropyridine derivatives and increase the risk of orthostatic hypotension.

Other drugs that can lower blood pressure

It can be expected that some drugs (for example, baclofen and amifostine), due to their pharmacological properties, will enhance the antihypertensive effect of amlodipine. Monitoring of blood pressure and renal function is necessary, as well as dose adjustment of amlodipine if necessary.

Corticosteroids (mineral and glucocorticosteroids), tetracosactide

Reduced antihypertensive effect of amlodipine (due to fluid and sodium ion retention as a result of the action of corticosteroids).

Calcium preparations

Calcium supplements can reduce the effect of BMCC.

Dantrolene (with intravenous administration)

In animal experiments, cases of fatal ventricular fibrillation and cardiovascular failure associated with hyperkalemia were observed after the administration of verapamil and dantrolene (intravenously). Given the risk of developing hyperkalemia, the simultaneous use of BMCC (including amlodipine) and dantrolene should be avoided in patients with malignant hyperthermia.

PHARMACOKINETIC INTERACTIONS

The influence of other drugs on the pharmacokinetics of amlodipine

CYP3A4 isoenzyme inhibitors

With the simultaneous use of diltiazem at a dose of 180 mg and amlodipine at a dose of 5 mg in elderly patients (69 to 87 years) with arterial hypertension, an increase in systemic exposure of amlodipine by 57% was observed. Concomitant use of amlodipine and erythromycin in healthy volunteers (18 to 43 years of age) does not lead to significant changes in amlodipine exposure (22% increase in AUC). The clinical significance of these effects is unclear.

Ritonavir (a potent inhibitor of the CYP3A4 isoenzyme) increases plasma concentrations of BMCC, including amlodipine.

It is possible that potent inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole, itraconazole, ritonavir) may increase the plasma concentration of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution simultaneously with inhibitors of the CYP3A4 isoenzyme (especially in elderly patients).

Clarithromycin

Clarithromycin is an inhibitor of the CYP3A4 isoenzyme. Patients taking clarithromycin and amlodipine at the same time have an increased risk of low blood pressure. Patients taking this combination are advised to be under close medical supervision.

Inducers of the CYP3A4 isoenzyme

There are no data on the effect of inducers of the CYP3A4 isoenzyme on the pharmacokinetics of amlodipine. Amlodipine should be used with caution simultaneously with inducers of the CYP3A4 isoenzyme (phenobarbital, phenytoin, carbamazepine, primidone, rifampicin, St. John’s wort preparations); carefully monitor blood pressure during their simultaneous use (the antihypertensive effect of amlodipine may be weakened).

Grapefruit juice

A simultaneous single dose of 240 ml of grapefruit juice and 10 mg of amlodipine orally is not accompanied by a significant change in the pharmacokinetics of amlodipine. However, it is not recommended to use grapefruit juice and amlodipine at the same time, since genetic polymorphism of the cytochrome P450 isoenzyme may increase the bioavailability of amlodipine and, as a result, enhance its antihypertensive effect.

Aluminum- or magnesium-containing antacids

When taken together once a day, they do not have a significant effect on the pharmacokinetics of amlodipine.

Sildenafil

A single dose of 100 mg of sildenafil in patients with essential hypertension does not affect the pharmacokinetic parameters of amlodipine.

Cimetidine

Cimetidine does not affect the pharmacokinetics of amlodipine.

Effect of amlodipine on the pharmacokinetics of other drugs

Simvastatin

Simultaneous repeated use of amlodipine at a dose of 10 mg and simvastatin at a dose of 80 mg leads to an increase in simvastatin exposure by 77%. In such cases, the dose of simvastatin should be limited to 20 mg.

Atorvastatin

Repeated co-administration of amlodipine at a dose of 10 mg and atorvastatin at a dose of 80 mg is not accompanied by significant changes in the pharmacokinetic parameters of AUC (increase by an average of 18%) Cmax and TCmax of atorvastatin.

Cyclosporine

A study of the simultaneous use of amlodipine and cyclosporine in healthy volunteers and all groups of patients, with the exception of patients after kidney transplantation, has not been conducted. Various studies of the interaction 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 trough concentration of cyclosporine to varying degrees, up to 40%. These data should be taken into account and cyclosporine concentrations should be monitored in this group of patients when cyclosporine and amlodipine are co-administered.

Tacrolimus

When used simultaneously with amlodipine, there is a risk of increasing the concentration of tacrolimus in the blood plasma. To avoid the toxicity of this drug when used concomitantly with amlodipine, tacrolimus plasma concentrations should be monitored and the tacrolimus dose adjusted if necessary.

mTOR inhibitors (mammalion Target of Rapamycin – target of rapamycin in mammalian cells)

mTOR inhibitors (eg, temsirolimus, sirolimus, everolimus) are CYP3A4 substrates. Because amlodipine is a weak CYP3A4 inhibitor, concomitant use may increase exposure to mTOR inhibitors.

Ethanol

Amlodipine with single and repeated use at a dose of 10 mg does not affect the pharmacokinetics of ethanol.

Lithium preparations

When BMCC is used together with lithium preparations (no data are available for amlodipine), their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) may increase.

Digoxin

Amlodipine does not affect serum digoxin concentrations or its renal clearance in healthy volunteers. In in vitro studies, amlodipine did not affect the binding of digoxin to plasma proteins.

Warfarin

Amlodipine does not have a significant effect on the effect of warfarin (prothrombin time). In in vitro studies, amlodipine did not affect the binding of warfarin to plasma proteins.

Phenytoin

In in vitro studies, amlodipine did not affect the plasma protein binding of phenytoin.

OTHER INTERACTIONS

Amlodipine can be safely used concomitantly with antibiotics and oral hypoglycemic agents.

Unlike other BMCCs, no clinically significant interaction was found between amlodipine when used in combination with non-steroidal anti-inflammatory drugs (NSAIDs), including indomethacin. In in vitro studies, amlodipine did not affect the binding of indomethacin to plasma proteins.

Although negative inotropic effects have generally not been observed in amlodipine studies, some CBMCs may enhance the negative inotropic effects of antiarrhythmic drugs that prolong the QT interval (eg, amiodarone and quinidine).

Valsartan

It has been established that during monotherapy with valsartan there are no clinically significant interactions with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.

Double blockade of the RAAS

Concomitant use of II ARBs, including valsartan, with other drugs that affect the RAAS (such as ACE inhibitors and aliskiren) is associated with an increased incidence of arterial hypotension, hyperkalemia and changes in renal function compared with monotherapy. It is recommended to monitor blood pressure, renal function and electrolyte levels in patients taking valsartan and other drugs that affect the RAAS.

The simultaneous use of ARA II with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

Concomitant use of ARB II with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

In children and adolescents, hypertension is often associated with impaired renal function. It is recommended to use valsartan with caution concomitantly with other drugs that affect the RAAS in patients in this category, because this may lead to an increase in serum potassium levels. Regular monitoring of renal function and serum potassium levels should be carried out in patients in this group.

Medicines that may increase plasma potassium levels

The simultaneous use of potassium-sparing diuretics (including spironolactone, eplerenone, triamterene, amiloride), potassium preparations, potassium-containing table salt substitutes and other drugs that can increase the level of potassium in the blood serum (including heparin) can lead to an increase in the content of potassium in the blood serum, and in patients with heart failure to an increase in the concentration of serum creatinine. If such combination treatment is considered necessary, caution should be exercised.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

When used simultaneously with NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors and acetylsalicylic acid in high doses (> 3 g per day), the antihypertensive effect of valsartan may be reduced. When using ARA II simultaneously with NSAIDs, renal function may deteriorate and the potassium content in the blood plasma may increase. If it is necessary to use valsartan and NSAIDs simultaneously, before starting treatment, it is necessary to assess renal function and correct disturbances in water and electrolyte balance.

Transport proteins

According to the results of an in vitro study on liver cultures, valsartan is a substrate for the transporter proteins OATP1B1 and MRP2. Concomitant use of valsartan with inhibitors of the OATP1B1 transport protein (rifampicin, cyclosporine) and with an inhibitor of the MRP2 transport protein (ritonavir) may increase the systemic exposure of valsartan (Cmax and AUC).

Lithium preparations

With the simultaneous use of lithium preparations with ACE inhibitors and ARA II, a reversible increase in the lithium content in the blood serum and, in connection with this, increased toxic manifestations were observed, therefore it is recommended to monitor the lithium content in the blood serum. The risk of toxic effects associated with the use of lithium may further increase when used concomitantly with valsartan and diuretics.

Overdose

There are currently no data on cases of overdose of the amlodipine + valsartan combination.

Symptoms: with an overdose of valsartan, you can expect the development of a pronounced decrease in blood pressure, accompanied by dizziness. Overdose of amlodipine can lead to excessive peripheral vasodilation and possible reflex tachycardia. Severe and prolonged systemic arterial hypotension has also been reported, leading to fatal shock.

Treatment: symptomatic, the nature of which depends on the time elapsed since taking the drug and the severity of the symptoms. If the drug has been taken recently, induce vomiting or perform gastric lavage. The use of activated charcoal in healthy volunteers immediately or within 2 hours after taking amlodipine significantly reduced its absorption. If there is a pronounced decrease in blood pressure in the event of a drug overdose, it is necessary to take active measures to maintain the activity of the cardiovascular system, including regular monitoring of the function of the heart and respiratory system, transfer the patient to the “lying” position with elevated legs, and pay special attention to the volume of urine excreted.

In the absence of contraindications, in order to restore vascular tone and blood pressure, it is possible to use (with caution) a vasoconstrictor. To eliminate the effect of BMCC, it is possible to administer calcium gluconate intravenously.

Removal of valsartan and amlodipine during hemodialysis is unlikely.

Storage conditions

Store at a temperature not exceeding 30 °C.
Keep out of the reach of children!

Shelf life

2 years. Do not use after expiration date.

Manufacturer

Balkanpharma – Dupnitsa AD, Bulgaria