Valz Combi pills 10mg + 160mg, 28pcs

Composition

1 tablet of 10 mg + 160 mg contains:

active ingredients:

amlodipine bezylate-13.90 mg, based on amlodipine base-10.00 mg,

valsartan-160.00 mg;

excipients: microcrystalline cellulose (type 101) – 50.50 mg, povidone (K 30) – 17.00 mg, croscarmellose sodium-17.00 mg, microcrystalline cellulose (type 102) – 76.84 mg, talc – 4.08 mg, magnesium stearate-2.04 mg;

shell composition: Opadray white 03B28796 (hypromellose-6,400 mg, titanium dioxide (E 171) – 3,200 mg, macrogol 400-0,640 mg) – 10,24 mg

Pharmacological action

Pharmacotherapy group: combined antihypertensive agent (BMCC + angiotensin II receptor antagonist)

ATX code: C09DB01

PHARMACOLOGICAL PROPERTIES

Pharmacological action

Pharmacological action-antihypertensive.

Pharmacodynamics

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 (BMCC), valsartan — 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 used separately.

Amlodipine

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

After taking therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation, leading to a decrease in blood pressure (in the patient’s “lying” and “standing”positions). A decrease in blood pressure is not accompanied by a significant change in heart rate (HR) and catecholamine levels with prolonged use.

In hypertensive patients with normal renal function, amlodipine in therapeutic doses reduces renal vascular resistance, increases glomerular filtration rate (GFR), and improves renal blood flow without changing the filtration fraction and degree of proteinuria.

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

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

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

Valsartan

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

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

When using angiotensin II antagonists, ACE inhibition and accumulation of bradykinin or substance P do not occur, and therefore the development of 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, there is a decrease in blood pressure, not accompanied by a change in heart rate.

The antihypertensive effect of the drug is manifested 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 persists for more than 24 hours. With repeated use, the maximum reduction in blood pressure, regardless of the dose taken, is usually achieved within 2-4 weeks and maintained at the achieved level with long-term therapy. Abrupt discontinuation of valsartan is not accompanied by a withdrawal syndrome (a 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 insufficiency (stable clinical course) or with impaired LV function after a myocardial infarction, a decrease in cardiovascular mortality is noted.

Amlodipine + Valsartan

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

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

Therapeutic efficacy is independent of 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 probability of developing peripheral edema in patients with previously achieved blood pressure control and severe peripheral edema on the background of amlodipine therapy.

Pharmacokinetics

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

Amlodipine

Suction

After oral use of amlodipine in therapeutic doses, its maximum plasma concentration (cmax) is reached in 6-12 hours. 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 approximately 97.5% of circulating amlodipine binds to plasma proteins in patients with hypertension.

Metabolism

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

Deduction

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

Valsartan

Suction

After oral use of valsartan, cmax in blood plasma is reached within 2-4 hours. The average absolute bioavailability is 23%. When taking valsartan with food, there is a decrease in bioavailability (according to the area under the pharmacokinetic curve “concentration-time” (AUC)) plasma concentrations of valsartan increased by 40% and plasma cmax by almost 50%, although approximately 8 hours after taking the drug, plasma concentrations of valsartan in the group of patients taking it with food and in the group taking it on an empty stomach are equal. A decrease in AUC, however, is not accompanied by a clinically significant decrease in the therapeutic effect, so valsartan can be prescribed regardless of the meal time.

The distribution

of VD valsartan at steady state after intravenous (iv) use is about 17 liters, which indicates that there is no extensive distribution of the drug in the tissues. Valsartan is largely bound to serum proteins (94-97%), mainly to albumins.

Metabolism

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

Elimination

The pharmacokinetic curve of valsartan has a descending multi-exponential character (T1/2α Valsartan is mainly excreted unchanged through the intestines (about 83% of the dose) and kidneys (about 13% of the dose). After intravenous use, the plasma clearance of valsartan is about 2 l / h, the renal clearance is 0.62 l / h (about 30% of the total clearance). T_1/2 valsartan — 6 hours.

Amlodipine + Valsartan

After oral use of the combined drug Valz Combi (amlodipine + valsartan), the cmax of valsartan and amlodipine is reached in 3 and 6-8 hours, respectively. The rate and degree of absorption of the drug is equivalent to the bioavailability of valsartan and amlodipine when each of them is taken as separate tablets.

Pharmacokinetics in special clinical cases

Pharmacokinetic features of the use of the combined 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 in young and elderly patients is the same. In elderly patients, the clearance of amlodipine is slightly reduced, which leads to an increase in AUC and T_1/2.

In elderly patients, 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 elderly 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 to 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 impaired liver function

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

Indications

Arterial hypertension (for patients who are indicated for combination therapy).

Use during pregnancy and lactation

Given the mechanism of action of ARA II, the risk of their use for the fetus cannot be excluded. It is known that the use of ACE inhibitors that 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 fetal and newborn pathology. Cases of spontaneous abortions, lack of water supply, and impaired renal function in newborns have been reported with unintentional use of valsartan in pregnant women.

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 and women who want to become pregnant. Patients of childbearing age should be informed about 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 not known whether valsartan and / or amlodipine pass into breast milk. Since the isolation of valsartan in breast milk has been noted in experimental studies, it is not recommended to use the combined drug Valz Combi during breastfeeding.

Contraindications

• hypersensitivity to amlodipine, other derivatives of dihydropyridine, valsartan, as well as auxiliary components of the drug;
• hereditary angioneurotic edema or edema in patients on the background of previous therapy with ARA II;
• heavy (more than 9 points on a scale child-Pugh) the degree of impairment of liver function, biliary cirrhosis, cholestasis;
• severe renal dysfunction (GFR < 30 ml/min/1.73 m 2 of the body surface area), hemodialysis;
• pregnancy, pregnancy and lactation;
• severe arterial hypotension (systolic blood pressure < 90 mm. Hg. calendar), collapse;
• shock, including cardiogenic shock;
• hemodynamically unstable heart failure after acute myocardial infarction;
• concurrent use with aliskiren and drugs containing aliskiren in patients with diabetes and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m 2 of the body surface area);
• concurrent use of ACE inhibitors in patients with diabetic nephropathy;
• children and adolescents up to 18 years (safety not established).

With caution:

• hereditary angioedema or angioedema during therapy with ARA II or ACE inhibitors in history (be careful);
• chronic heart failure of nonischemic etiology of III-IV functional class NYHA classification;
• ischemic heart disease with severe obstructive coronary artery disease; patients with CHF II-IV functional class NYHA classification, renal function which depends on the state of the renin-angiotensin-aldosterone system (RAAS);
• acute myocardial infarction (during the period and for 1 month after); unstable angina;
• aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy;
• hypotension;
• sick sinus syndrome node (marked tachycardia, bradycardia);
• concurrent use with inhibitors or inducers of CYP3A4;
• older age;
• the impairment of renal function with CC less than 10 ml/min (no clinical data);
• bilateral renal artery stenosis or stenosis of the artery to a solitary kidney;
• a diet with restriction of salt consumption;
• state, accompanied by a decrease in circulating blood volume (including diarrhea, vomiting, treatment with high doses of diuretics); hyponatremia;
• liver failure; violations of liver function of mild and moderate severity (< 9 points on a scale child-Pugh) namilyango Genesis without signs of cholestasis;
• concurrent use with other drugs that inhibit the RAAS, such as ACE inhibitors or aliskiren.

Side effects

The safety of using the combination of amlodipine + valsartan was evaluated in more than 2613 patients.

Adverse reactions are classified by organ-system classification according to MedDRA and with the frequency of occurrence: very common (≥ 1/10); common (≥ 1/100 <1/10); infrequent (≥ 1/1000 <1/100); rare (≥ 1/10000 <1/1000); very rare (

Within each group, distinguished by frequency of occurrence, adverse reactions are distributed in order of decreasing significance.

Amlodipine + valsartan

Infectious and parasitic diseases: often-nasopharyngitis, flu.

Immune system disorders: rarely-hypersensitivity.

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

Mental disorders: rarely-anxiety.

Nervous system disorders: often-headache; infrequently-coordination disorders, dizziness, drowsiness, postural vertigo, paresthesia.

Visual disturbances: infrequently-visual impairment; rarely-visual impairment.

Hearing disorders and labyrinth disorders: infrequently-vertigo; rarely-tinnitus.

Cardiac disorders: infrequently-tachycardia, palpitation sensation; rarely-syncopal state.

Vascular disorders: infrequently-orthostatic hypotension; rarely-a marked decrease in blood pressure.

Respiratory, thoracic and mediastinal disorders: infrequently-cough, pain in the pharynx and larynx.

Disorders of the digestive system: infrequently-diarrhea, nausea, abdominal pain, constipation, dryness of the oral mucosa.

Skin and subcutaneous tissue disorders: infrequently-erythema, skin rash; rarely-exanthema, hyperhidrosis, pruritus.

Musculoskeletal and connective tissuedisorders: infrequently-joint swelling, back pain, arthralgia; rarely-muscle spasms, a feeling of heaviness throughout the body.

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

Genital and breast disorders: rarely-erectile dysfunction.

Common disorders: often-pastyness, facial edema, asthenia, peripheral edema, increased fatigue, “flushes” of blood to the face, asthenia, feeling hot.

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

Laboratory and instrumental data: increased concentration of urea nitrogen in the blood (more than 3.1 mmol/l) was observed slightly more frequently 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 with the use of 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 rare – hypersensitivity.

Metabolic and nutritional disorders: very rare – hyperglycemia.

Mental disorders: infrequently-depression, insomnia/sleep disorders, mood lability; rarely-confusion.

Nervous system disorders: often – dizziness, headache, drowsiness; infrequently-taste disorders, paresthesia, syncope, tremor, hypesthesia; very rarely-muscle hypertonus, 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 – “hot flashes” of blood to the skin of the face; infrequently – a pronounced decrease in blood pressure; very rarely – vasculitis.

Respiratory, thoracic and mediastinal disorders: infrequently – shortness of breath, rhinitis; very rarely-cough.

Digestive system disorders: often-abdominal discomfort, upper abdominal pain, nausea; infrequently-stool changes, diarrhea, dry oral mucosa, dyspepsia, vomiting; very rarely – gastritis, gum hyperplasia, pancreatitis.

Liver and biliary tract disorders: very rarely – increased activity of “liver” enzymes, including increased serum bilirubin (usually associated with cholestasis), hepatitis, intrahepatic cholestasis, jaundice.

Skin and subcutaneous tissue disorders: infrequently-alopecia, exanthema, hyperhidrosis, purpura, skin discoloration, photosensitization, pruritus, skin rash; very rarely-angioedema (angioedema), urticaria, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders: often-ankle edema; infrequently-arthralgia, back pain, muscle spasms, myalgia.

Renal and urinary tractdisorders: infrequently-urinary disorders, nocturia, pollakiuria.

Genital and breast disorders: infrequently-impotence, gynecomastia.

General disorders: often-increased fatigue, edema; infrequently-asthenia, discomfort, malaise, non-cardiogenic pain in the heart, pain of various localization.

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

Valsartan

The following are AES identified in patients with hypertension in clinical studies, as well as in clinical practice and laboratory studies. For AES detected in clinical practice and laboratory studies, it is impossible to determine the frequency of occurrence, so for these AES it is indicated: “frequency unknown”.

Disorders of the blood and lymphatic system: frequency unknown-decreased hemoglobin and hematocrit, neutropenia, thrombocytopenia.

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

Hearing disorders and labyrinth disorders: infrequently-vertigo.

Vascular disorders: frequency unknown – vasculitis.

Respiratory, thoracic and mediastinaldisorders: infrequently-cough.

Disorders of the digestive system: infrequently – 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 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, impaired renal function, including acute renal failure.

General disorders: infrequently-increased fatigue, asthenia.

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

If any of the side effects listed 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 medications

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, with prolonged or short-acting nitrates, beta-blockers.

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

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

It is possible to increase 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. It is necessary to monitor blood pressure and renal function, as well as adjust the dose of amlodipine if necessary.

Corticosteroids (mineral and glucocorticosteroids), tetracosactide

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

Calcium supplements

Calcium supplements can reduce the effect of BMCC.

Dantrolene (for intravenous use)

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

PHARMACOKINETIC INTERACTIONS

Effect of other drugs on the pharmacokinetics of amlodipine

Inhibitors of the CYP3A4 isoenzyme

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, there is an increase in systemic exposure to amlodipine by 57%. Concomitant use of amlodipine and erythromycin in healthy volunteers (18 to 43 years of age) did not result in significant changes in amlodipine exposure (a 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 powerful inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole, itraconazole, ritonavir) may increase the concentration of amlodipine in blood plasma to a greater extent than diltiazem. Caution should be exercised when using amlodipine concomitantly with CYP3A4 inhibitors (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 lowering 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. Caution should be exercised when using amlodipine concomitantly with inducers of the CYP3A4 isoenzyme (phenobarbital, phenytoin, carbamazepine, primidone, rifampicin, St. John’s wort), blood pressure should be carefully monitored when used simultaneously (the antihypertensive effect of amlodipine may be weakened).

Grapefruit juice

Simultaneous single use 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 simultaneously, since the genetic polymorphism of the cytochrome P450 isoenzyme may increase the bioavailability of amlodipine and, consequently, increase its antihypertensive effect.

Aluminum-or magnesium-containing antacids

With a single co-use, they do not significantly affect the pharmacokinetics of amlodipine.

Sildenafil

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

Cimetidine

Cimetidine does not affect the pharmacokinetics of amlodipine.

Effect of amlodipine on the pharmacokinetics of other drugs

Simvastatin

Simultaneous multiple use of 10 mg amlodipine and 80 mg simvastatin resulted in a 77% increase in simvastatin exposure. In such cases, the dose of simvastatin should be limited to 20 mg.

Atorvastatin

Repeated co-use 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 (an average increase of 18%) cmax and TC_max of atorvastatin.

Cyclosporine

A study of concomitant use of amlodipine and cyclosporine in healthy volunteers and all groups of patients, with the exception of patients after kidney transplantation, was not 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 minimum concentration of cyclosporine to varying degrees up to 40%. These data should be taken into account and the concentration of cyclosporine should be monitored in this group of patients with concomitant use of cyclosporine and amlodipine.

Tacrolimus

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

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

mTOR inhibitors (e. g., temsirolimus, sirolimus, everolimus) are substrates of CYP3A4. Since amlodipine is a weak inhibitor of CYP3A4, co-use may increase exposure to mTOR inhibitors.

Ethanol

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

Lithium preparations

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

Digoxin

Amlodipine has no effect on serum digoxin concentrations and renal clearance in healthy volunteers. In vitro studies, amlodipine did not affect the binding of digoxin to plasma proteins.

Warfarin

Amlodipine does not significantly affect the effect of warfarin (prothrombin time). In vitro studies, amlodipine did not affect the binding of warfarin to plasma proteins.

Phenytoin

In vitro studies, amlodipine did not affect the binding of phenytoin to plasma proteins.

OTHER INTERACTIONS

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

Unlike other BMCs, there was no clinically significant interaction of amlodipine when co-administered with nonsteroidal anti-inflammatory drugs (NSAIDs), including Indometacin. In vitro studies, amlodipine did not affect the binding of Indometacin to plasma proteins.

Although no negative inotropic effects have usually been observed in studies of amlodipine, however, some BMCs may increase the severity of the negative inotropic effects of antiarrhythmic agents that cause prolongation of the QT interval (for example, amiodarone and quinidine).

Valsartan

Valsartan monotherapy was found to have no clinically significant interactions with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, Indometacin, hydrochlorothiazide, amlodipine, glibenclamide.

Double blockade of the RAAS

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

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

Concomitant use of ARA 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 at the same time as other drugs that affect the RAAS in patients of this category, as this may lead to an increase in the content of potassium in the blood serum. Regular monitoring of renal function and serum potassium should be performed in patients of this group.

Medications that may lead to an increase in the potassium content in the blood plasma

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

Nonsteroidal anti-inflammatory drugs (NSAIDs)

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

Carrier proteins

According to the results of an in vitro study on liver cultures, valsartan is a substrate for OATP1V1 and MRP2 transporter proteins. Concomitant use of valsartan with 1-In-1 OATP transporter protein inhibitors (rifampicin, cyclosporine) and MRP2 transporter protein inhibitor (ritonavir) may increase the systemic exposure of valsartan (with_max and AUC).

Lithium preparations

With the simultaneous use of lithium preparations with ACE inhibitors and ARA II, a reversible increase in the content of lithium in the blood serum and an increase in toxic manifestations, therefore, it is recommended to monitor the content of lithium 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.

How to take, course of use and dosage

Inside, with a small amount of water,1 time a day, regardless of the time of meal.

The recommended daily dose is 1 tablet containing amlodipine + valsartan at a dose of 5 mg + 80 mg,5 mg +160 mg or 10 mg + 160 mg. It is recommended to start taking the drug with a dose of 5 mg + 80 mg once a day. You can increase the dose 1-2 weeks after the start of therapy. In patients who do not manage to achieve adequate blood pressure control, the daily dose of the drug can be gradually increased under the supervision of a doctor: the recommended maximum daily dose (according to amlodipine) is 10 mg + 160 mg; the maximum daily dose of the drug is: 10 mg + 320 mg (2 tablets of Valz Combi in a dosage of 5 mg + 160 mg 1 time a day).

For elderly patients (> 65 years) and for patients with impaired liver function or liver diseases without cholestasis, it is possible to reduce the initial dose of the drug to the lowest dose of amlodipine, i. e. 1 tablet containing the combination of amlodipine + valsartan at a dose of 5 mg + 80 mg or 5 mg + 160 mg. >

No initial dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance > 30 ml / min).

Overdose

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

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 hypotension, up to fatal shock, has also been reported.

Treatment: symptomatic, the nature of which depends on the time that has elapsed since taking the drug, and on the severity of symptoms. If the drug has been taken recently, you should 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. With a marked decrease in blood pressure in the event of an overdose of the drug, 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 raised legs, and pay special attention to the volume of urine released.

In the absence of contraindications, a vasoconstrictor may be used (with caution) to restore vascular tone and blood pressure. To eliminate the effect of BMCC, intravenous use of calcium gluconate is possible.

Elimination of valsartan and amlodipine during hemodialysis is unlikely.

Description

Oval biconvex film-coated tablets of white color with the inscription “3” on one side and “LD” on the other side.

Special instructions

Aortic stenosis / mitral stenosis / hypertrophic obstructive cardiomyopathy

The combined 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, with severe aortic stenosis), the drug is not recommended.

Amlodipine

Cardiovascular diseases

The efficacy 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, patients with coronary artery disease (especially those with severe obstructive coronary artery disease) have experienced an increase in the frequency, duration, and/or severity of angina attacks after starting BMCC or after increasing their dosage.

Although BMCC should generally be used with caution in patients with CHF, amlodipine has not been shown to increase mortality or cardiovascular events in patients with CHF in short – and long-term clinical trials. In patients with non-ischemic CHF (NYHA functional class III and IV), there was an increase in the incidence of pulmonary edema, despite the absence of signs of heart failure progression, when amlodipine was used.

Withdrawal syndrome

Despite the absence of “withdrawal” syndrome in BMCC, discontinuation of treatment with amlodpine should be carried out gradually reducing the dose of the drug. Amlodipine does not prevent the development of “withdrawal” syndrome when abruptly stopping taking beta-blockers.

Peripheral edema

Mild to moderate peripheral edema was the most common adverse event of amlodipine in clinical trials. The frequency 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 progressive left ventricular heart failure.

Impaired liver function

No controlled studies have been conducted in patients with hepatic impairment. In a small number of patients with mild to moderate hepatic insufficiency, an increase in T_1/2 of amlodipine was noted. Patients with hepatic insufficiency should be monitored by a doctor if necessary for the use of amlodipine. In some cases (for example, in moderate hepatic insufficiency), a lower initial dose of amlodipine (2.5 mg per day) is recommended.

Advanced age

In elderly patients, T_{1/2 may increase} and clearance of amlodipine may decrease. In clinical trials, the incidence of adverse events in patients aged >> 65 years was approximately 6% higher than in younger patients. There is no need to change the dose of amlodipine, but more careful monitoring of patients in this category is necessary.

Other things

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

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

Valsartan

Impaired renal function

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

Impaired liver function

Valsartan should be used with caution in patients with mild to moderate hepatic impairment without cholestasis.

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 the concentration of potassium in the blood (for example, with heparin), care should be taken and regular monitoring of the potassium content in the blood should be carried out.

Bilateral renal artery stenosis or single kidney artery stenosis

The use of valsartan in a short course in patients with renovascular hypertension, which developed a second time due to unilateral stenosis of the artery of a single kidney, does not lead to any significant changes in renal hemodynamics, serum creatinine concentration or blood urea nitrogen. However, given that other drugs that affect the RAAS may cause an increase in serum urea and creatinine concentrations in patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney, monitoring of these indicators is recommended as a precautionary measure.

Primary hyperaldosteronism

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

Kidney transplantation

There are no data on the safety of valsartan in patients undergoing kidney transplantation.

Lack of sodium in the body and / or a decrease in BCC

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

Angioedema, including angioedema

Angioedema, including laryngeal and vocal cord edema leading to airway obstruction and/or swelling of the face, lips, pharynx, and / or tongue edema, has been reported in patients treated with valsartan, and some of these patients have previously experienced angioedema with other medications, including ACE inhibitors. Valsartan should be discontinued immediately if angioedema develops, and the resumption of valsartan is prohibited.

CHF / post-myocardial infarction period

In patients with CHF or after a previous myocardial infarction, starting treatment with valsartan, there is often a slight decrease in blood pressure, and therefore, it is recommended to control blood pressure at the beginning of therapy. If the recommended dosage regimen is followed, it is usually not necessary to discontinue valsartan due to hypotension. Assessment of patients with CHF should include an assessment of renal function.

Due to the inhibition of the RAAS system, some patients may have impaired renal function. In patients with CHF of NYHA functional class III-IV, whose renal function depends on the state of RAAS, treatment with ACE inhibitors and ARA II may be accompanied by oliguria and/or increased azotemia and, in rare cases, the development of acute renal failure and / or death. Therefore, in these categories of patients, renal function should be evaluated before using valsartan, as well as periodically during treatment with the drug.

Combination therapy for arterial hypertension

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

Combination therapy in the period after myocardial infarction

It is possible to use valsartan in combination with other medications used after a 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 monotherapy with valsartan or an ACE inhibitor in terms of overall mortality for any reason.

Combination therapy for CHF

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

Triple combination therapy with ACE inhibitors, beta-blockers and valsartan is not recommended in this category of patients.

Double blockade of the RAAS

Severe blood pressure reduction, syncope, stroke, hyperkalemia, and impaired renal function (including acute renal failure) have been reported in sensitive patients treated with drugs that affect the RAAS, especially when combined with them. Caution should be exercised when combining ARA II, including valsartan, with other drugs that block RAAS, such as ACE inhibitors or aliskiren.

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

Concomitant use of ARA 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 are no data on the effect of Valz Combi on the ability to drive vehicles and mechanisms.

Due to the possible occurrence of dizziness or increased fatigue, care should be taken when driving vehicles or working with mechanisms.

Form of production

Film-coated tablets,5 mg + 80 mg,5 mg +160 mg,10 mg + 160 mg.

7 or 14 tablets in a PVC blister/PVDH/Al.

4 blisters of 7 tablets; 2 or 7 blisters of 14 tablets together with the instructions for use in a cardboard pack with the control of the first opening.

Storage conditions

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

Shelf

life is 2 years. Do not use after the expiration date.

Active ingredient

Amlodipine, Valsartan

Conditions of release from pharmacies

By prescription

Dosage form

Tablets