KKo-Vamloset pills 10mg+160mg+25mg, 30pcs

Composition

1 film-coated tablet,5 mg + 160 mg + 12.5 mg/10 mg + 160 mg + 12.5 mg/10 mg + 160 mg + 25 mg contains:

Core:

Active ingredients:

Amlodipine Besylate (Amlodipine besylate) 6.94 mg/13.88 mg/13.88 mg, equivalent to Amlodipine 5.00 mg/10.00 mg/10.00 mg

Valsartan A, substance-granules 251.35 mg/251.35 mg/251.35 mg

[Active ingredient of the granule substance: valsartan 160.00 mg/160.00 mg/160.00 mg

Excipients of the granule substance: microcrystalline cellulose (type 200), croscarmellose sodium, povidone K-25, sodium lauryl sulfate]

Hydrochlorothiazide 12.50 mg/12.50 mg/25.00 mg

Auxiliary substances:

Mannitol, magnesium stearate, colloidal silicon dioxide

Film shell:

Film-forming mixture:

– polyvinyl alcohol

-macrogol-3350

-titanium dioxide (E171)

– talcum powder

Iron oxide red dye (E 172) (for tablets 10 mg + 160 mg + 12.5 mg)

Iron oxide yellow dye (E 172) (for tablets 10 mg + 160 mg + 25 mg)

Pharmacological action

combined antihypertensive agent (slow calcium channel blocker [BMCC] + angiotensin II receptor antagonist [ARA II] + diuretic)

Clinical Pharmacology

Pharmacodynamics

The drug Co-Vamloset is a combination of three antihypertensive components with a complementary mechanism for controlling blood pressure (BP): amlodipine (a dihydropyridine derivative) –BMCC, valsartan –ARA II and hydrochlorothiazide (HCTZ) – a thiazide diuretic. The combination of these components leads to a more pronounced decrease in blood pressure compared to that on the background of monotherapy with each drug separately.

 

 

Amlodipine

Amlodipine, which is part of the drug Co-Vamloset, 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. Experimental data show that amlodipine binds to dihydro-and non-dihydropyridine active sites of the receptor. Reduction of cardiomyocytes and vascular wall myocytes occurs due to the penetration of calcium ions into them through calcium channels.

In patients with arterial hypertension, the use of amlodipine in therapeutic doses 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 activity with prolonged use.

Plasma concentrations of the drug correlate with the therapeutic response in both young and elderly patients. In hypertensive patients with normal renal function, amlodipine in therapeutic doses leads to a decrease in renal vascular resistance, an increase in glomerular filtration rate (GFR) and effective renal plasma blood flow without changing the filtration fraction and severity of proteinuria.

As with other BMCs, patients with normal left ventricular (LV) function experienced changes in the hemodynamic parameters of cardiac function at rest and during exercise: a slight increase in the cardiac index without a significant effect on the maximum rate of increase in LV pressure, end-diastolic pressure and LV volume. Hemodynamic studies in intact animals and healthy volunteers have shown that 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 and does not affect atrioventricular conduction in intact animals and healthy volunteers. 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 electrocardiographic parameters.

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

Valsartan

Valsartan is an active and specific ARA II intended for oral use. It acts selectively on AT1 subtype receptors, which are responsible for the effects of angiotensin II. An increase in the plasma concentration of unbound angiotensin II due to AT1-receptor blockade under the influence of valsartan can stimulate unblocked_AT2-receptors, which counteract the effects of AT1-receptor stimulation. Valsartan does not have any pronounced agonistic activity against AT1receptors. The affinity of valsartan for AT1 subtype receptors is approximately 20,000 times higher than for AT2 subtype receptors.

Valsartan does not inhibit the angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II and causes the breakdown of bradykinin. Since the use of ARA II does not cause ACE inhibition and accumulation of bradykinin or substance P, the development of dry cough is unlikely.

In comparative clinical trials of valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (p In a clinical study that included patients who had previously developed a dry cough during treatment with an ACE inhibitor, this complication was noted in 19.5% of cases when treated with valsartan, and in 19.0% of cases when treated with a thiazide diuretic. At the same time, in the group of patients treated with an ACE inhibitor, cough was observed in 68.5% of cases (p

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 appears within 2 hours in most patients after a single oral dose of valsartan. The maximum decrease in blood pressure develops in 4-6 hours. After taking valsartan, the duration of the antihypertensive effect persists for more than 24 hours. With repeated use, the maximum reduction in blood pressure, regardless of the oral dose, is usually achieved within 2-4 weeks and maintained at the achieved level during long-term therapy. Abrupt discontinuation of valsartan is not accompanied by a sharp increase in blood pressure or other undesirable clinical consequences. The use of valsartan in patients with chronic heart failure (CHF) (NYHA functional class II-IV) leads to a significant reduction in the number of hospitalizations for cardiovascular diseases (which is especially pronounced in patients who do not receive ACE inhibitors or beta-blockers). When taking valsartan in patients with left ventricular insufficiency (with stable hemodynamic parameters) or with impaired LV function after a myocardial infarction, a decrease in cardiovascular mortality is noted.

HCTZ

The point of application of thiazide diuretics is the distal convoluted renal tubules. When thiazide diuretics are applied to highly sensitive receptors of the distal tubules of the cortical layer of the kidneys, the reabsorption of sodium and chlorine ions is suppressed. The suppression of the co-transport system of sodium and chlorine ions seems to occur due to competition for the binding sites of chlorine ions in this system. As a result, the removal of sodium and chlorine ions increases approximately equally. As a result of diuretic action, there is a decrease in the volume of circulating blood (BCC), which increases the activity of renin, aldosterone secretion, excretion of potassium by the kidneys and, consequently, a decrease in the content of potassium in the blood serum.

Pharmacokinetics

The pharmacokinetic parameters of amlodipine, valsartan, and HCTZ are linear.

Amlodipine

Suction

After oral use of amlodipine in therapeutic doses, the maximum concentration (cmax) in blood plasma 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 is approximately 21 l / kg. In vitro studies with amlodipine 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 from blood plasma is biphasic with a half-life (_half-life) of approximately 30 to 50 hours.Steady-state plasma concentrations are reached after prolonged use for 7-8 days. 10% is excreted unchanged,60% – in the form of metabolites.

Valsartan

Suction

After oral use of valsartan_{, cmax}in blood plasma is reached in 2-4 hours. The average absolute bioavailability is 23%.

When taken with food, there is a decrease in the bioavailability (the value of area under the curve “concentration-time” [AUC]) of 40% and_max in blood plasma by almost 50%, although approximately 8 hours after use of valsartan valsartan inside the concentration in blood plasma in people taking it with food, and in the group treated with valsartan on an empty stomach, even. 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.

Distribution

The volume of distribution (Vd) of valsartan at steady state after intravenous use was about 17 liters, which indicates that there is no extensive distribution of valsartan in 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 is a descending multi-exponential pattern (Half-alpha < 1 hour and_half-beta about 9 hours). 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 and its renal clearance is 0.62 l / h (about 30% of the total clearance). The_half-life is 6 hours.

HCTZ

Suction

Absorption of HCTZ after oral use is rapid (the time to reach_cmaxin blood plasma is about 2 hours). On average, the increase in AUC is linear and proportional to the oral dose in the therapeutic range. Both an increase and a decrease in the systemic bioavailability of HCTZ compared to fasting food intake have been reported with concomitant food intake. The magnitude of this effect is small and clinically insignificant. The absolute bioavailability of HCTZ after oral use is 70%.

Distribution

The kinetics of distribution and elimination in general is described as a biexponential decreasing function with_half-life-6-15 hours. With repeated use, the kinetics of HCTZ does not change, and when applied once a day, the accumulation is minimal. The apparent volume of distribution is 4-8 l/kg. 40-70% of HCTZ circulating in the blood plasma binds to plasma proteins, mainly albumins. HCTZ also accumulates in red blood cells at concentrations approximately 3 times higher than those in blood plasma.

The metabolism

of HCT is excreted unchanged.

The elimination_half-life of the final phase is 6-15 hours. With repeated use of the drug, the kinetics of HCTZ does not change, with the appointment of the drug once a day, the accumulation of the drug is minimal. More than 95% of the absorbed HCT dose is excreted unchanged by the kidneys.

Amlodipine+valsartan+HCT

After oral use of Co-Vamloset S_{, the maximum} values of amlodipine, valsartan, and HCTZ in blood plasma are reached in 6-8,3, and 2 hours, respectively.

Pharmacokinetics in selected groups of patients

Patients under 18 years

of age The pharmacokinetic characteristics of the use of Co-Vamloset in children under 18 years of age have not been established.

Elderly patients (over 65 years of age)

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_half-life.

In elderly patients, systemic exposure to valsartan was slightly more pronounced than in young patients, but this was not clinically significant.

There are limited data on a decrease in the systemic clearance of HCT in patients over 65 years of age (healthy volunteers or patients with arterial hypertension) compared with young patients.

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 valsartan systemic exposure (AUC) in patients with varying degrees of renal impairment.

In the presence_{of renal insufficiency}, the average plasma cmax and HCT AUC values increase, and the rate of excretion decreases. In patients with mild to moderate renal impairment_{, the half}-life is almost doubled. Renal clearance of HCTZ in patients with impaired renal function is reduced compared to normal values (about 300 ml / min).

Co-Vamloset is contraindicated in patients with severe renal insufficiency (creatinine clearance < 30 ml / min), anuria, and should be used with caution in patients with moderate renal impairment (estimated GFR ≥ 30 ml / min/1.73 m2 of body surface area).

Patients with impaired liver function

There are only limited clinical data on the use of amlodipine in 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) hepatic impairment, the bioavailability (AUC) of valsartan doubled compared to healthy subjects (of appropriate age, gender, and body weight). Co-Vamloset is contraindicated in patients with impaired liver function (see sections “Contraindications” and “Dosage and use”).

Indications

Arterial hypertension of II and III degrees.

Use during pregnancy and lactation

Like any drug that affects the renin-angiotensin-aldosterone system (RAAS), Co-Vamloset should not be used in women planning pregnancy. When prescribing any drug that affects the RAAS, the doctor should inform women of childbearing age about the potential dangers of these drugs during pregnancy.

The use of Co-Vamloset during pregnancy is contraindicated.

It is known that the use of ACE inhibitors that affect the RAAS in the second and third trimesters of pregnancy leads to damage or death of the developing fetus. Given the mechanism of action of ARA II, the risk to the fetus cannot be excluded. According to a retrospective analysis, the use of ACE inhibitors in the first trimester of pregnancy was accompanied by the development of fetal and newborn pathology. HCTZ passes through the placenta. When using thiazide diuretics, including HCT, during pregnancy, fetal or neonatal jaundice or thrombocytopenia may develop, as well as other adverse reactions observed in adult patients. 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. Data on the use of amlodipine in pregnant women are insufficient to assess its effect on the fetus.

If pregnancy is diagnosed during treatment with Co-Vamloset, the drug should be discontinued as soon as possible.

It is not known whether valsartan and/or amlodipine are excreted in breast milk. In experimental studies, the excretion of valsartan in breast milk was noted. HCT is also excreted in breast milk. The use of Co-Vamloset is contraindicated during breastfeeding.

Contraindications

·                    Hypersensitivity to amlodipine, valsartan, HCTZ, other derivatives of sulfonamide and dihydropyridine series, as well as other auxiliary components of the drug.

·                   Hereditary angioedema, or edema in patients with previous ARA II therapy

· * Pregnancy, pregnancy planning, and lactation.

·                    Liver failure, biliary cirrhosis and cholestasis.

·                    Severe renal impairment (CC

* Hypokalemia, hyponatremia, hypercalcemia, and hyperuricemia with clinical manifestations that are refractory to adequate therapy.

* Under 18 years of age (efficacy and safety have not been established).

·  Severe arterial hypotension (systolic blood pressure

* Clinically significant aortic stenosis.

* Hemodynamically unstable heart failure after acute myocardial infarction.

* Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and / or moderate to severe renal impairment (GFR

* Concomitant use with ACE inhibitors in patients with diabetic nephropathy.

Interaction

Amlodipine

Monotherapy with amlodipine is not observed clinically significant interactions with thiazide diuretics, beta-blockers, ACE inhibitors, a long-acting nitrates, sublingual nitroglycerin for use, digoxin, warfarin, atorvastatin, sildenafilum, aluminium – and magnesium hydroxide, simethicone a, cimetidine, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics and hypoglycemic drugs for oral use.

Concomitant use of amlodipine and ethanol does not affect the pharmacokinetics of the latter.

Inhibitors of the CYP3A4 isoenzyme

When amlodipine was co-administered at a dose of 5 mg/day with diltiazem at a dose of 180 mg/day in elderly patients with arterial hypertension, there was a 1.6-fold increase in systemic exposure to amlodipine. When using amlodipine with potent inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole, itraconazole and ritonavir), an even more pronounced increase in systemic exposure to amlodipine is possible. Caution should be exercised when using amlodipine with inhibitors of the CYP3A4 isoenzyme.

Due to inhibition of the CYP3A4 isoenzyme, the bioavailability of amlodipine may increase when taken concomitantly with grapefruit juice. However, in a clinical study in healthy volunteers, no significant changes in pharmacokinetics were detected when taking amlodipine at a dose of 10 mg with 240 ml of grapefruit juice.

Inducers of the CYP3A4 isoenzyme

Since the use of amlodipine with inducers of the CYP3A4 isoenzyme (for example, carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidone, rifampicin, herbal preparations containing St. John’s wort) can lead to a pronounced decrease in its concentration in blood plasma, caution should be exercised when using amlodipine with inducers of the CYP3A4 isoenzyme.

Simvastatin

Multiple simultaneous use of simvastatin 80 mg / day and amlodipine 10 mg / day leads to a 77% increase in simvastatin plasma exposure. It is recommended to reduce the dose of simvastatin to 20 mg / day in patients taking amlodipine.

Tacrolimus

There is a risk of increased serum concentrations of tacrolimus when co-administered with amlodipine. In order to avoid tacrolimus toxicity, when using amlodipine in patients receiving tacrolimus, it is necessary to monitor the serum concentration of tacrolimus and adjust its dose if necessary.

Clarithromycin

Clarithromycin is an inhibitor of the CYP3A4 isoenzyme. There is an increased risk of hypotension in patients taking clarithromycin concomitantly with amlodipine. When amlodipine is co-administered with clarithromycin, careful monitoring of patients is recommended.

Valsartan

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

Double blockade of the RAAS with ARA II, ACE inhibitors or aliskiren

Concomitant use of ARA II with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and / or with moderate or severe renal insufficiency (GFR Concomitant use of ARA IIc with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Concomitant use of ARA II with other drugs that affect the RAAS leads to an increase in the frequency of cases of arterial hypotension, hyperkalemia, and impaired renal function. It is necessary to monitor blood pressure, renal function, and plasma electrolyte levels when using Co-Vamloset with other drugs that affect the RAAS.

Drugs and substances that affect the content of potassium in the blood serum

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

NSAIDs, including selective cyclooxygenase-2 (COX-2)inhibitors

It is possible to reduce the diuretic and antihypertensive effects of valsartan when used simultaneously with NSAIDs, including selective COX-2 inhibitors, for example, with salicylic acid derivatives, Indometacin. Moreover, in elderly patients with concomitant hypovolemia (including due to diuretics) or impaired renal function, concomitant use of ARA II and NSAIDs, including selective COX-2 inhibitors, may lead to deterioration of renal function. Monitoring of renal function is recommended in this group of patients.

Carrier proteins

Concomitant use of valsartan with 1-in-1 OATP transporter protein inhibitors (rifampicin, cyclosporin) and with the MRP2 transporter protein inhibitor (ritonavir) It may lead to an increase in the systemic bioavailability of valsartan.

HCTZ

Other antihypertensive drugs

Thiazide diuretics enhance the antihypertensive effect of other antihypertensive drugs (including guanethidine, methyldopa, beta-blockers, vasodilators, BMCC, ACE inhibitors, ARA II, direct renin inhibitors).

Curare-like muscle relaxants

Thiazide diuretics, including HCT, potentiate the action of curare-like muscle relaxants (for example, tubocurarin chloride).

NSAIDs

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

Medications that affect serum potassium The

risk of hypokalemia increases with the simultaneous use of other diuretics, glucocorticosteroids, adrenocorticotropic hormone, amphotericin B, carbenoxolone and acetylsalicylic acid (at a dose of more than 3 g).

Medications that affect the sodium content in the blood serum

The hyponatremic effect caused by diuretics may be increased when used concomitantly with antidepressants, antipsychotics, anticonvulsants, etc. Caution should be exercised when using Co-Vamloset with the above drugs for a long time.

Hypoglycemic agents

When using HCT, there is a change in glucose tolerance, and therefore in patients with diabetes mellitus, it may be necessary to adjust the doses of insulin and hypoglycemic agents for oraluse.

Since lactic acidosis may occur when HCT is used with metformin (due to impaired renal function during HCT therapy), caution should be exercised when using Co-Vamloset in patients receiving metformin treatment.

Cardiac Glycosides

Hypokalemia and hypomagnesemia (undesirable effects of thiazide diuretics) may contribute to the development of cardiac arrhythmias in patients receiving cardiac glycosides.

N – and m-holinoblockers

N-and m-holinoblockers(including atropine, biperiden) can increase the bioavailability of HCT, which is associated with a decrease in gastrointestinal motility and gastric emptying rate. Accordingly, gastrointestinal motility stimulants (cisapride) may reduce the bioavailability of HCT.

Anion exchange resins

HCT absorption decreases in the presence of colestyramine and colestipol. HCT should be taken 4 hours before or 4-6 hours after taking these compounds.

Vitamin D and calcium salts

Concomitant use of HCT with vitamin Dcalcium supplementation may lead to an increase in serum calcium levels.

Cyclosporine

Concomitant use of HCT and cyclosporine increases the risk of hyperuricemia and gout-like symptoms.

Methyldopa

Cases of hemolytic anemia have been reported with concomitant use of HCT and methyldopa.

Other types of interaction

Concomitant use of thiazide diuretics, including HCT, may lead to an increase in the frequency of hypersensitivity reactions to allopurinol, an increased risk of side effects of amantadine, an increase in the hyperglycemic effectof diazoxide, a decrease in renal excretion of drugs with cytotoxic effects (for example, cyclophosphamide, methotrexate), and to potentiation of their myelosuppressive effect. HCT can also reduce the body’s response to the use of pressor amines (norepinephrine), but this effect is clinically insignificant and cannot prevent the simultaneous use of drugs.

Ethanol, barbiturates and narcotic drugs

Concomitant use with HCT may contribute to the development of orthostatic hypotension.

Common drug interactions for valsartan and HCT

Lithium preparations

When lithium preparations were co-administered with ACE inhibitors, ARA II inhibitors, or thiazide diuretics, a reversible increase in serum lithium content and the associated increase in toxic manifestations were observed. The risk of toxic effects associated with the use of lithium preparations may further increase with simultaneous use with Co-Vamloset, since the renal clearance of lithium preparations slows down under the influence of thiazide diuretics. In this regard, it is recommended to conduct careful monitoring of the lithium content in the blood serum.

How to take, course of use and dosage

Co-Vamloset should be taken orally with a small amount of water, regardless of the meal time.

The recommended daily dose is 1 tablet containing amlodipine + valsartan + HCT at a dose of 5 mg + 160 mg + 12.5 mg,10 mg + 160 mg + 12.5 mg (as Co – Vamloset, film-coated tablets,5 mg + 160 mg + 12.5 mg,10 mg + 160 mg + 12.5 mg) or 1 tablet containing amlodipine + valsartan + HCT at a dose of 10 mg + 160 mg + 25 mg (as a drug Co-Vamloset, film-coated tablets,10 mg + 160 mg + 25 mg).

The drug Co-Vamloset is taken once a day.

For convenience, patients receiving monotherapy with amlodipine, valsartan and HCTZ in separate tablets can be transferred to therapy with Co-Vamloset, which contains the same doses of active ingredients. If there is insufficient blood pressure control on the background of double combination therapy (valsartan+HCT, amlodipine+valsartan and amlodipine+HCT), patients can be transferred to triple combination treatment with Co-Vamloset in appropriate doses. The dose of Co-Vamloset is selected after previously performed titration of doses of monocomponent drugs containing active substances that are part of the drug Co-Vamloset. If you need to change the dose of one of the active substances in the composition of the drug Co-Vamloset (for example, in connection with a newly diagnosed disease, a change in the patient’s condition or drug interaction), then individual selection of doses of individual components is necessary.

Patients with sodium deficiency and / or hypovolemia, such as those receiving high-dose diuretics, may develop symptomatic hypotension at the start of Co-Vamloset therapy. This combination should be used only after correction of hyponatremia and / or hypovolemia.

If the patient has dose-dependent side effects when using double combination therapy with any components of the drug Co-Vamloset, to achieve a comparable reduction in blood pressure, it is possible to use the drug Co-Vamloset containing a lower dose of the active component that caused this side effect.

You can increase the dose 2 weeks after the start of therapy.

The maximum antihypertensive effect of Co-Vamloset is observed 2 weeks after increasing the dose. The maximum dose is 10 mg + 320 mg + 25 mg per day.

Use in patients over 65 years of age

No dose adjustment is required. In patients of this category, if necessary, it is possible to reduce the initial dose to the lowest dose of amlodipine, i. e. 1 tablet containing amlodipine + valsartan + HCTZ at a dose of 5 mg + 160 mg + 12.5 mg (in the form of Co-Vamloset, film-coated tablets,5 mg + 160 mg + 12.5 mg) or 5 mg + 160 mg + 25 mg (in the form of Co-Vamloset, film-coated tablets,5 mg + 160 mg +25 mg)..

Use in children and adolescents under 18 years of age

Because the safety and efficacy of Co-Vamlosetu in children and adolescents (under 18 years of age) not established, the drug is not recommended for use in patients of this category.

Patients with impaired renal function

For patients with mild to moderate renal impairment (GFR ≥ 30 ml/min/1.73 m2 body surface area, but ≤ 90 ml/min/1.73 m2 body surface area), no initial dose adjustment is required. The drug should not be used in patients with severe renal impairment (GFR

Use of thiazide diuretics in monotherapy in patients with severe renal impairment (GFR

Patients with impaired liver function

Due to the presence of valsartan, HCTZ and amlodipine, Co-Vamloset is contraindicated in patients with severe hepatic impairment (> 9 points on the Child-Pugh scale). In patients with mild or moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg of valsartan, and therefore Co-Vamloset (contains 160 mg of valsartan) cannot be used in this group of patients (see sections “Contraindications”, “Special instructions” and ” Pharmacological properties. Pharmacokinetics”). Recommendations for the dosage of amlodipine in patients with mild or moderate hepatic impairment have not been developed. In patients of this category, if necessary, the drug with the lowest dose of amlodipine should be prescribed.

Overdose

Data on drug overdose cases are currently unavailable.

Amlodipine

Overdose of amlodipine can lead to excessive peripheral vasodilation and possible reflex tachycardia. There have also been reports of a marked and prolonged decrease in blood pressure, up to the development of shock with a fatal outcome.

Valsartan

With an overdose of valsartan, you can expect the development of a pronounced decrease in blood pressure and dizziness.

If there is a marked decrease in blood pressure, the patient should be given a horizontal position with raised legs and take active measures to maintain the activity of the cardiovascular system, including regular monitoring of the activity of the heart and respiratory system, BCC and the amount of urine released.

Vasopressors may be used to maintain normal vascular tone in the absence of contraindications. If Co-Vamloset has been taken recently, vomiting or gastric lavage may be effective. The use of activated charcoal in healthy volunteers was accompanied by a decrease in the absorption of amlodipine.

Valsartan and amlodipine are not removed by hemodialysis, whereas hemodialysis may be effective in removing HCT.

Description

Tablets 5 mg + 160 mg + 12.5 mg:

Oval, biconvex tablets, film-coated in white or almost white color with the inscription K 1 on one side.

View at the break: white or almost white rough surface with a film shell of white or almost white color.

Tablets 10 mg + 160 mg + 12.5 mg:

Oval, biconvex tablets, covered with a pink film-coated surface with the K 2 inscription on one side.

View at the break: white or almost white rough surface with a pink film shell.

Tablets 10 mg + 160 mg + 25 mg:

Oval, biconvex tablets, covered with a film-coated brown-yellow color with an engraving K 4 on one side.

View at the break: white or almost white rough surface with a film shell of brown-yellow color.

Special instructions

If you have any of the following medical conditions, tell your doctor before taking this medicine.

Caution should be exercised when using the drug in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, in conditions accompanied by a decrease in BCC and water-electrolyte disorders: nephropathies accompanied by loss of salts, prerenal (cardiogenic) renal dysfunction, in patients with hypercalcemia, in patients with mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy, hypokalemia, hyponatremia, hypomagnesemia, hypochloremia, in patients with CHF of NYHA functional class III-IV, with acute coronary syndrome, with diabetes mellitus, with systemic lupus erythematosus, with hyperuricemia, elevated plasma cholesterol and triglyceride concentrations, in patients with angle-closure glaucoma, in patients with a history of non-melanoma skin cancer (NSCC) (see the section “Special instructions”), as well as in patients after kidney transplants. Caution should be exercised when using the drug in elderly patients.

Caution should be exercised when Co-Vamlosse is co-administered with potassium salts, potassium-sparing diuretics, potassium-containing food salt substitutes, as well as with medications that may cause an increase in the potassium content in blood plasma (for example, heparin).

Use in children and adolescents under 18 years of age

Because the safety and efficacy of Co-Vamlosetu in children and adolescents (under 18 years of age) not established, the drug is not recommended for use in patients of this category.

Use in patients over 65 years of age

No dose adjustment is required. In patients of this category, if necessary, it is possible to reduce the initial dose to the lowest dose of amlodipine, i. e. 1 tablet containing amlodipine + valsartan + HCTZ at a dose of 5 mg + 160 mg + 12.5 mg (in the form of Co-Vamloset, film-coated tablets,5 mg + 160 mg + 12.5 mg) or 5 mg + 160 mg + 25 mg (in the form of Co-Vamloset, film-coated tablets,5 mg + 160 mg +25 mg)..

Patients with impaired renal function

For patients with mild to moderate renal impairment (GFR ≥ 30 ml/min/1.73 m2 body surface area, but ≤ 90 ml/min/1.73 m2 body surface area), no initial dose adjustment is required. The drug should not be used in patients with severe renal impairment (GFR

Use of thiazide diuretics in monotherapy in patients with severe renal impairment (GFR

Patients with impaired liver function

Due to the presence of valsartan, HCTZ and amlodipine, Co-Vamloset is contraindicated in patients with severe hepatic impairment (> 9 points on the Child-Pugh scale). In patients with mild or moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg of valsartan, and therefore Co-Vamloset (contains 160 mg of valsartan) cannot be used in this group of patients (see sections “Contraindications”, “Special instructions” and ” Pharmacological properties. Pharmacokinetics”). Recommendations for the dosage of amlodipine in patients with mild or moderate hepatic impairment have not been developed. In patients of this category, if necessary, the drug with the lowest dose of amlodipine should be prescribed.

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

Sodium deficiency and / or hypovolemia

Severe arterial hypotension, including orthostatic hypotension, was observed in 1.7% of patients receiving the maximum dose of the combination of amlodipine + valsartan + HCT (10 mg + 320 mg + 25 mg) compared to 1.8% of patients receiving the combination of valsartan + HCT (320 mg + 25 mg),0.4% of patients receiving the combination of amlodipine + valsartan (10 mg + 320 mg) and 0.2% of patients receiving the combination of amlodipine + HCT (25 mg + 10 mg) in a controlled trial involving patients with moderate or severe uncomplicated arterial hypertension.

Patients with sodium deficiency and/or hypovolemia, such as those receiving high-dose diuretics, may develop symptomatic hypotension at the start of Co-Vamloset therapy. This combination should be used only after correction of hyponatremia and / or hypovolemia.

In case of severe hypotension during the use of Co-Vamloset, the patient should be placed in a supine position and, if necessary, an intravenous infusion of 0.9% sodium chloride solution should be performed. Treatment with the drug can be continued after blood pressure stabilizes.

Changes in the content of electrolytes in blood plasma

Ko-Vamloset

In a controlled study, the effects of 320 mg valsartan and 25 mg HCT on serum potassium were almost balanced in many patients treated with the combination of amlodipine + valsartan + HCT. In other patients, one of the effects may have prevailed. Periodic determination of the electrolyte content in the blood plasma in order to detect a possible electrolyte imbalance should be performed at specified intervals.

Periodic determination of serum electrolytes, in particular potassium, should be performed at appropriate intervals to identify possible electrolyte disturbances, especially in patients with risk factors, such as impaired renal function, the use of other medications, or the presence of a history of electrolyte disturbances.

Valsartan

Concomitant use with dietary supplements containing potassium, potassium-sparing diuretics, eplerenone, potassium-containing salt substitutes, or other drugs that may cause an increase in the content of potassium in blood plasma (for example, with heparin) is not recommended. The potassium content in the blood plasma should be monitored.

HCTZ

Therapy with Co-Vamloset should be started only after the elimination of hypokalemia and concomitant hypomagnesemia. Thiazide diuretics may contribute to the recurrence of hypokalemia or worsen existing hypokalemia. Thiazide diuretics should be used with caution in patients with conditions with increased potassium loss, such as nephropathy, and prerenal (cardiogenic) renal dysfunction. If hypokalemia develops during treatment with HCT, the use of Co-Vamloset should be discontinued until stable normalization of the potassium content in the blood plasma.

Thiazide diuretics can contribute to the re-development of hyponatremia and hypochloremic alkalosis, or aggravate existing hyponatremia. Hyponatremia was observed, accompanied by neurological symptoms (nausea, progressive disorientation, apathy). Treatment of HCTZ should be started only after the elimination of existing hyponatremia. In the case of severe or rapidly developing hyponatremia associated with the use of a combination of amlodipine + valsartan + HCT, treatment should be discontinued until the blood sodium content normalizes.

All patients receiving thiazide diuretics should be monitored periodically for electrolyte disturbances, especially for potassium, sodium and magnesium levels in the blood plasma.

Impaired renal function

Thiazide diuretics may contribute to the development of azotemia in patients with chronic kidney disease. When using Co-Vamloset in patients with impaired renal function, it is recommended to periodically monitor the content of electrolytes (including potassium), serum creatinine and uric acid concentrations. Co-Vamloset is contraindicated in patients with severe renal impairment(CC).

Patients with mild to moderate renal impairment (GFR ≥ 30 ml/min/1.73 m2 of body surface area) do not need to adjust the dose of Co-Vamloset.

Renal artery stenosis

In patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, Co-Vamloset may be associated with increased serum urea and creatinine concentrations, so Co-Vamloset should be used with caution in such patients.

Kidney transplantation

To date, there are no data on the safe use of the combination of amlodipine + valsartan + HCT in patients after kidney transplantation.

Impaired liver function

Valsartan is mainly excreted unchanged in the bile. The_half-life of amlodipine is long, and AUC values are higher in patients with impaired liver function; there are no recommendations for dose selection. In patients with mild or moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg of valsartan, so Co-Vamloset is contraindicated in these patients.

Angioedema

Patients treated with valsartan have experienced angioedema, including laryngeal and pharyngeal edema that causes airway obstruction and/or swelling of the face, lips, larynx, and / or tongue. Some of these patients have previously experienced angioedema with other medications, including ACE inhibitors. If angioedema develops, Co-Vamloset should be discontinued immediately and the drug should not be used again.

CHF and ischemic heart disease/post-myocardial infarction status

In susceptible patients, changes in renal function may occur due to RAAS inhibition. In patients whose renal function depends on the activity of the RAAS (for example, patients with CHF of functional class III-IV [NYHA classification]), therapy with ACE inhibitors and ARA II may be accompanied by oliguria and / or progressive azotemia and in rare cases may lead to acute renal failure and death. Similar outcomes were observed with valsartan therapy. Assessment of patients with CHF or post – myocardial infarction should always include an examination of renal function.

In the long-term placebo-controlled study (PRAISE-2) of amlodipine, patients with NYHA functional class III-IV CHF of non-ischemic etiology were treated with amlodipine with an increased incidence of pulmonary edema, despite a slight difference in the incidence of exacerbation of heart failure compared to placebo.

In patients with NYHA functional class III-IV CHF, BMCC, including amlodipine, should be used with caution, as they may increase the risk of cardiovascular events and death.

Caution is recommended in patients with CHF and coronary heart disease, as the available data in these patient populations are limited.

Aortic and mitral valve stenosis

As with other vasodilators, caution should be exercised in patients with mitral valve stenosis or severe aortic valve stenosis of low severity.

Pregnancy

ARA II therapy should not be initiated during pregnancy. Patients planning pregnancy should switch to alternative antihypertensive therapy with an established safety profile for use during pregnancy. If pregnancy is diagnosed, ARA II therapy should be stopped immediately or switched to alternative antihypertensive therapy with an established safety profile for use during pregnancy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not use ARA II (including valsartan), since the RAAS is not activated in such patients. Therefore, Co-Vamloset should not be used in this population.

Systemic lupus erythematosus

Exacerbation or development of systemic lupus erythematosus has been reported with the use of thiazide diuretics, including HCT.

Other metabolic disorders

Thiazide diuretics, including HCT, can alter glucose tolerance and increase serum cholesterol, triglycerides, and uric acid concentrations. In patients with diabetes mellitus, it may be necessary to adjust the dose of insulin or hypoglycemic drugs for oral use.

Due to the content of the HCTZ component, Co-Vamloset is contraindicated in symptomatic hyperuricemia. HCT can increase the concentration of uric acid in the blood serum due to a decrease in uric acid clearance and cause or exacerbate hyperuricemia, as well as contribute to the development of gout in susceptible patients.

Thiazides reduce the excretion of calcium by the kidneys and can cause periodic and slight increases in serum calcium concentrations in the absence of known calcium metabolism disorders. Co-Vamlocet is contraindicated in patients with hypercalcemia and should only be used after the existing hypercalcemia has been eliminated. Co-Vamloset should be discontinued if hypercalcaemia develops during treatment. Serum calcium concentrations should be monitored periodically during thiazide therapy. Severe hypercalcemia may be a sign of latent hyperparathyroidism. Before studying the function of the parathyroid glands, thiazide therapy should be interrupted.

Photosensitivity

Photosensitivity reactions have been reported with thiazide diuretics (see section “Side effects”). If a photosensitivity reaction develops during treatment with Co-Vamloset, it is recommended to discontinue therapy. If it is necessary to re-use the diuretic, it is recommended to protect the skin areas exposed to sunlight or artificial UV radiation.

Acute angle-closure glaucoma

HCTZ, being a sulfonamide, causes an idiosyncratic reaction leading to the development of acute transient myopia and acute angle-closure glaucoma. Symptoms include a sudden decrease in visual acuity or the appearance of pain in the eye, usually within a few hours or a week after starting the drug. If left untreated, acute angle-closure glaucoma can lead to permanent vision loss.

Primary therapy consists in stopping the use of HCT as soon as possible. If intraocular pressure remains uncontrolled, urgent conservative or surgical treatment may be required. Risk factors for acute angle-closure glaucoma may include a history of allergic reactions to sulfonamides and penicillin.

General information

Caution should be exercised in patients who have previously had hypersensitivity to other ARA II agents. Hypersensitivity reactions to HCT are more likely in patients with allergies and bronchial asthma.

Elderly patients (≥ 65 years)

Caution should be exercised, including frequent blood pressure monitoring, in elderly patients, as the available data in this patient population are limited.

Double blockade of the RAAS

Concomitant use of ACE inhibitors, ARA II or aliskiren is associated with a higher incidence of adverse events, such as hypotension, hyperkalemia and decreased renal function (including acute renal failure). If combination therapy by double blockade of the RAAS is considered absolutely necessary, it should only be carried out under the supervision of a specialist and with careful monitoring of renal function, blood plasma electrolytes and blood pressure.

Concomitant use of ARA IIc with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and / or with moderate or severe renal insufficiency (GFR Concomitant use of ARA IIc with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Hypertensive crisis

Do not use the drug Co-Vamloset for relief of hypertensive crises.

Doping test

When using the drug Co-Vamloset in athletes, positive results of a doping test are possible (due to the presence of HCT in the drug).

NMRC

Two pharmacoepidemiological studies using data from the Danish National Cancer Registry demonstrated an association between HCT intake and an increased risk of NSCLC-basal cell carcinoma and squamous cell carcinoma. The risk of developing NSCLC increased with an increase in the total (accumulated) dose of HCT. A possible mechanism for the development of NSCLC is the photosensitizing effect of HCT.

Patients taking HCT alone or in combination with other medications should be aware of the risk of developing NSCLC. Such patients are advised to have their skin examined regularly to identify any new suspicious lesions, as well as changes to existing skin lesions.

All suspicious skin changes should be reported to your doctor immediately. Suspicious skin areas should be examined by a specialist. To clarify the diagnosis, histological examination of skin biopsies may be required.

In order to minimize the risk of developing NSCLC, patients should be advised to take preventive measures, such as limiting exposure to sunlight and ultraviolet (UV) rays, as well as using appropriate protective equipment.

In patients with a history of NSCLC, it is recommended to reconsider the use of HCT.

Some side effects of the drug, including dizziness or visual disturbances, can negatively affect the ability to perform potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions (driving vehicles, working with moving mechanisms). Patients taking Co-Vamloset should be careful when driving vehicles and when working with moving mechanisms.

Form of production

Film-coated tablets,5 mg + 160 mg + 12.5 mg,10 mg + 160 mg + 12.5 mg,10 mg + 160 mg + 25 mg.

7,10,14,15 tablets in a contour cell package made of combined OPA/Al/PVC material and aluminum foil.1,2,4,8,12,14 contour cell packs (7 tablets each); 1,2,3,6,9 contour cell packs (10 tablets each); 1,2,4,6,7 contour cell packages (14 tablets each); 1,2,4,6 contour cell packages (15 tablets each) together with the instructions for use are placed in a cardboard pack.

Storage conditions

At a temperature not exceeding 25 °C, in the original contour cell packaging.

Keep out of reach of children.

Shelf

life is 2 years.

Do not use the drug after the expiration date.

Active ingredient

Amlodipine, Valsartan, Hydrochlorothiazide

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Hypertension