Co-valodip tablets 5 mg + 160 mg + 12.5 mg No. 30

Instructions for Co-valodip tablets 5 mg + 160 mg + 12.5 mg No. 30

Composition

active ingredient: amlodipine in the form of amlodipine besylate, valsartan, hydrochlorothiazide;

1 film-coated tablet contains 5 mg amlodipine as amlodipine besylate, 160 mg valsartan and 12.5 mg hydrochlorothiazide or 10 mg amlodipine as amlodipine besylate, 160 mg valsartan and 12.5 mg hydrochlorothiazide, or 10 mg amlodipine as amlodipine besylate, 160 mg valsartan and 25 mg hydrochlorothiazide;

excipients: microcrystalline cellulose (type 200), mannitol, magnesium stearate, croscarmellose sodium, povidone K 25, colloidal anhydrous silicon dioxide, sodium lauryl sulfate;

film coating: polyvinyl alcohol, macrogol 3350, titanium dioxide (E 171), talc, yellow iron oxide (E 172) (only for dosage 10 mg/160 mg/25 mg), red iron oxide (E 172) (only for dosage 10 mg/160 mg/12.5 mg).

Dosage form

Film-coated tablets.

Main physicochemical properties:

Co-Valodip, film-coated tablets, 5 mg/160 mg/12.5 mg: white or almost white, oval, biconvex, film-coated tablets, engraved with K1 on one side;

Co-Valodip, film-coated tablets, 10 mg/160 mg/12.5 mg: pink oval biconvex film-coated tablets, engraved with K2 on one side;

Co-Valodip, film-coated tablets, 10 mg/160 mg/25 mg: brownish-yellow oval biconvex film-coated tablets, engraved with K4 on one side.

Pharmacotherapeutic group

Angiotensin II antagonists, other combinations. Valsartan, amlodipine and hydrochlorothiazide.

ATX code C09D X01.

Pharmacological properties

Pharmacodynamics.

Co-Valodip contains 3 antihypertensive agents with complementary mechanisms of blood pressure control in patients with essential hypertension: amlodipine belongs to the class of calcium antagonists, valsartan to the class of angiotensin II antagonists, and hydrochlorothiazide to the class of thiazide diuretics. The combination of these three components is characterized by a complementary antihypertensive effect.

Amlodipine

Amlodipine, which is part of Co-Valodip, inhibits the transmembrane entry of calcium ions into the heart muscle and vascular smooth muscle. The mechanism of antihypertensive action of amlodipine occurs through a direct relaxing effect on vascular smooth muscle, causing a decrease in peripheral vascular resistance and blood pressure.

Experimental data confirm that amlodipine binds to dihydropyridine and non-hydropyridine binding sites. Contractility of cardiac muscle and vascular smooth muscle depends on the passage of extracellular calcium into these cells through specific ion channels. Amlodipine at therapeutic doses in patients with arterial hypertension causes vasodilation, which leads to a decrease in blood pressure in the supine and standing positions. This decrease in blood pressure is not accompanied by pronounced changes in heart rate or plasma catecholamine levels with prolonged use.

Plasma concentrations correlate with effect in both young and elderly patients.

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

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise in patients with normal ventricular function treated with amlodipine generally showed a small increase in cardiac index without significant effects on dP/dt and on left ventricular and diastolic pressure or volume. In hemodynamic studies, amlodipine did not produce a negative inotropic effect in intact animals or humans at therapeutic doses, even when administered concomitantly to humans with beta-blockers.

Amlodipine does not alter sinoatrial node function or atrioventricular conduction in healthy animals or humans. In clinical studies in which amlodipine was used in combination with beta-blockers in patients with hypertension or angina, no changes in electrocardiogram parameters were noted.

Positive clinical effects of amlodipine have been observed in patients with chronic stable angina, vasospastic angina, and angiographically confirmed coronary artery disease.

Valsartan

Valsartan is an orally active, potent and specific angiotensin II receptor antagonist (ARB). Valsartan acts selectively on the AT1 receptor subtype, which is responsible for the known effects of angiotensin II.

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

Hydrochlorothiazide

The site of action of thiazide diuretics is mainly the distal convoluted tubules of the kidneys. It has been confirmed that there are high-affinity receptors in the renal cortex, which are the main binding site for thiazide diuretics and inhibit NaCl transport into the distal convoluted tubules. The mechanism of action of thiazides is to inhibit Na+Cl– transporters, possibly by competing for Cl– sites, which in turn affects the mechanisms of electrolyte reabsorption: directly increases the excretion of sodium and chlorine to an approximately equivalent extent and indirectly, due to the diuretic effect, reduces plasma volume with subsequent increases in plasma renin activity, aldosterone secretion and urinary potassium excretion, as well as a decrease in serum potassium.

Pharmacokinetics.

Linearity

Amlodipine, valsartan and hydrochlorothiazide exhibit linear pharmacokinetics.

Amlodipine/valsartan/hydrochlorothiazide

After oral administration of the combination of amlodipine/valsartan/hydrochlorothiazide to healthy adult volunteers, peak plasma concentrations were reached within 6-8 hours, 3 hours and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan and hydrochlorothiazide from the combination product are similar to those observed when the components are administered as separate agents.

Amlodipine

Absorption: After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations were reached within 6–12 hours. Absolute bioavailability ranged from 64% to 80%. Food intake did not affect the bioavailability of amlodipine.

Distribution: The volume of distribution is approximately 21 L/kg. In vitro studies of amlodipine have shown that approximately 97.5% of the drug in circulating blood is bound to plasma proteins.

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

Elimination: Amlodipine is eliminated from plasma in two phases, with a terminal half-life of approximately 30–50 hours. Steady-state plasma levels are reached after 7–8 days of continuous dosing. 10% of the parent amlodipine and 60% of the metabolites of amlodipine are excreted in the urine.

Valsartan

Absorption. After oral administration of valsartan alone, peak concentrations are reached within 2–4 hours. The mean absolute bioavailability is 23%. Food intake reduces exposure (as determined by AUC) to valsartan by approximately 40% and the maximum plasma concentration (Cmax) by approximately 50%, although approximately 8 hours after administration, valsartan concentrations are similar in the fasted and fed groups. However, this decrease in AUC is not accompanied by a clinically significant reduction in therapeutic effect, and valsartan can be administered without regard to food intake.

Distribution: The volume of distribution of valsartan at steady state after intravenous administration is approximately 17 liters, indicating that valsartan is not extensively distributed. Valsartan is extensively bound to serum proteins (94–97%), mainly to serum albumin.

Biotransformation: Valsartan is not significantly transformed, with only approximately
20% of the dose is excreted as metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.

Elimination: Valsartan is excreted primarily in the feces (approximately 83% of the dose) and urine (approximately 13% of the dose), mainly as unchanged drug. After intravenous administration, plasma clearance of valsartan is about 2 l/h and renal clearance is 0.62 l/h (approximately 30% of total clearance). The elimination half-life of valsartan is 6 hours.

Hydrochlorothiazide

Absorption. Hydrochlorothiazide is rapidly absorbed after oral administration (Tmax approximately 2 hours). The increase in mean AUC is linear and dose-proportional over the therapeutic dose range. The effect of food on the absorption of hydrochlorothiazide, if any, is clinically insignificant. The absolute bioavailability of hydrochlorothiazide is 70% after oral administration.

Distribution: The apparent volume of distribution is 4–8 L/kg. Hydrochlorothiazide in the circulating blood is bound to plasma proteins (40–70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes in amounts approximately three times higher than plasma levels.

Elimination: Hydrochlorothiazide is eliminated from plasma with a terminal elimination half-life of 6 to 15 hours. There is no change in the kinetics of hydrochlorothiazide with repeated dosing, and accumulation is minimal with once-daily dosing. More than 95% of the absorbed dose is excreted unchanged in the urine. Renal clearance consists of passive filtration and active tubular secretion.

Certain patient groups

Children (under 18 years of age)

There are no pharmacokinetic data in children.

Elderly patients (aged 65 years and over)

The time to reach Cmax of amlodipine is similar in young and elderly patients. In elderly patients, the clearance of amlodipine tends to decrease, resulting in an increase in the area under the curve (AUC) and half-life. The mean systemic AUC of valsartan is 70% higher in elderly patients than in younger patients, so caution should be exercised when increasing the dose in such patients.

Systemic exposure to valsartan is slightly higher in elderly patients compared to younger patients, but this is not clinically relevant.

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

Since the three components of the drug are equally well tolerated by young and elderly patients, the usual dosage regimen is recommended (see section "Method of administration and dosage").

Kidney dysfunction

Renal impairment does not significantly affect the pharmacokinetics of amlodipine. As expected, for a drug whose renal clearance accounts for only 30% of total plasma clearance, there was no relationship between renal function and systemic exposure to valsartan.

Therefore, patients with mild to moderate renal impairment can use the drug at the usual starting dose (see sections “Method of administration and dosage” and “Special precautions for use”).

In renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide increase, and the urinary excretion rate decreases. A three-fold increase in the AUC of hydrochlorothiazide has been observed in patients with mild to moderate renal impairment. An 8-fold increase in the AUC has been observed in patients with severe renal impairment. Amlodipine/valsartan/hydrochlorothiazide is contraindicated in patients with severe renal impairment, anuria, or those on dialysis (see section 4.3).

Liver dysfunction

There are very limited clinical data on the use of amlodipine in patients with hepatic impairment. In patients with hepatic impairment, the clearance of amlodipine is reduced, resulting in an increase in AUC of approximately 40-60%. On average, in patients with chronic diseases of mild to moderate severity, the exposure (determined by AUC) to valsartan is 2 times higher than in adult volunteers (grouped by age, gender and body weight). Due to the content of valsartan, Co-Valodip is contraindicated in patients with severe hepatic impairment.

Indication

Treatment of essential hypertension in adult patients whose blood pressure is adequately controlled with a combination of amlodipine, valsartan and hydrochlorothiazide and who are taking three separate drugs or two drugs, one of which is a combination.

Contraindication

Hypersensitivity to the active substances, other sulfonamides, dihydropyridine derivatives or to any of the excipients.

Pregnancy or planning a pregnancy (see section "Use during pregnancy or breastfeeding").

Liver dysfunction, biliary cirrhosis or cholestasis.

Severe renal impairment (glomerular filtration rate (GFR) <30 mL/min/1.73 m2), anuria, and dialysis.

Concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2).

Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.

Severe hypotension.

Shock (including cardiogenic shock).

Left ventricular outflow tract obstruction (e.g. hypertrophic obstructive cardiomyopathy and severe aortic stenosis).

Hemodynamically unstable heart failure after acute myocardial infarction.

Interaction with other medicinal products and other types of interactions

No drug interaction studies have been conducted with the combination product amlodipine/valsartan/hydrochlorothiazide. This section only provides information on drug interactions known for each individual active substance.

However, it is important to consider that Co-Valodip may enhance the hypotensive effect of other antihypertensive drugs.

Concomitant use is not recommended.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant use of lithium with ACE inhibitors (ACEIs), ARBs including valsartan, or thiazides such as hydrochlorothiazide.

Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity is likely to be increased with Co-Valodip. Therefore, careful monitoring of serum lithium levels is recommended when these drugs are used concomitantly.

Concomitant use requires caution

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

Clinical data have shown that dual blockade of the RAAS through the concomitant use of ACE inhibitors, ARBs or aliskiren is associated with an increased risk of adverse reactions such as hypotension, hyperkalaemia and renal impairment (including acute renal failure) compared to monotherapy with a substance affecting the RAAS (see sections "Contraindications", "Special instructions for use" and "Pharmacodynamics").

Application features

The safety and efficacy of amlodipine in hypertensive crisis have not been studied.

Patients with sodium deficiency and dehydration

Excessive hypotension, including orthostatic hypotension, was observed in 1.7% of patients receiving the maximum dose of the combination of amlodipine, valsartan and hydrochlorothiazide (10 mg/320 mg/25 mg) compared with 1.8% of patients receiving valsartan/hydrochlorothiazide (320 mg/25 mg), 0.4% of patients receiving amlodipine/valsartan (10 mg/320 mg), and 0.2% of patients receiving hydrochlorothiazide/amlodipine (25 mg/10 mg) in a controlled study in patients with moderate to severe uncomplicated hypertension.

In patients with salt deficiency and/or dehydration receiving high doses of diuretics, symptomatic hypotension may occur after the start of Co-Valodip. Co-Valodip should only be used after correction of salt deficiency and/or dehydration.

If severe hypotension occurs during the use of the drug, the patient should be placed in a horizontal position, the lower extremities should be raised and, if necessary, intravenous saline should be administered. Treatment can be continued after stabilization of blood pressure.

Changes in serum electrolyte levels

Amlodipine/valsartan/hydrochlorothiazide

The opposing effects of valsartan 320 mg and hydrochlorothiazide 25 mg on serum potassium levels approximately balance each other in many patients. In other patients, one or the other effect may be dominant.

Serum electrolyte levels should be checked periodically to identify possible electrolyte imbalance.

Periodic determination of serum electrolytes and potassium levels should be performed at appropriate intervals to prevent possible electrolyte imbalance, especially in patients with risk factors such as renal impairment, treatment with other drugs and a history of electrolyte imbalance.

Valsartan

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels (e.g. heparin) is not recommended. Potassium levels should be monitored if necessary.

Hydrochlorothiazide

Hypokalemia has been reported with thiazide diuretics, including hydrochlorothiazide.

Treatment with Co-Valodip should only be initiated after correction of hypokalemia and any concomitant hypomagnesemia. Thiazide diuretics may induce hypokalemia or exacerbate existing hypokalemia. Thiazide diuretics should be used with caution in patients with conditions involving potassium loss, such as salt-wasting nephropathy and prerenal (cardiogenic) renal impairment. If hypokalemia develops during therapy with hydrochlorothiazide, the combination drug should be discontinued until stable correction of potassium balance has occurred.

Thiazide diuretics may cause hyponatremia and hypochloraemic alkalosis or exacerbate existing hyponatremia. Hyponatremia accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed. Treatment with hydrochlorothiazide should be started only after correction of existing hyponatremia. In the event of severe or rapid hyponatremia during treatment with Co-Valodip, the drug should be discontinued until sodium levels normalize. Thiazides, including hydrochlorothiazide, increase the urinary excretion of magnesium, which can lead to hypomagnesemia. When using thiazide diuretics, calcium excretion is reduced, which can lead to hypercalcemia.

All patients receiving thiazide diuretics should have periodic monitoring of electrolyte levels, especially potassium, sodium, and magnesium.

Kidney dysfunction

Thiazide diuretics may precipitate azotemia in patients with chronic kidney disease.

When using Co-Valodip, it is recommended to periodically monitor the level of electrolytes (including potassium), creatinine and uric acid in the serum of patients with impaired renal function. Co-Valodip is contraindicated in patients with severe renal failure, anuria or patients on dialysis.

There is no need to adjust the dose of the combination drug in patients with mild to moderate renal impairment (GFR ≥30 mL/min/1.73m2).

Renal artery stenosis

The drug should be used with caution for the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, as serum urea and creatinine levels may increase.

Kidney transplantation

There is currently no information on the safety of the drug in patients who have recently undergone a kidney transplant.

Valsartan is mainly excreted unchanged in the bile. The half-life of amlodipine is prolonged and the AUC (plasma concentration-time) is higher in patients with impaired liver function; no dosage recommendations are available. For patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose of valsartan is 80 mg. Therefore, Co-Valodip is not indicated in this group of patients.

Angioedema

Angioedema, including swelling of the larynx and glottis, which may lead to airway obstruction, and/or swelling of the face, lips, pharynx and/or tongue, has been reported in patients treated with valsartan. Some of these patients had a history of angioedema while taking other drugs, including ACE inhibitors. Co-Valodip should be discontinued immediately if angioedema occurs; re-administration is not recommended.

Heart failure and coronary artery disease/post-myocardial infarction

Due to inhibition of the RAAS, renal dysfunction may be expected in susceptible patients. In patients with severe heart failure, in whom renal function may depend on RAAS activity, treatment with ACE inhibitors and ARBs has resulted in oliguria and/or progressive azotemia (rarely) with acute renal failure and/or fatal outcome. Similar results have been reported with valsartan. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function.

In a long-term placebo-controlled study of amlodipine (PRAISE-2) in patients with non-ischemic heart failure of NYHA class III and IV, the incidence of pulmonary edema was higher with amlodipine, despite a small difference in the occurrence or worsening of heart failure compared with placebo.

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure as they may increase the risk of cardiovascular events and death.

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

Aortic and mitral valve stenosis

As with other vasodilators, the drug should be administered with extreme caution to patients with mild aortic and mitral valve stenosis.

Pregnancy

Angiotensin II receptor antagonists (ARBs) should not be initiated during pregnancy. Unless continued ARB therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, ARB treatment should be stopped immediately, and, if appropriate, alternative therapy should be started.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan, as they do not have an activated renin-angiotensin system. Therefore, Co-Valodip is not recommended for this group of patients.

Systemic lupus erythematosus

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

Other metabolic disorders

Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and increase serum cholesterol, triglycerides, and uric acid levels. Dosage adjustment of insulin or oral hypoglycemic agents may be necessary in patients with diabetes mellitus.

Oskil

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