Co-Vamloset, 5 mg+160 mg 30 pcs

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

Indications

Arterial hypertension II and III degrees.

Pharmacological effect

Combination antihypertensive drug (slow calcium channel blocker [SCBC] + angiotensin II receptor antagonist [ARA II] + diuretic)

Special instructions

If you have one of the diseases listed below, tell your doctor before taking this drug.

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 disturbances: nephropathies accompanied by salt loss, 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 III-IV functional class according to the NYHA classification, with acute coronary syndrome, with diabetes mellitus, with systemic lupus erythematosus, with hyperuricemia, elevated concentrations of cholesterol and triglycerides in the blood plasma, in patients with angle-closure glaucoma, in patients with non-melanoma skin cancer (NSC) in history (see section “Special instructions”), as well as in patients after kidney transplantation. Caution should be exercised when using the drug in elderly patients.

Caution should be exercised when using Co-Vamlosets simultaneously with potassium salts, potassium-sparing diuretics, potassium-containing table salt substitutes, as well as with drugs that can cause an increase in potassium levels in the blood plasma (for example, heparin).

Use in children and adolescents under 18 years of age

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

Use in patients over 65 years of age

No dose adjustment is required. In patients in this category, if necessary, it is possible to reduce the initial dose to the one containing the lowest dose of amlodipine, i.e. 1 tablet containing amlodipine + valsartan + HCTZ at a dose of 5 mg + 160 mg + 12.5 mg (as Co-Vamloset, film-coated tablets, 5 mg + 160 mg + 12.5 mg) or 5 mg + 160 mg + 25 mg (as Co-Vamloset, film-coated tablets) coated, 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 < 30 ml/min/1.73 m2 body surface area) due to the presence of HCTZ in the drug.

The use of thiazide diuretics in monotherapy in patients with severe renal impairment (GFR < 30 ml/min/1.73 m2 body surface area) is ineffective, but simultaneous use with loop diuretics in patients in this category is possible.

Patients with liver dysfunction

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 patients (see sections “Contraindications”, “Special instructions” and “Pharmacological properties. Pharmacokinetics”).

Recommendations for dosing of amlodipine in patients with mild or moderate hepatic impairment have not been developed. In patients in this category, if necessary, the drug with the lowest dose of amlodipine should be prescribed.

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

Sodium deficiency and/or hypovolemia

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

Patients with sodium deficiency and/or hypovolemia, for example, patients receiving high doses of diuretics, may develop symptomatic hypotension when starting therapy with Co-Vamloset. This combination should be used only after correction of hyponatremia and/or hypovolemia.

If severe arterial hypotension develops while using Co-Vamloset, the patient should be placed in a supine position and, if necessary, given an intravenous infusion of 0.9% sodium chloride solution. Treatment with the drug can be continued after stabilization of blood pressure.

Changes in electrolyte content in blood plasma

Ko Vamloset

In a controlled study in many patients using the combination of amlodipine + valsartan + HCTZ, the effects of valsartan at a dose of 320 mg and HCTZ at a dose of 25 mg on serum potassium levels were almost counterbalanced. In other patients, one of the effects may have predominated. Periodic determination of plasma electrolytes to identify possible electrolyte imbalances should be performed at specified intervals.

Periodic determination of serum electrolytes, particularly potassium, should be performed at appropriate intervals to identify possible electrolyte abnormalities, especially in patients with risk factors such as renal impairment, use of other medications, or a history of electrolyte abnormalities.

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 plasma potassium (for example, heparin) is not recommended. Plasma potassium levels should be monitored.

HCTZ

Therapy with Co-Vamloset should be started only after hypokalemia and concomitant hypomagnesemia have been eliminated. Thiazide diuretics may promote the recurrence of hypokalemia or aggravate existing hypokalemia. Thiazide diuretics should be used with caution in patients with conditions that involve increased potassium loss, such as nephropathy, and prerenal (cardiogenic) renal impairment. If hypokalemia develops during treatment with HCTZ, use of Co-Vamloset should be discontinued until plasma potassium levels are stable and normalized.

Thiazide diuretics may promote the re-development of hyponatremia and hypochloremic alkalosis or aggravate existing hyponatremia. Hyponatremia was observed, accompanied by neurological symptoms (nausea, progressive disorientation, apathy). Treatment with HCTZ should be started only after existing hyponatremia has resolved. In case of severe or rapidly developing hyponatremia during the use of the combination of amlodipine + valsartan + HCTZ, treatment should be discontinued until the sodium content in the blood plasma normalizes.

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

Renal dysfunction

Thiazide diuretics may contribute to the development of azotemia in patients with chronic kidney disease. When using the drug Co-Vamloset in patients with impaired renal function, it is recommended to periodically monitor the content of electrolytes (including potassium), the concentration of creatinine and uric acid in the blood serum. The drug Co-Vamloset is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min), anuria and patients on dialysis (see section “Contraindications”).

Patients with mild to moderate renal dysfunction (GFR ≥ 30 ml/min/1.73 m2 body surface area) do not require dose adjustment of Co-Vamloset.

Renal artery stenosis

In patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, taking Co-Vamloset may be accompanied by an increase in serum urea and creatinine concentrations, therefore, in such patients, Co-Vamloset should be used with caution.

Kidney transplant

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

Liver dysfunction

Valsartan is excreted mainly in unchanged form with 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, therefore Co-Vamloset is contraindicated in these patients.

Angioedema

Angioedema, including swelling of the larynx and pharynx, causing airway obstruction and/or swelling of the face, lips, larynx and/or tongue, has been reported in patients receiving valsartan. Some of these patients had previously experienced angioedema due to the use of other drugs, including ACE inhibitors. If angioedema develops, use of the drug Co-Vamloset should be stopped immediately and the drug should not be reused.

CHF and coronary heart disease/condition after myocardial infarction

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 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 can lead to acute renal failure and death. Similar outcomes were observed during therapy with valsartan. Evaluation of patients with CHF or post-myocardial infarction should always include testing of renal function.

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

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

Caution is advised in patients with CHF and coronary artery disease as 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 low-grade severe aortic valve stenosis.

Pregnancy

ARA II therapy should not be started 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 immediately discontinued or switched to alternative antihypertensive therapy with an established safety profile for use during pregnancy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not use ARB 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

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

Other metabolic disorders

Thiazide diuretics, including HCTZ, may alter glucose tolerance and increase serum concentrations of cholesterol, triglycerides, and uric acid. In patients with diabetes mellitus, dose adjustment of insulin or oral hypoglycemic drugs may be required.

Due to the content of the HCTZ component, Co-Vamloset is contraindicated for symptomatic hyperuricemia. HCTZ may increase serum uric acid concentrations due to decreased clearance of uric acid and cause or worsen hyperuricemia and contribute to the development of gout in susceptible patients.

Thiazides reduce renal calcium excretion and may cause intermittent and slight increases in serum calcium concentrations in the absence of known disturbances in calcium metabolism. Co-Vamloset is contraindicated in patients with hypercalcemia and should be used only after the existing hypercalcemia has been corrected. Co-Vamloset should be discontinued if hypercalcemia develops during treatment. Serum calcium concentrations should be monitored periodically during thiazide therapy. Severe hypercalcemia may be a sign of hidden hyperparathyroidism. Thiazide therapy should be interrupted before testing parathyroid function.

Photosensitivity

Cases of photosensitivity reactions have been reported with the use of thiazide diuretics (see section “Side effects”). If a photosensitivity reaction develops during treatment with Co-Vamloset, it is recommended to discontinue therapy. If repeated use of a diuretic is necessary, it is recommended to protect 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 pain in the eye, usually within a few hours to a week after starting to use the drug. If left untreated, acute angle-closure glaucoma can lead to permanent vision loss.

Primary therapy is to discontinue HCTZ as soon as possible. If intraocular pressure remains uncontrolled, emergency medical or surgical treatment may be required. Risk factors for the development of acute angle-closure glaucoma may include anamnestic data on allergic reactions to sulfonamides and penicillin.

General

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

Elderly patients (≥ 65 years)

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

Double blockade of the RAAS

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

Concomitant use of ARB IIc with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR < 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients. Concomitant use of ARB IIc and ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Hypertensive crisis

The drug Co-Vamloset should not be used to relieve hypertensive crises.

Doping test

When using the drug Co-Vamloset, athletes may have positive results of a doping test (due to the presence of HCTZ in the drug).

NMRK

Two pharmacoepidemiological studies using data from the Danish National Cancer Registry demonstrated an association between HCTZ use and an increased risk of NMSC basal cell carcinoma and squamous cell carcinoma. The risk of developing NMSC increased with increasing total (cumulative) dose of HCTZ. A possible mechanism for the development of NMSC is the photosensitizing effect of HCTZ.

Patients taking HCTZ as monotherapy or in combination with other drugs should be aware of the risk of developing NMSC. It is recommended that such patients undergo regular skin examination to identify any new suspicious lesions as well as changes in existing skin lesions.

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

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

In patients with a history of NMSC, it is recommended to reconsider the advisability of using HCTZ.

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

Active ingredient

Amlodipine, Valsartan, Hydrochlorothiazide

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 besilate (amlodipine besilate) 6.94 mg/13.88 mg/13.88 mg, equivalent to amlodipine 5.00 mg/10.00 mg/10.00 mg

Valsartan A, granule substance 251.35 mg/251.35 mg/251.35 mg

[Active ingredient of granular 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

Excipients:

Mannitol, magnesium stearate, colloidal silicon dioxide

Film shell:

Film-forming mixture:

– polyvinyl alcohol

– macrogol-3350

– titanium dioxide (E171)

– talc

Red iron oxide dye (E172) (for tablets 10 mg + 160 mg + 12.5 mg)

Iron oxide yellow dye (E172) (for tablets 10 mg + 160 mg + 25 mg)

Pregnancy

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 physician 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, which 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, a 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 pathology in the fetus and newborn.

HCTZ crosses the placenta. When using thiazide diuretics, including HCTZ, during pregnancy, the development of fetal or neonatal jaundice or thrombocytopenia, as well as other adverse reactions observed in adult patients, is possible. With the unintentional use of valsartan in pregnant women, cases of spontaneous abortion, oligohydramnios and renal dysfunction in newborns have been described. There is insufficient data on the use of amlodipine in pregnant women to judge 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 is excreted in breast milk. In experimental studies, valsartan was excreted in breast milk. HCTZ is also excreted in breast milk. The use of Co-Vamloset is contraindicated during breastfeeding.

Contraindications

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

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

· Pregnancy, pregnancy planning and breastfeeding.

· Liver failure, biliary cirrhosis and cholestasis.

· Severe renal dysfunction (creatinine clearance < 30 ml/min), anuria, patients on hemodialysis.

· Refractory to adequate therapy: hypokalemia, hyponatremia, hypercalcemia, as well as hyperuricemia with clinical manifestations.

· Age up to 18 years (efficacy and safety have not been established).

· Severe arterial hypotension (systolic blood pressure <90 mmHg), collapse, cardiogenic shock.

· 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 < 60 ml/min/1.73 m2 body surface area).

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

Interaction

Amlodipine

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

Simultaneous administration of amlodipine and ethanol does not affect the pharmacokinetics of the latter.

CYP3A4 isoenzyme inhibitors

With simultaneous use of amlodipine at a dose of 5 mg/day with diltiazem at a dose of 180 mg/day in elderly patients with arterial hypertension, an increase in systemic exposure of amlodipine by 1.6 times was observed. When amlodipine is used with potent inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole, itraconazole and ritonavir), an even more pronounced increase in the systemic exposure of amlodipine is possible. Amlodipine should be used with caution with inhibitors of the CYP3A4 isoenzyme.

Due to inhibition of the CYP3A4 isoenzyme, when taken concomitantly with grapefruit juice, the bioavailability of amlodipine may increase. However, in a clinical study in healthy volunteers, no significant changes in pharmacokinetics were detected when amlodipine was taken 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, fosphenytoin, primidone, rifampicin, herbal preparations containing St. John’s wort) can lead to a marked decrease in its concentration in the blood plasma, caution should be exercised when using amlodipine with inducers of the CYP3A4 isoenzyme.

Simvastatin

Repeated simultaneous use of simvastatin at a dose of 80 mg/day and amlodipine at a dose of 10 mg/day leads to an increase in simvastatin exposure in blood plasma by 77%. 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 used concomitantly with amlodipine. In order to avoid tacrolimus toxicity, when amlodipine is used in patients receiving tacrolimus, monitoring serum concentrations of tacrolimus and adjusting its dose if necessary.

Clarithromycin

Clarithromycin is an inhibitor of the CYP3A4 isoenzyme. There is an increased risk of developing arterial hypotension in patients concomitantly using clarithromycin with amlodipine. When amlodipine is used concomitantly with clarithromycin, careful monitoring of patients is recommended.

Valsartan

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

Double blockade of the RAAS when using 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 impairment (GFR < 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients. Concomitant use of ARB IIc and ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

The simultaneous use of ARA II with other drugs that affect the RAAS leads to an increase in the incidence of cases of arterial hypotension, hyperkalemia, and renal dysfunction. It is necessary to monitor blood pressure, renal function, and the content of blood plasma electrolytes when using Co-Vamlosets with other drugs that affect the RAAS.

Drugs and substances affecting the content of potassium in blood serum

When used simultaneously with dietary supplements containing potassium, potassium-sparing diuretics, eplerenone, potassium-containing salt substitutes, or with other drugs that may cause an increase in plasma potassium levels (for example, heparin), caution should be exercised and regular monitoring of plasma potassium levels should be performed.

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

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

Transport proteins

Concomitant use of valsartan with inhibitors of the OATP1B1 transport protein (rifampicin, cyclosporine) and with an inhibitor of the MRP2 transport protein (ritonavir) may increase the systemic 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 HCTZ, potentiate the action of curare-like muscle relaxants (for example, tubocurarine chloride).

NSAIDs

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

Drugs that affect serum potassium levels

The risk of developing 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).

Medicines that affect serum sodium levels

The hyponatremic effect caused by diuretics may be enhanced when used simultaneously with antidepressants, antipsychotics, anticonvulsants, etc. Caution should be exercised during long-term simultaneous use of Co-Vamlosets with the above drugs.

Hypoglycemic agents

When using HCTZ, a change in glucose tolerance is observed, and therefore in patients with diabetes mellitus, dose adjustments of insulin and oral hypoglycemic agents may be required.

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

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-anticholinergics

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

Anion exchange resins

The absorption of HCTZ is reduced in the presence of cholestyramine and colestipol. HCTZ should be taken 4 hours before or 4-6 hours after taking these compounds.

Vitamin D and calcium salts

Concomitant use of HCTZ with vitamin D or calcium supplements may lead to an increase in serum calcium levels.

Cyclosporine

With simultaneous use of HCTZ and cyclosporine, the risk of developing hyperuricemia and the appearance of symptoms resembling gout increases.

Methyldopa

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

Other types of interaction

The simultaneous use of thiazide diuretics, including HCTZ, can lead to an increase in the frequency of hypersensitivity reactions to allopurinol, an increase in the risk of developing side effects of amantadine, an increase in the hyperglycemic effect of diazoxide, a decrease in the renal excretion of drugs with cytotoxic effects (for example, cyclophosphamide, methotrexate), and a potentiation of their myelosuppressive effect. HCTZ can also reduce the body’s response to the administration 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 HCTZ may contribute to the development of orthostatic hypotension.

Common drug interactions for valsartan and HCTZ

Lithium preparations

With the simultaneous use of lithium preparations with ACE inhibitors, ARB II or thiazide diuretics, a reversible increase in the lithium content in the blood serum and an associated increase in toxic manifestations were noted. The risk of toxicities associated with the use of lithium preparations may be further increased when used concomitantly with Co-Vamloset, since the renal clearance of lithium preparations is slowed by the influence of thiazide diuretics. In this regard, it is recommended to carefully monitor the lithium content in the blood serum.

Overdose

There are currently no data on cases of drug overdose.

Amlodipine

Overdose of amlodipine can lead to excessive peripheral vasodilation and possible reflex tachycardia. It has also been reported that a pronounced and prolonged decrease in blood pressure has occurred, leading to the development of shock with a fatal outcome.

Valsartan

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

If a pronounced decrease in blood pressure occurs, the patient should be placed in a horizontal position with his legs elevated and take active measures to maintain the activity of the cardiovascular system, including regular monitoring of the activity of the heart and respiratory system, blood volume and the amount of urine excreted.

To maintain normal vascular tone, in the absence of contraindications, the use of vasopressor drugs is possible. If you have recently taken Co-Vamloset, vomiting or gastric lavage may be effective. The use of activated carbon in healthy volunteers was accompanied by a decrease in the absorption of amlodipine.

Valsartan and amlodipine cannot be removed by hemodialysis, whereas hemodialysis may be effective for the removal of HCTZ.

Clinical pharmacology

Pharmacodynamics

The drug Co-Vamloset is a combination of three antihypertensive components with a complementary mechanism for controlling blood pressure (BP): amlodipine (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 during monotherapy with each drug separately.

Amlodipine

Amlodipine, which is part of the drug Co-Vamloset, inhibits the transmembrane entry of calcium ions into cardiomyocytes and vascular smooth muscle cells. The mechanism of the antihypertensive effect of amlodipine is associated with a direct relaxing effect on vascular smooth muscle, causing a decrease in total peripheral vascular resistance (TPVR) and a decrease in blood pressure. Experimental data show that amlodipine binds to the dihydropyridine and non-dihydropyridine active sites of the receptor. The contraction of cardiomyocytes and myocytes of the vascular walls 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” position). The decrease in blood pressure is not accompanied by a significant change in heart rate (HR) and catecholamine activity with long-term use.

Plasma drug concentrations correlate with therapeutic response in both young and elderly patients. In arterial hypertension in 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 the severity of proteinuria.

Also, as with the use of other BMCCs, while taking amlodipine in patients with normal left ventricular (LV) function, changes in hemodynamic parameters of cardiac function at rest and during physical activity were observed: a slight increase in cardiac index without a significant effect on the maximum rate of increase in pressure in the LV, end-diastolic pressure and LV volume. Hemodynamic studies in intact animals and healthy volunteers showed that the decrease in blood pressure under the influence of amlodipine in the range of therapeutic doses is not accompanied by a negative inotropic effect, even when used simultaneously with beta-blockers.

Amlodipine does not change the function of the sinoatrial node and does not affect atrioventricular conduction in intact animals and healthy volunteers. When amlodipine is used in combination with beta-blockers in patients with arterial hypertension or angina pectoris, a decrease in blood pressure is not accompanied by undesirable changes in electrocardiographic parameters.

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

Valsartan

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

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

In comparative clinical studies of valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (p < 0.05) in patients receiving valsartan (in 2.6% of patients receiving valsartan and in 7.9% of patients receiving an ACE inhibitor). 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 during treatment with valsartan, and in 19.0% of cases during treatment 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 < 0.05).

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

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

The antihypertensive effect appears within 2 hours in most patients after a single oral dose of valsartan. The maximum decrease in blood pressure develops after 4-6 hours. After taking valsartan, the duration of the antihypertensive effect lasts more than 24 hours.

With repeated use, the maximum reduction in blood pressure, regardless of the oral dose taken, is usually achieved within 2-4 weeks and is maintained at the achieved level during long-term therapy. Abrupt cessation of valsartan is not accompanied by a sharp increase in blood pressure or other undesirable clinical consequences. The use of valsartan in patients with chronic heart failure (CHF) (II-IV functional class according to the NYHA classification) leads to a significant reduction in the number of hospitalizations for cardiovascular diseases (which is especially pronounced in patients not receiving ACE inhibitors or beta-blockers).

When taking valsartan in patients with left ventricular failure (with stable hemodynamic parameters) or with impaired LV function after myocardial infarction, a decrease in cardiovascular mortality is observed.

HCTZ

The point of action of thiazide diuretics is the distal convoluted renal tubules. When thiazide diuretics act on highly sensitive receptors of the distal tubules of the renal cortex, the reabsorption of sodium and chloride ions is suppressed.

Suppression of the co-transport system of sodium and chlorine ions apparently occurs due to competition for the binding sites for chlorine ions in this system. As a result, the excretion of sodium and chloride ions increases approximately equally. As a result of the diuretic effect, a decrease in circulating blood volume (CBV) is observed, as a result of which renin activity, aldosterone secretion, potassium excretion by the kidneys and, consequently, a decrease in the potassium content in the blood serum increase.

Pharmacokinetics

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

Amlodipine

Suction

After oral administration of amlodipine in therapeutic doses, the maximum concentration (Cmax) in the blood plasma is achieved after 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 in patients with arterial hypertension, approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Metabolism

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

Removal

Elimination from blood plasma is biphasic with a half-life (T½) of approximately 30 to 50 hours. Equilibrium plasma concentrations are achieved after prolonged use for 7-8 days. 10% is excreted unchanged, 60% in the form of metabolites.

Valsartan

Suction

After oral administration of valsartan, Cmax in blood plasma is achieved within 2-4 hours. The average absolute bioavailability is 23%.

When taken with food, there is a decrease in bioavailability (measured by the area under the concentration-time curve [AUC]) by 40% and Cmax in the blood plasma by almost 50%, although approximately 8 hours after taking valsartan orally, the concentrations of valsartan in the blood plasma in people taking it with food and in the group receiving valsartan on an empty stomach level out. The decrease in AUC, however, is not accompanied by a clinically significant decrease in the therapeutic effect, so valsartan can be prescribed regardless of the timing of meals.

Distribution

The volume of distribution (Vd) of valsartan at steady state after intravenous administration was approximately 17 L, indicating the absence of extensive tissue distribution of valsartan. Valsartan is highly bound to serum proteins (94-97%), mainly to albumin.

Metabolism

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

Removal

The pharmacokinetic curve of valsartan is descending multi-exponential (T½α < 1 hour and T½β about 9 hours). Valsartan is excreted mainly unchanged through the intestines (about 83% of the dose) and by the kidneys (about 13% of the dose). After intravenous administration, the plasma clearance of valsartan is about 2 L/hour and its renal clearance is 0.62 L/hour (about 30% of the total clearance). T½ is 6 hours.

HCTZ

Suction

Absorption of HCTZ after oral administration is rapid (time to reach Cmax in blood plasma is about 2 hours). On average, the increase in AUC is linear and proportional to the oral dose within the therapeutic range. When administered concomitantly with food, both increased and decreased systemic bioavailability of HCTZ was reported compared to administration of the drug on an empty stomach. The magnitude of this effect is small and clinically insignificant. The absolute bioavailability of HCTZ after oral administration is 70%.

Distribution

The kinetics of distribution and elimination are generally described as a biexponential decreasing function with T½ – 6-15 hours. With repeated use, the kinetics of HCTZ does not change, and when used once a day, accumulation is minimal. The apparent volume of distribution is 4-8 l/kg. 40-70% of HCTZ circulating in blood plasma binds to blood plasma proteins, mainly albumin. HCTZ also accumulates in erythrocytes in concentrations approximately 3 times higher than those in blood plasma.

Metabolism

HCTZ is excreted unchanged.

Removal

T½ of the final phase is 6-15 hours. With repeated use of the drug, the kinetics of HCTZ does not change; when the drug is prescribed once a day, the accumulation of the drug is minimal. More than 95% of the absorbed dose of HCTZ is excreted unchanged by the kidneys.

Amlodipine+valsartan+HCTZ

After oral administration of the drug Co-VamlosetC, the maximum levels of amlodipine, valsartan and HCTZ in the blood plasma are achieved after 6-8, 3 and 2 hours, respectively.

Pharmacokinetics in selected patient groups

Patients under 18 years of age

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

Elderly patients (over 65 years old)

The time to reach Cmax of amlodipine in blood plasma is the same in young patients and elderly patients. In elderly patients, the clearance of amlodipine is slightly reduced, which leads to an increase in AUC and T½.

In elderly patients, systemic exposure to valsartan was slightly greater than in younger patients, but this was not clinically significant.

There is limited data on a decrease in the systemic clearance of HCTZ in patients over 65 years of age (healthy volunteers or patients with arterial hypertension) compared with younger 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 systemic exposure of valsartan (AUC) in patients with varying degrees of renal impairment.

In the presence of renal failure, the average plasma Cmax and AUC values ​​of HCTZ increase, and the excretion rate decreases. In patients with mild to moderate renal impairment, T½ is almost doubled. The renal clearance of HCTZ in patients with impaired renal function is reduced compared to normal levels (about 300 ml/min).

Co-Vamloset is contraindicated for use in patients with severe renal impairment (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 body surface area and < 60 ml/min/1.73 m2 body surface area).

Patients with liver dysfunction

There are only limited clinical data on the use of amlodipine in patients with impaired liver function. Patients with impaired liver function have reduced clearance of amlodipine, resulting in an increase in AUC of approximately 40-60%. On average, in patients with mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale) liver dysfunction, the bioavailability (according to AUC) of valsartan is doubled compared to healthy volunteers (matched age, gender and body weight). The drug Co-Vamloset is contraindicated in patients with impaired liver function (see sections “Contraindications” and “Dosage and Administration”).

Storage conditions

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

Keep out of the reach of children.

Shelf life

2 years.

Do not use the drug after the expiration date.

Manufacturer

KRKA-RUS, Russia