Co-Vamsolet tabs 10mg + 160mg + 12.5mg #30

Co-Vamsolet instruction

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The composition and release form of the drug

Tablets, film coated brown-yellow, oval, biconvex, engraved with "K4" on one side; the view on the fracture is a rough mass of white or almost white color with a brown-yellow film coating.
1 tab.
Amlodipine besylate 13.88 mg,
which corresponds to the content of amlodipine 10 mg
valsartan A, substance granules * 251.35 mg,
which corresponds to the content of valsartan 160 mg
hydrochlorothiazide 25 mg
* Auxiliary substances of the substance granules: microcrystalline cellulose, crosspovidone, povidone, sodium lauryl sulfate.
Excipients: mannitol, magnesium stearate, colloidal silicon dioxide.
The composition of the film shell: film-forming mixture (polyvinyl alcohol, macrogol 3350, titanium dioxide (E171), talc, iron dye yellow oxide (E172)).

pharmachologic effect

Combined antihypertensive drug containing three components with the complementary mechanism of BP control: amlodipine (calcium channel blocker), valsartan (angiotensin II receptor antagonist) and hydrochlorothiazide (thiazide diuretic). The combination of these components leads to a more pronounced decrease in blood pressure compared with that on the background of monotherapy with each drug separately.
Amlodipine is a dihydropyridine derivative, a calcium channel blocker. It has antianginal and hypotensive effects. Inhibits the transmembrane transition of calcium ions into cardiomyocytes and smooth muscle cells of the vascular wall. The antihypertensive effect of amlodipine is due to the direct relaxing effect on the smooth muscle cells of the vascular wall. The mechanism of the antianginal action of amlodipine is not fully understood; it is presumably associated with the following effects: it causes the expansion of peripheral arterioles, reducing OPSS (afterload), which leads to a decrease in myocardial oxygen demand; causes expansion of the coronary arteries and arterioles in both intact and ischemic sites of the myocardium, which increases the oxygen supply to the myocardium, including in patients with Prinzmetal angina. Amlodipine reduces the severity of left ventricular hypertrophy. Does not affect the contractility and conductivity of the myocardium, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases GFR, has a weak natriuretic effect.
In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure (while lying and standing) for 24 hours. The antihypertensive effect develops slowly, and therefore the development of acute arterial hypotension is not typical. In patients with angina, taking amlodipine 1 time / day increases exercise tolerance, the time before the development of an attack of angina and the ischemic depression of the ST segment, reduces the frequency of strokes and the need for nitroglycerin (short-acting form).
Clinical efficacy of amlodipine in patients with stable exertional angina, vasospastic angina, and angiographically confirmed coronary artery disease has been proven.
Amlodipine does not adversely affect lipid metabolism and does not cause changes in the lipid profile of blood plasma. Amlodipine can be used in patients with bronchial asthma, diabetes mellitus and gout.
When taken orally, the effect of amlodipine begins after 2-4 hours and lasts for 24 hours. The maximum hypotensive effect is achieved not earlier than 4 weeks from the start of Co-Vamsolet. Hemodynamic effects of the drug remain unchanged with long-term use.
Valsartan is a selective antagonist of angiotensin II receptors (type AT1) for oral administration. Selectively blocks the AT1 subtype receptors, which are responsible for the effects of angiotensin II. Increasing the plasma concentration of angiotensin II due to blockade of AT1 receptors by valsartan can stimulate unblocked receptors of the AT2 subtype, which counteract the effects of stimulation of AT1 receptors. Valsartan does not have agonistic activity on AT1 receptors. The affinity of valsartan for receptors of the AT1 subtype is approximately 20,000 times higher than that for receptors of the AT2 subtype.
Valsartan does not interact and does not block the receptors of other hormones or ion channels involved in the regulation of the functions of the cardiovascular system.
Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. Due to the lack of effect on ACE, the effects of bradykinin or substance P are not potentiated, therefore, when using angiotensin II receptor antagonists, the development of dry cough is unlikely. It is proved that the incidence of dry cough in the treatment of valsartan is significantly lower than when using ACE inhibitors. In the treatment of hypertension, valsartan lowers blood pressure without affecting heart rate.
After ingestion of valsartan in a single dose, the hypotensive effect develops within 2 hours, the maximum decrease in blood pressure is reached within 4-6 hours. The antihypertensive effect of valsartan persists for 24 hours after it is taken. With repeated use of valsartan, the maximum reduction in blood pressure, regardless of the dose, is achieved in 2-4 weeks and is maintained at the achieved level during long-term therapy. Sudden cessation of valsartan is not accompanied by a significant increase in blood pressure or other adverse events (withdrawal syndrome).
The use of valsartan in patients with chronic heart failure (NYHA Class II-IV FC) 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 using valsartan in patients with left ventricular failure (with stable hemodynamic parameters) or with impaired left ventricular function after suffering a myocardial infarction, a decrease in cardiovascular mortality is noted.
Hydrochlorothiazide is a thiazide diuretic, the diuretic effect of which is associated with impaired reabsorption of sodium, chlorine, potassium, magnesium, and water in the distal nephron; delays the excretion of calcium ions, uric acid. It has antihypertensive properties; hypotensive effect develops due to the expansion of arterioles. Virtually no effect on normal blood pressure.
The removal of electrolytes and water begins approximately 2 hours after ingestion, the maximum effect is reached within 3-6 hours and lasts for 6-12 hours. The antihypertensive effect is achieved within 3-4 days of treatment and lasts for 1 week after completion of Co-Vamsolet. With long-term treatment, a decrease in blood pressure is achieved by using smaller doses than are necessary for the diuretic effect. Reduction of blood pressure is accompanied by a slight increase in glomerular filtration rate, vascular resistance of the renal bed and renin activity in the blood plasma.
Hydrochlorothiazide with a single dose in high doses leads to a decrease in plasma volume, glomerular filtration rate, renal blood flow and mean blood pressure. With long-term intake in small doses, the volume of blood plasma remains reduced, while the minute volume and glomerular filtration rate return to the initial level preceding the start of treatment. Mean blood pressure and systemic vascular resistance remain reduced. Thiazide diuretics may interfere with breast milk products.

Pharmacokinetics

Pharmacokinetic parameters of amlodipine, valsartan and hydrochlorothiazide are characterized by linearity.

Amlodipine

After oral administration, amlodipine is slowly and almost completely absorbed from the gastrointestinal tract. A simultaneous meal does not affect the absorption of amlodipine. Cmax in blood plasma is achieved 6-12 hours after administration. The average absolute bioavailability is 64-80%. The average Vd is 21 l / kg body weight, which indicates that most of the amlodipine is in the tissues, and a smaller part is in the blood. Most of the amlodipine in the blood (97.5%) is bound to plasma proteins. Css in the blood plasma is reached after 7-8 days of continuous administration of amlodipine. Amlodipine penetrates the BBB and placental barrier.
Amlodipine undergoes a slow but active metabolism in the liver in the absence of a significant “first pass” effect through the liver. Metabolites do not have significant pharmacological activity.
After a single dose of amlodipine, T1 / 2 varies from 35 to 50 hours, with repeated use it is approximately 45 hours. About 60% of the ingested dose is excreted by the kidneys mainly in the form of metabolites, 10% - unchanged, 20-25% - through the intestines bile. The total clearance of amlodipine is 0.116 ml / s / kg (7 ml / min / kg, 0.42 l / h / kg). Amlodipine is not removed by hemodialysis.
Elongation of T1 / 2 in patients with hepatic insufficiency suggests that with prolonged use cumulation of amlodipine in the body will be higher (up to 60 hours).

Valsartan

After taking valsartan inside C max is achieved in 2-3 hours. The average absolute bioavailability is 23%. When taking valsartan with food, there is a decrease in bioavailability (by AUC value) by about 40%, and Cmax - by about 50%. Approximately 8 hours after oral administration, plasma concentrations of valsartan in the group of patients taking Co-Vamsolet with food and in the group taking the drug on an empty stomach are aligned. AUC reduction is not clinically significant, so valsartan can be taken regardless of the meal.
Vd of valsartan in the period of equilibrium after iv administration is about 17 liters, which indicates the absence of an extensive distribution of valsartan in the tissues. Valsartan is largely associated with serum proteins (94-97%), mainly with serum albumin.
Valsartan is not subject to pronounced metabolism. About 20% of the dose taken is determined in plasma in the form of metabolites. Hydroxyl metabolite is determined in plasma in low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.
Valsartan is biphasic: the α phase with T1 / 2α is less than 1 hour and the β phase with T1 / 2β is about 9 hours. Valsartan is mainly excreted unchanged through the intestines (about 83%) and the kidneys (about 13%). After IV injection, 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). T1 / 2 valsartan is 6 hours.
On average, in patients with impaired mild liver function (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale), the bioavailability (in terms of AUC) of Valsartan is doubled compared with healthy volunteers of the corresponding age , sex and body weight.

Hydrochlorothiazide

After oral administration, Cmax of hydrochlorothiazide is achieved within 1–3 hours. Absolute bioavailability is assessed by cumulative renal excretion of hydrochlorothiazide and is about 60%. Binding to plasma proteins is 40-70%. Vd - 0.8 ± 0.3 l / kg. Not metabolized in the human body and excreted in the urine almost unchanged. About 60% of the dose taken orally is removed within 48 hours. Renal clearance is about 250-300 ml / min. T1 / 2 - 10-15 hours. There is a difference in plasma concentrations in men and women. Women tend to have a clinically significant increase in the plasma concentration of hydrochlorothiazide. In patients with impaired renal function, the rate of elimination of hydrochlorothiazide is reduced. Studies conducted with patients with CC 90 ml / min showed that T1 / 2 of hydrochlorothiazide increases. In patients with reduced T1 / 2 kidney function, about 34 h.

Indications

- Arterial hypertension II and III degree.

Contraindications for Co-Vamsolet

- severe liver dysfunction (more than 9 points on the Child-Pugh scale);
- biliary cirrhosis and cholestasis;
- severe renal dysfunction (CC <30 ml / min), anuria, hemodialysis patients;
- severe hypotension (systolic blood pressure less than 90 mm Hg);
- collapse, cardiogenic shock;
- clinically significant aortic stenosis;
- hypokalemia, hyponatremia, hypercalcemia, as well as hyperuricemia with clinical manifestations, refractory to adequate therapy;
- hereditary angioedema, or edema in patients against the background of previous therapy with angiotensin II receptor antagonists;
- pregnancy and pregnancy planning;
- breastfeeding period;
- age up to 18 years (efficacy and safety have not been established);
- hypersensitivity to amlodipine, valsartan, hydrochlorothiazide, other sulfonamide derivatives, dihydropyridine derivatives and other auxiliary components of Co-Vamsolet.
Care should be taken when prescribing Co-Vamsolet to patients with unilateral or bilateral stenosis of the renal arteries or arterial stenosis of a single kidney, in conditions accompanied by a decrease in the BCC, in disorders of water and electrolyte balance (including hyponatremia, hyperkalemia), patients with mitral or aortic stenosis, hypertrophic obstructive cardiac artery. , mild and moderate liver dysfunction, especially against the background of biliary tract obstruction (less than 9 points on the Child-Pugh scale), sugar diabetes, SLE.
The safety of Co-Vamsolet in patients after recently transferred kidney transplantation, as well as in patients with heart failure or coronary heart disease has not been established.

Dosage

Co-Vamsolet is taken orally, regardless of the meal, preferably in the morning, with a small amount of water.
For convenience, patients receiving therapy with amlodipine, valsartan and hydrochlorothiazide in separate tablets can be transferred to therapy with this combination, containing the same doses of active ingredients, as well as with insufficient blood pressure control against the background of dual combination therapy (valsartan + hydrochlorothiazide, amlodipine + valsartan and amlodipine + hydrochlorothiazide) patients can be transferred to the triple combination treatment with Co-Vamsolet in appropriate doses.
If a patient has dose-dependent side effects when using dual combination therapy with any of the components of Co-Vamsolet, to achieve a similar reduction in blood pressure, patients may be prescribed a drug containing a lower dose of the active component that caused this side effect.
Recommended daily doses of Co-Vamsolet are: 5 mg + 160 mg + 12.5 mg (1 tab. Containing amlodipine + valsartan + hydrochlorothiazide in doses of 5 mg + 160 mg + 12.5 mg); 10 mg + 160 mg + 12.5 mg (1 tab. Containing amlodipine + valsartan + hydrochlorothiazide in doses of 10 mg + 160 mg + 12.5 mg); 10 mg + 320 mg + 25 mg (2 tab., Containing amlodipine + valsartan + hydrochlorothiazide in doses of 5 mg + 160 mg + 12.5 mg).
The maximum antihypertensive effect of Co-Vamsolet is observed 2 weeks after increasing the dose. The maximum dose of the drug is 10 mg + 320 mg + 25 mg / day.
Patients over 65 years of age do not require dose adjustment.
Since the safety and efficacy of Co-Vamsolet in children and adolescents under the age of 18 years have not yet been established, the drug is not recommended for use in this category of patients.
In patients with mild and moderate renal dysfunction (CC> 30 ml / min) and liver (5-9 points on the Child-Pugh scale), dose adjustment is not required.

Side effects of Co-Vamsolet

Amlodipine + valsartan + hydrochlorothiazide
When using Co-Vamsolet, adverse events were mostly low or moderate. Termination of drug treatment due to the development of adverse events was required in rare cases. Most often, Co-Vamsolet was discontinued due to the development of dizziness and a pronounced decrease in blood pressure.
When using Co-Vamsolet, no new adverse events were detected compared with dual combination therapy and monotherapy with individual components.
As with short-term use, good tolerability of the drug was observed with its long-term use (during the year).
The incidence of adverse events was not related to gender, age, or race.
When using Co-Vamsolet, changes in laboratory parameters were minimal and did not differ from those on the background of monotherapy with individual components. With simultaneous use of hydrochlorothiazide together with valsartan (triple combination therapy) there is a decrease in the hypokalemic effect of hydrochlorothiazide.
The most frequent adverse events reported in clinical studies (regardless of identifying a connection with the drug) were dizziness, peripheral edema, headache, dyspepsia, fatigue, muscle spasm, back pain, nasopharyngitis, nausea.
The following criteria were used to estimate the frequency (according to the WHO classification): very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10,000, <1/1000); very rarely (<1/10 000), the frequency is unknown (not enough data to estimate the frequency of development).
Metabolism: often - hypokalemia; infrequently - hypercalcemia, hyperlipidemia, hyponatremia.
The nervous system: often - dizziness, headache; infrequently - insomnia / sleep disorders, lack of coordination, postural dizziness and dizziness due to exercise, taste disorders, lethargy, paresthesias, neuropathy, incl. peripheral, drowsiness, fainting.
From the senses: infrequently - visual disturbances, vertigo.
Since the cardiovascular system: often - a pronounced decrease in blood pressure; infrequently - tachycardia, orthostatic hypotension, phlebitis, thrombophlebitis.
On the part of the respiratory system: Infrequently - cough, shortness of breath, irritation in the throat.
On the part of the digestive system: often - dyspepsia; infrequently - anorexia, abdominal discomfort, pain in the upper abdomen, bad breath, diarrhea, dry mouth, nausea, vomiting.
Dermatological reactions: infrequently - increased sweating, itching.
On the part of the musculoskeletal system and connective tissue: infrequently - back pain, swelling in the joints, muscle spasms, muscle weakness, myalgia, pain in the extremities.
From the urinary system: often - pollakiuria; infrequently - an increase in plasma creatinine concentration, acute renal failure.
On the part of the reproductive system: infrequently - erectile dysfunction.
On the part of the body as a whole: often - peripheral edema, fatigue; infrequently - abasia, gait disturbances, asthenia, general weakness, pain in the chest.
From the laboratory parameters: infrequently - an increase in the content of urea nitrogen in the blood plasma, hyperuricemia, increase in body weight.

Amlodipine

The following criteria were used to estimate the frequency (according to the WHO classification): very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10,000, <1/1000); very rarely (<1/10 000), the frequency is unknown (not enough data to estimate the frequency of development).
From the hemopoietic system: very rarely - leukopenia, thrombocytopenia.
On the part of the immune system: very rarely - hypersensitivity reactions.
On the part of the metabolism: very rarely - hyperglycemia.
On the part of the nervous system: often - dizziness, headache, drowsiness; infrequently - insomnia / sleep disturbances, mood lability, paresthesias, syncope, tremor; very rarely - muscle hypertension, peripheral neuropathy, neuropathy; frequency unknown - extrapyramidal disorders.
On the part of the senses: infrequently - visual disturbances, tinnitus, taste disturbances.
Since the cardiovascular system: often - a feeling of palpitations, flushing of the face; infrequently - pronounced decrease in blood pressure; very rarely - vasculitis, arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation).
On the part of the respiratory system: infrequently - shortness of breath, rhinitis; very rarely - cough.
On the part of the digestive system: often - abdominal discomfort, pain in the upper abdomen, nausea; infrequently - change in the frequency of bowel movements, diarrhea, dry mouth, dyspepsia, vomiting; very rarely - gastritis, gingival hyperplasia, pancreatitis.
On the part of the liver and biliary tract: very rarely - increased activity of liver enzymes, increased plasma bilirubin concentration, hepatitis, intrahepatic cholestasis, jaundice.
Dermatological reactions: infrequently - alopecia, increased sweating, itching, rash, incl. exanthema, purpura, discoloration of the skin; very rarely - angioedema, erythema multiforme, urticaria.
On the part of the musculoskeletal system and connective tissue: infrequently - arthralgia, back pain, muscle spasms, myalgia.
From the urinary system: infrequently - urination disorders, nocturia, pollakiuria.
On the part of the reproductive system: infrequently - erectile dysfunction, gynecomastia.
On the part of the body as a whole: often - increased fatigue, edema; infrequently - asthenia, discomfort, general weakness, pain in the chest, pain of different localization.
From laboratory indicators: infrequently - increase or decrease in body weight.

Valsartan

The following criteria were used to estimate the frequency (according to the WHO classification): very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥ 1/1000, <1/100); rarely (≥ 1/10 000, <1/1000); very rarely (<1/10 000), the frequency is unknown (not enough data to estimate the frequency of development).
From the hematopoietic system: the frequency is unknown - decrease in hemoglobin and hematocrit, leukopenia, thrombocytopenia.
On the part of the immune system: the frequency is unknown - hypersensitivity reactions.
On the part of the organ of hearing: infrequently - vertigo.
Since the cardiovascular system: the frequency is unknown - vasculitis.
On the part of the respiratory system: Infrequently - cough.
On the part of the digestive system: infrequently - abdominal discomfort, pain in the upper abdomen.
On the part of the liver and biliary ducts: the frequency is unknown - an increase in the activity of liver enzymes, an increase in plasma bilirubin concentration.
Allergic reactions: frequency is unknown - angioedema, pruritus, rash.
On the part of the musculoskeletal system: the frequency is unknown - myalgia.
On the part of the urinary system: the frequency is unknown - increasing the concentration of creatinine in the blood plasma, renal dysfunction, including acute renal failure.
On the part of the body as a whole: infrequently - increased fatigue.
From the laboratory parameters: the frequency is unknown - an increase in the content of potassium in the blood plasma.
In clinical studies with the use of valsartan in monotherapy, the following adverse events were noted (regardless of their causal relationship with the studied drug): viral infections, upper respiratory tract infections, sinusitis, rhinitis, neutropenia, insomnia.
In rare cases, the use of valsartan may be accompanied by a decrease in hemoglobin and hematocrit. In controlled studies, 0.8% and 0.4% of patients treated with valsartan showed a significant decrease (over 20%) in hematocrit and hemoglobin, respectively. For comparison, in patients receiving placebo, a decrease in both hematocrit and hemoglobin was noted in 0.1% of cases.
Neutropenia was detected in 1.9% of patients who received valsartan and 1.6% of patients who received an ACE inhibitor.
In controlled studies, 3.9% and 16.6% of patients with chronic heart failure treated with valsartan showed an increase in the concentration of creatinine and blood urea nitrogen by more than 50%, respectively. For comparison, in patients receiving placebo, an increase in the concentration of creatinine and urea nitrogen was observed in 0.9% and 6.3% of cases.
Doubling of serum creatinine concentration was detected in 4.2% of patients after myocardial infarction who received valsartan and 3.4% of those who received captopril.
In controlled studies, an increase in the serum potassium content of more than 20% was observed in 10% of patients with chronic heart failure. For comparison, in patients receiving placebo, an increase in potassium was observed in 5.1% of cases.

Hydrochlorothiazide

The following criteria were used to estimate the frequency (according to the WHO classification): very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10,000, <1/1000); very rarely (<1/10 000), the frequency is unknown (not enough data to estimate the frequency of development).
From the hematopoietic system: rarely - thrombocytopenia; very rarely - agranulocytosis, inhibition of bone marrow hematopoiesis, hemolytic anemia, leukopenia.
On the part of the immune system: very rarely - hypersensitivity reactions.
Metabolism: often - hypokalemia; infrequently - hyperuricemia, hypomagnesemia, hyponatremia; rarely - hypercalcemia, hyperglycemia; very rarely - hypochloremic alkalosis.
On the part of the nervous system: rarely - insomnia / sleep disorders, depression, dizziness, headache, lethargy.
On the part of the organ of vision: infrequently - visual disturbances.
Since the cardiovascular system: infrequently - orthostatic hypotension; rarely, arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation).
On the part of the respiratory system: very rarely - respiratory distress syndrome, pulmonary edema and pneumonitis.
On the part of the digestive system: rarely - loss of appetite, nausea, vomiting; rarely - abdominal discomfort, pain in the upper abdomen, constipation, diarrhea; very rarely - pancreatitis.
On the part of the liver and biliary tract: rarely - hepatitis, intrahepatic cholestasis, jaundice.
Dermatological reactions: infrequently - rash, urticaria; rarely, increased photosensitivity, purpura; very rarely - necrotizing vasculitis, toxic epidermal necrolysis, lupus-like reactions, exacerbation of skin manifestations of systemic lupus erythematosus.
From the urinary system: rarely - renal dysfunction, including acute renal failure.
On the part of the reproductive system: infrequently - erectile dysfunction.
From the laboratory indicators: often - hyperlipidemia; rarely - glucosuria

Pregnancy and lactation

It is known that the appointment of ACE inhibitors that affect the RAAS, pregnant in the II and III trimesters, leads to damage or death of the developing fetus. Given the mechanism of action of angiotensin II receptor antagonists, the risk to the fetus cannot be ruled out. According to a retrospective analysis of the use of ACE inhibitors in the first trimester of pregnancy was accompanied by the development of pathology of the fetus and newborn. Hydrochlorothiazide penetrates the placental barrier. When using thiazide diuretics, including hydrochlorothiazide, pregnancy may develop embryonic or neonatal thrombocytopenia, as well as other undesirable reactions observed in adult patients. In case of unintentional intake of valsartan in pregnant women, cases of development of spontaneous abortions, low water and impaired renal function in newborns are described. Like any other drug that has a direct effect on the RAAS, it should not be prescribed during pregnancy and women planning pregnancy.
Patients of childbearing age should be informed of the possible risk to the fetus associated with the use of drugs that affect the RAAS. If pregnancy is diagnosed during the period of drug treatment, Co-Vamsolet should be canceled as soon as possible.
It is not known whether valsartan and / or amlodipine passes into breast milk. In experimental studies, the release of valsartan with breast milk was noted. Hydrochlorothiazide is excreted in breast milk. Co-Vamsolet should not be used during breastfeeding.

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