Co-Exforge tablets 10 mg + 160 mg + 12.5 mg, 28 pcs. (Amlodipine, Valsartan, Hydrochlorothiazide)

Packing

28 pcs.

Pharmacological action of

KO-EXFORGE is a combination of three antihypertensive components with a complementary mechanism of blood pressure control: amlodipine (a derivative of dihydropyridine) - a slow calcium channel blocker, valsartan - an antagonist of angiotensin II receptors (thiazide dihydrogen azothiazide). 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

Amlodipine, a component of Co-Exforge, inhibits the transmembrane intake of calcium ions in 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 OPSS and a decrease in blood pressure.

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

Plasma concentrations in the blood correlate with the 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 and effective renal plasma blood flow without changing the filtration fraction and the severity of proteinuria.

As with other slow calcium channel blockers, amlodipine in patients with normal left ventricular function showed a change in hemodynamic parameters of cardiac function at rest and during exercise: a slight increase in the cardiac index, without a significant effect on the maximum rate of pressure increase in left ventricle on end-diastolic pressure and volume of the left ventricle. Hemodynamic studies in intact animals and healthy volunteers showed that a 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 with beta-blockers.

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

Clinical efficacy of amlodipine in patients with stable angina has been proven, vasospastic angina pectoris and angiographically confirmed coronary artery disease.

In a lengthy placebo-controlled study (PRAISE-2) in patients with chronic heart failure (NYHA class III and IV functional class) of non-ischemic etiology, amlodipine increased the incidence of pulmonary edema, in the absence of significant differences in the incidence of worsening chronic heart failure versus placebo.

Risk of myocardial infarction or an increase in the severity of angina pectoris: rarely, when therapy with slow calcium channel blockers is started or when their dose is increased in patients, especially with hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, an increase in frequency occurs the duration and severity of angina attacks or acute myocardial infarction developed. Arrhythmia (including ventricular tachycardia and atrial fibrillation) has also been observed with slow calcium channel blockers. It was impossible to differentiate these undesirable effects from the natural course of diseases.

Valsartan

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

Valsartan does not inhibit ACE, which converts angiotensin I to angiotensin II and causes the destruction of bradykinin. Because when using angiotensin II antagonists, ACE inhibition and the accumulation of bradykinin or substance P do not occur, 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

In the treatment of patients with arterial hypertension with valsartan, a decrease in blood pressure was observed, not accompanied by a change in heart rate.

The antihypertensive effect is manifested within 2 hours in most patients after a single oral administration of valsartan. The maximum decrease in blood pressure develops after 4-6 hours. After taking valsartan, the duration of the hypotensive effect persists for more than 24 hours. With repeated use, the maximum decrease in blood pressure, regardless of the dose taken, is usually achieved within 2-4 weeks and is maintained at the achieved level during long-term therapy. A sharp 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 (NYHA class II-IV functional class) 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 (stable clinical course) or with dysfunction of the left ventricle after myocardial infarction, a decrease in cardiovascular mortality is noted.

Hydrochlorothiazide

The point of application of the 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 ions (Na +) and chlorine (Cl-) is suppressed. The suppression of the co-transport system Na + and Сl–, apparently, occurs due to competition for the sites of binding of Сl– ions in this system. As a result, the excretion of sodium and chlorine ions increases approximately equally. As a result of the diuretic action, a decrease in BCC is observed, as a result of which the activity of renin, the secretion of aldosterone, excretion of potassium by the kidneys and, consequently, a decrease in the potassium content in the blood serum increase.

Amlodipine + valsartan + hydrochlorothiazide

When using triple combination therapy with amlodipine + valsartan + hydrochlorothiazide, a more pronounced decrease in systolic and diastolic blood pressure was observed compared with the double combinations: valsartan + hydrochlorothiazide, amlodipidine + amlipidine + valine. In patients with arterial hypertension of the II and III degree (initial mean blood pressure of 170/107 mm Hg) when using the combination therapy of amlodipine + valsartan + hydrochlorothiazide in a daily dose of 10 mg + 320 mg + 25 mg for 8 weeks, the average decrease in systolic and diastolic blood pressure was 39.7 / 24. 7 mmHg (compared with 32.0 / 19.7 mm Hg, 33.5 / 21.5 mm Hg, 31.5 / 19.5 mm Hg in combination with valsartan + hydrochlorothiazide at a dose of 320 mg + 25 mg, amlodipine + valsartan at a dose 10 mg + 320 mg and amlodipine + hydrochlorothiazide at a dose of 10 mg + 25 mg, respectively).

The highest antihypertensive effect of the drug Co-Exforge is observed 2 weeks after the start of the drug in the maximum individual dose inside.

When using Co-Exforge, the achievement of the target blood pressure (less than 140/90 mm Hg) was observed in 71% of patients, compared with 45-54% against the background of the use of double combinations.

After taking the drug, the antihypertensive effect persists for 24 hours.

The therapeutic efficacy of Co-Exforge does not depend on the age, gender and race of the patients.

Contraindications

Hypersensitivity to amlodipine, valsartan, hydrochlorothiazide, other sulfonamide derivatives, dihydropyridine derivatives and other auxiliary components of the

drug (Cl creatinine less than 30 ml / min), anuria

Refractory to adequate therapy hypokalemia, hyponatremia, hypercalcemia, as well as hyperuricemia with clinical pro detecting

Age 18 years (effectiveness and safety have been established).

Special instructions

Impaired renal function. When using Co-Exforge, it is necessary to regularly monitor the content of creatinine and potassium in the blood plasma.

Cancel beta-blockers. If it is necessary to cancel beta-blockers before starting therapy with Co-Exforge, the dose of beta-blockers should be reduced gradually. Since the composition of the drug Co-Exforge does not include beta-blocker, the use of the drug does not prevent the development of the withdrawal syndrome that occurs when the treatment with beta-blockers is abruptly stopped.

Pronounced decrease in blood pressure. In controlled studies, when using Co-Exforge in the maximum daily dose (10 mg + 320 mg + 25 mg) in patients with grade II and III arterial hypertension, a marked decrease in blood pressure, including orthostatic hypotension, was observed in 1.7% of cases (compared to 1 , 8, 0.4 and 0.2% in combination therapy with valsartan + hydrochlorothiazide at a dose of 320 mg + 25 mg, amlodipine + valsartan at a dose of 10 mg + 320 mg and amlodipine + hydrochlorothiazide at a dose of 10 mg + 25 mg, respectively) . In the event of the development of arterial hypotension, the patient should be laid with raised legs, if necessary, intravenously infuse 0.9% sodium chloride solution. After stabilization of blood pressure, treatment with Co-Exforge can be continued.

Hyponatremia and / or decreased bcc. In patients with activated RAAS (for example, with a deficiency of bcc and / or hyponatremia, as well as in patients receiving high doses of diuretics), when taking antagonists of angiotensin receptors, the development of symptomatic arterial hypotension is possible. Before starting treatment with Co-Exforge, a correction of the sodium content in the body and / or BCC should be carried out or therapy should be started under close medical supervision. When using Co-Exforge, regular monitoring of blood plasma electrolytes is necessary.

Change in plasma potassium concentration. In controlled trials, when using the combination of amlodidine + valsartan + hydrochlorothiazide in a maximum daily dose of 10 mg + 320 mg + 25 mg in patients with moderate to severe degree of arterial hypertension, the incidence of hypokalemia (plasma potassium content of less than 3.5 mmol / L) was 9.9% compared to 24.5, 6.6 and 2, 7% in combination therapy with amlodipine + hydrochlorothiazide at a dose of 10 mg + 25 mg, valsartan + hydrochlorothiazide at a dose of 320 mg + 25 mg and amlodipine + valsartan at a dose of 10 mg + 320 mg, respectively. The frequency of discontinuation of therapy due to the development of hypokalemia was 0.2% (1 patient) in the groups of Co-Exforge and amlodipine + hydrochlorothiazide. In patients treated with Co-Exforge, hyperkalemia (potassium in the blood plasma of more than 5.7 mmol / l) was observed in 0.4% of cases (compared with 0.20.7% with double combinations). When using Co-Exforge in a controlled study, the opposite effects of valsartan at a dose of 320 mg per day and hydrochlorothiazide at a dose of 25 mg per day on potassium in the blood serum almost balanced each other in many patients. In other cases, patients had either hypo- or hyperkalemia. When using Co-Exforge, regular monitoring of potassium in the blood plasma is necessary.

Systemic lupus erythematosus. When using thiazide diuretics, including hydrochlorothiazide, an aggravation of the course or development of systemic lupus erythematosus has been reported.

Other metabolic disorders. Thiazide diuretics can interfere with glucose tolerance and increase plasma concentrations of cholesterol, triglycerides and uric acid.

When using thiazide diuretics, a decrease in calcium excretion is possible, leading to the development of moderate hypercalcemia. Severe hypercalcemia during therapy with Co-Exforge may indicate latent hyperparathyroidism.

Influence on the ability to drive vehicles and work with mechanisms. Some side effects of the drug, including dizziness or visual impairment can adversely affect the ability to drive vehicles and perform potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.

Composition of

Amlodipine besilate 6.94 mg, which corresponds to the content of amlodipine 5 mg, valsartan 160 mg, hydrochlorothiazide 12.5 mg.

Excipients: microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate.

The composition of the film membrane: hypromellose, titanium dioxide (E171), macrogol, talc.

Dosage and administration

The drug should be taken orally (preferably in the morning), washed down with a small amount of water, regardless of food intake.

For convenience, patients, receiving therapy with amlodipine, valsartan and hydrochlorothiazide in separate tablets can be transferred to therapy with Co-Exforge containing the same doses of active components, as well as with insufficient control of blood pressure during dual combination therapy (valsartan + hydrochlorothiazide, amlodipine + valsartan and amlodipine + hydrochlorothiazide), patients can be transferred to a triple combination treatment with Co-Exforge in appropriate doses.

If a patient has dose-related side effects when using double combination therapy with any components of Co-Exforge, to achieve a similar decrease in blood pressure, patients may be prescribed Co-Exforge containing a lower dose of the active component that caused this side effect.

Recommended daily doses of Co-Exforge are:

- 5 mg + 160 mg + 12.5 mg (1 tablet containing amlodipine + valsartan + hydrochlorothiazide in doses of 5 mg + 160 mg + 12.5 mg)

- 10 mg + 160 mg + 12.5 mg (1 tablet containing amlodipine + valsartan + hydrochlorothiazide in doses of 10 mg + 160 mg + 12.5 mg)

- 10 mg + 320 mg + 25 mg (2 tablets containing amlodipine + valsartan + hydrochlorothiazide in doses of 5 mg + 160 mg + 12.5 mg).

The maximum antihypertensive effect of the drug is observed 2 weeks after increasing the dose. The maximum dose of the drug is 10 mg + 320 mg + 25 mg /

In patients over 65 years of age, dose adjustment of the drug is not required.

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

In patients with mild to moderate impaired renal function (CC more than 30 ml / min) and liver (5-9 points on the Child-Pugh scale) dose adjustment is not required.

Side effects

The following criteria were used to estimate the frequency (according to the WHO classification): very often (? 1/10) often (? 1/100, metabolic and nutritional disorders: often - hypokalemia infrequently - anorexia, hypercalcemia, hyperlipidemia hyponatremia

Mental disorders: infrequently - insomnia / sleep disturbances, drowsiness

From the nervous system: often - dizziness, headache infrequently - impaired coordination postural dizziness and dizziness due to physical exertion, taste disorders, lethargy, paresthesia, neuropathy, including peripheral, fainting.

From the side of the organ of vision: infrequently - visual disturbances.

On the part of the organ of hearing and labyrinth disorders: infrequently - vertigo.

From the cardiovascular system: often - a marked decrease in blood pressure infrequently - tachycardia, orthostatic hypotension, phlebitis, thrombophlebitis.

From the respiratory system, chest and mediastinal organs: infrequently - cough, shortness of breath, sore throat.

From the digestive system: often - dyspepsia infrequently - discomfort in the abdomen, pain in the upper abdomen, bad breath, diarrhea, dry mouth, nausea, vomiting.

From the skin and subcutaneous fat: infrequently - increased sweating, itching.

From the side of the musculoskeletal system and connective tissue: infrequently - back pain, swelling in the joints, muscle cramps, muscle weakness, myalgia, pain in the limbs.

From the side of the kidneys and urinary tract: often - pollakiuria infrequently - increased plasma creatinine concentration, acute renal failure.

From the genitals and mammary gland: infrequently - erectile dysfunction.

General disorders and disorders at the injection site: often - peripheral edema, fatigue infrequently - abasia, gait disorders, asthenia, general weakness, pain in the chest area.

Laboratory and instrumental data: infrequently - increased plasma urea nitrogen, hyperuricemia, increased body weight.

Amlodipine

The following criteria were used to estimate the frequency (according to the WHO classification): very often (? 1/10) often (? 1/100, On the part of the blood and lymphatic system: very rarely - leukopenia, thrombocytopenia.

On the part of the immune system: very rarely - hypersensitivity reactions.

Disorders from metabolism and nutrition: very rarely - hyperglycemia.

Mental disorders: infrequently - insomnia / sleep disturbances, drowsiness, lability of mood.

From the nervous system: often - dizziness, headache infrequently - taste disturbances, paresthesias, fainting, tremors very rarely - muscle hypertonicity, peripheral neuropathy, neuropathy, frequency is unknown - extrapyramidal disorders.

From the side of the organ of vision: infrequently - visual disturbances.

Hearing and labyrinth disorders: infrequently - tinnitus.

From the cardiovascular system: often - a feeling of a strong heartbeat, inflows to the face infrequently - a pronounced decrease in blood pressure is very rare - vasculitis, arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation).

From the respiratory system, chest and mediastinal organs: infrequently - shortness of breath, rhinitis very rarely - cough.

From the digestive system: often - discomfort in the abdomen, pain in the upper abdomen, nausea infrequently - changes in the frequency of bowel movements, diarrhea, dry mouth, dyspepsia, vomiting very rarely - gastritis, gingival hyperplasia, pancreatitis.

From the liver and biliary tract: very rarely - increased activity of liver enzymes, increased plasma bilirubin concentration, hepatitis, intrahepatic cholestasis, jaundice.

On the part of the skin and subcutaneous fat: infrequently - alopecia, increased sweating, itching, rash, including exanthema, purpura, discoloration of the skin is very rare - angioedema, erythema multiforme, urticaria.

From the side of the musculoskeletal system and connective tissue: infrequently - arthralgia, back pain, muscle cramps, myalgia.

From the kidneys and urinary tract: infrequently - impaired urination, nocturia, pollakiuria.

From the genitals and mammary gland: infrequently - erectile dysfunction, gynecomastia.

General disorders and disorders at the injection site: often - fatigue, swelling infrequently - asthenia, discomfort, general weakness, pain in the chest area, pain of various localization.

Laboratory and instrumental data: 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 appointments) often (? 1/100, from the blood and lymphatic system: frequency is unknown - decrease in hemoglobin and hematocrit, leukopenia, thrombocytopenia.

From the immune system: frequency is unknown - hypersensitivity reactions.

From hearing and labyrinth disorders: infrequently - vertigo

From the cardiovascular system: unknown frequency - vasculitis

From the respiratory system, chest and mediastinal organs: infrequently - cough

From the digestive system: infrequently Abdominal discomfort, pain in the upper abdomen

Liver and Biliary:. the frequency is unknown - increase in liver enzymes, increased bilirubin concentration in plasma

With the skin side and subcutaneous fat:. frequency unknown - angioedema, pruritus, rash.

From the side of the musculoskeletal system and connective tissue: frequency unknown - myalgia.

On the part of the kidneys and urinary tract: frequency unknown - increased plasma creatinine, impaired renal function, including acute renal failure.

General disorders and disorders at the injection site: infrequently - increased fatigue.

Overdose

There are currently no data on overdose cases.

Symptoms: with an overdose of valsartan, a pronounced decrease in blood pressure and dizziness can be expected.

An overdose of amlodipine can lead to excessive peripheral vasodilation and possible reflex tachycardia. I also report the occurrence of a pronounced and prolonged decrease in blood pressure until the development of shock with a fatal outcome.

The main clinical manifestations of an overdose of hydrochlorothiazide are symptoms associated with loss of electrolytes (hypokalemia, hypochloremia) and dehydration due to the stimulation of diuresis. The most common symptoms of an overdose are nausea and drowsiness. Hypokalemia may be accompanied by muscle cramps. With the concomitant use of cardiac glycosides (or other antiarrhythmic drugs), hypokalemia can increase cardiac arrhythmia.

Treatment: in case of accidental overdose, induce vomiting (if the drug was recently taken) or gastric lavage. The use of activated carbon in healthy volunteers immediately or 2 hours after taking amlodipine significantly reduced its absorption. With a marked decrease in blood pressure, the patient should be laid with raised legs, take active measures to increase blood pressure, maintain the activity of the cardiovascular system, including regular monitoring of the function of the heart and respiratory system, BCC and the amount of urine excreted. In the absence of contraindications in order to restore vascular tone and blood pressure, it is possible to use (with caution) a vasoconstrictor. In / in the introduction of solutions of calcium salts can be effective for eliminating BKK.

Excretion of valsartan and amlodipine during hemodialysis is unlikely. Hydrochlorothiazide can be removed from the systemic circulation by hemodialysis.

Storage conditions

The product should be stored in a dry, out of reach of children at a temperature not exceeding 25 ° C.

Expiration

1.5 years.

Dosage form

tablet

Novartis Farma Stein AG, Switzerland



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