Co-Exforge, pills 5mg+160mg+12.5mg, 28pcs

Composition

Amlodipine bezylate 6.94 mg, which corresponds to the content of amlodipine 5 mg,

valsartan 160 mg,

hydrochlorothiazide 12.5 mg. Auxiliary substances:

microcrystalline cellulose,

crospovidone,

colloidal silicon dioxide,

magnesium stearate. Composition of the film shell:

hypromellose,

titanium dioxide (E 171),

macrogol,

talc.

Pharmacological action

of CO-EXFORGE is a combination of three antihypertensive components with a complementary mechanism of blood pressure control: amlodipine (a dihydropyridine derivative) – a slow calcium channel blocker, valsartan-an angiotensin II (ATII) receptor antagonist and hydrochlorothiazide-a thiazide diuretic. The combination of these components leads to a more pronounced decrease in blood pressure compared to that on the background of monotherapy with each drug separately. Amlodipinamlodipine, which is part of the Co-Exforge preparation, inhibits the transmembrane supply of calcium ions to cardiomyocytes and vascular smooth muscle cells. The mechanism of antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscles, causing a decrease in OPSS and a decrease in blood pressure. After taking therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation, leading to a decrease in blood pressure (in the patient’s “lying” and “standing”positions). A decrease in blood pressure is not accompanied by a significant change in heart rate and catecholamine activity with prolonged use. Plasma concentrations of the drug 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 severity of proteinuria. As with other slow calcium channel blockers, patients with normal left ventricular function experienced a change in the hemodynamic parameters of cardiac function at rest and during exercise: a slight increase in the cardiac index, without a significant effect on the maximum rate of increase in left ventricular pressure, end-diastolic pressure and left ventricular volume. Hemodynamic studies in intact animals and healthy volunteers have shown that lowering blood pressure under the influence of amlodipine in the therapeutic dose range is not accompanied by a negative inotropic effect, even when used simultaneously with beta-blockers. Amlodipine does not alter sinoatrial node function and does not affect AV conduction in intact animals and healthy volunteers. When using amlodipine in combination with beta-blockers in patients with arterial hypertension or angina, a decrease in blood pressure is not accompanied by undesirable changes in electrocardiographic parameters. The clinical efficacy of amlodipine has been demonstrated in patients with stable angina, vasospastic angina and angiographically confirmed coronary artery disease. In a long-term placebo-controlled study (PRAISE-2) in patients with chronic heart failure (NYHA functional class III and IV) of non-ischemic etiology, when using amlodipine, there was an increase in the incidence of pulmonary edema, with no significant differences in the incidence of worsening of the course of chronic heart failure compared with placebo. Risk of myocardial infarction or increased severity of angina: rarely, when starting therapy with slow calcium channel blockers or increasing their dose, patients, especially with hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, experienced an increase in the frequency, duration and severity of angina attacks or developed acute myocardial infarction. Arrhythmias (including ventricular tachycardia and atrial fibrillation) have also been reported with slow calcium channel blockers. These adverse events could not be differentiated from the natural course of diseases. Valsartan Valsartan is an active and specific angiotensin II receptor antagonist intended for oral use. It acts selectively on AT1 subtype receptors, which are responsible for the effects of angiotensin II. An increase in the plasma concentration of unbound angiotensin II due to AT1-receptor blockade under the influence of valsartan can stimulate unblocked AT2-receptors, which counteract the effects of AT1-receptor stimulation. Valsartan does not have any pronounced agonistic activity against AT1 receptors. The affinity of valsartan for the AT1 subtype receptors is approximately 20,000 times higher than for the AT2 subtype receptors. Valsartan does not inhibit ACE, which converts angiotensin I to angiotensin II and causes the destruction of bradykinin. Since angiotensin II antagonists do not inhibit ACE and the accumulation of bradykinin or substance P, the development of dry cough is unlikely. In comparative clinical studies of valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (RR In valsartan treatment of patients with arterial hypertension, a decrease in blood pressure is noted, not accompanied by a change in heart rate. The antihypertensive effect appears within 2 hours in most patients after a single oral dose of valsartan. The maximum decrease in blood pressure develops in 4-6 hours. After taking valsartan, the duration of the antihypertensive effect persists for more than 24 hours. With repeated use, the maximum reduction in blood pressure, regardless of the dose taken, is usually achieved within 2-4 weeks and maintained at the achieved level during long-term therapy. Abrupt discontinuation of valsartan is not accompanied by a sharp increase in blood pressure or other undesirable clinical consequences. The use of valsartan in patients with chronic heart failure (NYHA functional class II-IV) leads to a significant reduction in the number of hospitalizations for cardiovascular diseases (which is especially pronounced in patients who do not receive ACE inhibitors or beta-blockers). When taking valsartan in patients with left ventricular insufficiency (stable clinical course) or with impaired left ventricular function after a myocardial infarction, a decrease in cardiovascular mortality is noted. Hydrochlorothiaz Idethe point of application of thiazide diuretics is the distal convoluted renal tubules. When thiazide diuretics are applied to highly sensitive receptors of the distal tubules of the cortical layer of the kidneys, reabsorption of sodium (Na+) and chlorine (Cl -) ions is suppressed. Suppression of the Na+ and Cl-co-transport system is probably due to competition for the binding sites of Cl-ions in this system. As a result, the removal of sodium and chlorine ions increases approximately equally. As a result of diuretic action, a decrease in BCC is observed, which increases the activity of renin, aldosterone secretion, excretion of potassium by the kidneys and, consequently, a decrease in the content of potassium in the blood serum. Amlodipine+valsartan +hydrochlorothiaz Ide When using triple combination therapy with amlodipine+valsartan+hydrochlorothiazide, there was a more pronounced decrease in systolic and diastolic blood pressure, compared with the use of double combinations: valsartan+hydrochlorothiazide, amlodipine+valsartan and amlodipine+hydrochlorothiazide. In patients with grade II and III hypertension (baseline mean BP 170/107 mm Hg), combined therapy with amlodipine+valsartan+hydrochlorothiazide at a daily dose of 10 mg+320 mg+25 mg for 8 weeks resulted in an average reduction in systolic and diastolic blood pressure of 39.7/24.7 mm Hg (compared to 32.0/19.7 mm Hg,33.5/21.5 mm Hg,31.5/19.5 mm Hg). combined 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). The greatest antihypertensive effect of Co-Exforge is observed 2 weeks after the start of the drug use in the maximum individual oral dose. When using Co-Exforge, the target blood pressure (less than 140/90 mm Hg) was achieved in 71% of patients, compared with 45-54% when using 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, or race of patients.

Indications

Arterial hypertension of II and III degrees.

Use during pregnancy and lactation

Contraindicated.

Contraindications

• Hypersensitivity to amlodipine, valsartan, hydrochlorothiazide, other sulfonamide derivatives, dihydropyridine derivatives and other auxiliary components of the drug;
• Pregnancy and breast-feeding period;
• Severe liver function disorders (more than 9 points on the Child-Pough scale);
• Severe renal dysfunction (creatinine clearance less than 30 ml / min), anuria;
• Hypokalemia, hyponatremia, hypercalcemia, as well as hyperuricemia with clinical manifestations that are refractory to adequate therapy;
• Age up to 18 years (efficacy and safety have not been established).

Side effects

The following criteria (according to the WHO classification) were used to assess the frequency: very common (≥1/10); frequent (≥1/100,

From the side of metabolism: often-hypokalemia; infrequently – anorexia, hypercalcemia, hyperlipidemia, hyponatremia.

From the nervous system: often – dizziness, headache; infrequently-insomnia/sleep disorders, coordination disorders, postural dizziness and dizziness due to physical exertion, taste disorders, lethargy, paresthesia, neuropathy, including peripheral, drowsiness, fainting.

From the sensory organs: infrequently-visual disturbances, vertigo.

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

From the respiratory system: infrequently-cough, shortness of breath, irritation in the throat.

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

Dermatological reactions: infrequently-increased sweating, itching.

Musculoskeletal and connective tissue disorders: infrequently-back pain, joint swelling, muscle spasms, muscle weakness, myalgia, pain in the extremities.

From the urinary system: often-pollakiuria; infrequently-increased creatinine concentration in blood plasma, acute renal failure.

From the side of the reproductive system: infrequently-erectile dysfunction.

From the body as a whole: often – peripheral edema, increased fatigue; infrequently – abasia, gait disorders, asthenia, general weakness, chest pain.

From the side of laboratory parameters: infrequently-increased urea nitrogen content in blood plasma, hyperuricemia, increased body weight.

Interaction

Amlodipine When amlodipine is administered alone, there is no clinically significant interaction with thiazide diuretics, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, antacids (magnesium hydroxide, aluminum hydroxide gel, simethicone), cimetidine, NSAIDs, antibiotics, etc. hypoglycemic drugs for oral use.

Inhibitors of the CYP 3A4 isoenzyme. When amlodipine is co-administered with diltiazem, elderly patients show a slowdown in amlodipine metabolism, probably due to inhibition of the CYP3A4 isoenzyme, which leads to an increase in the concentration of amlodipine in blood plasma by approximately 50% and an increase in its systemic exposure. When amlodipine is co-administered with potent CYP3A4 inhibitors (e. g. ketoconazole, itraconazole, and ritonavir), systemic exposure to amlodipine may be significantly increased.

Inducers of the CYP3A4 isoenzyme. Since the use of amlodipine together with inducers of the CYP3A4 isoenzyme (for example, carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidone, rifampicin, grapefruit juice, herbal preparations containing St. John’s wort) can lead to a pronounced decrease in its concentration in blood plasma, when prescribing amlodipine with inducers of CYP3A4, its content in blood plasma should be monitored. Valsartan Monotherapy with valsartan was found to have no clinically significant interaction with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, Indometacin, hydrochlorothiazide, amlodipine, glibenclamide. When used concomitantly with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other drugs that may cause an increase in the blood potassium content (for example, with heparin), care should be taken and regular monitoring of the blood potassium content should be carried out.

When valsartan is used together with NSAIDs, the antihypertensive effect of valsartan may be reduced. Hydrochlorothiazide lithium. When used concomitantly with ACE inhibitors and diuretics, cases of reversible increases in the plasma concentration of lithium and its toxic effect have been reported. Therefore, when using hydrochlorothiazide and lithium preparations simultaneously, it is recommended to monitor the concentration of lithium in blood plasma.

Peripheral muscle relaxants. Thiazide diuretics, including hydrochlorothiazide, potentiate the effect of peripheral muscle relaxants.

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

Medications that may cause an increase in the potassium content in the blood plasma. The risk of hypokalemia increases with the simultaneous use of other diuretics, corticosteroids, ACTH, amphotericin B, carbenoxolone and acetylsalicylic acid (at a dose of more than 3 g). Caution should be exercised when using Co-Exforge concomitantly with potassium salts, potassium-sparing diuretics, potassium-containing food salt substitutes, as well as with medications that may cause an increase in blood potassium (for example, heparin).

Cardiac glycosides. Thiazide diuretics may cause undesirable effects such as hypokalemia or hypomagnesemia; these conditions increase the risk of arrhythmia with concomitant use of cardiac glycosides.

Hypoglycemic agents for oral use and insulin. When using the drug in patients with diabetes mellitus, it may be necessary to adjust the dose of insulin or hypoglycemic agents for oral use. Since lactic acidosis may develop when using hydrochlorothiazide together with metformin (due to impaired function during hydrochlorothiazide therapy), caution should be exercised when using Co-Exforge in patients receiving metformin treatment.

Anticholinergic drugs. It is possible to increase the bioavailability of a thiazide diuretic with simultaneous use of m-holinoblockers (for example, atropine, biperiden), which, apparently, is associated with a decrease in gastrointestinal motility and a slowdown in the rate of gastric emptying.

Methyldopa. Cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa. Colestyramine reduces the absorption of thiazide diuretics, including hydrochlorothiazide.

Vitamin D and calcium salts. When combined with thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts, an increase in serum calcium content may occur.

Cyclosporine. Concomitant use of cyclosporine may increase the risk of hyperuricemia and gout-like symptoms.

Carbamazepine. Hyponatremia may occur in patients taking hydrochlorothiazide concomitantly with carbamazepine. Since hyponatremia may occur in patients receiving concomitant treatment with hydrochlorothiazide and carbamazepine, appropriate monitoring of the sodium content in blood plasma should be performed when Co-Exforge is prescribed together with carbamazepine.

Other types of interaction. Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol; increase the risk of side effects of amantadine; increase the hyperglycemic effect of diazoxide; decrease renal excretion of cytotoxic agents (for example, cyclophosphamide, methotrexate) and potentiate their myelosuppressive effect.

How to take, course of use and dosage

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 blood pressure control on the background of double combination therapy (valsartan+hydrochlorothiazide, amlodipine+valsartan and amlodipine+hydrochlorothiazide), patients can be transferred to triple combination treatment with Co-Exforge in appropriate cases. in different doses. If a patient has dose-dependent side effects when using double combination therapy with any components of the drug Co-Exforge, to achieve a similar reduction in blood pressure, patients can be prescribed a drug 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, no dose adjustment is required. Since the safety and efficacy 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 renal impairment (creatinine clearance greater than 30 ml/min) and liver (5-9 points on the Child-Pugh scale), no dose adjustment is required.

Overdose

Data on drug overdose cases are currently unavailable.

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

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

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

Treatment: in case of accidental overdose, induce vomiting (if the drug was taken recently) or perform gastric lavage. The use of activated charcoal 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 placed 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 released.

In the absence of contraindications, a vasoconstrictor may be used (with caution) to restore vascular tone and blood pressure. Intravenous use of calcium salt solutions can be effective in eliminating calcium channel blockages. Elimination of valsartan and amlodipine during hemodialysis is unlikely. Hydrochlorothiazide can be removed from the systemic circulation by hemodialysis.

Special instructions

Impaired renal function

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

Withdrawal of 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 Co-Exforge does not contain a beta-blocker, the use of the drug does not prevent the development of a “withdrawal” syndrome that occurs when beta-blockers are abruptly discontinued.

Marked decrease in blood pressure

In controlled trials, when Co-Exforge was administered at 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 was observed in 1.7% of cases, including orthostatic hypotension (compared to 1.8%,0.4% and 0.2% against the background of combined 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). If arterial hypotension develops, the patient should be placed with raised legs, if necessary, an intravenous infusion of 0.9% sodium chloride solution should be performed. After blood pressure stabilizes, treatment with Co-Exforge can be continued.

Hyponatremia and / or decreased BCC

In patients with activated RAAS (for example, with BCC deficiency and/or hyponatremia, as well as in patients receiving high doses of diuretics), when taking angiotensin receptor antagonists, symptomatic hypotension may develop. Before starting treatment with Co-Exforge, the body’s sodium content and/or BCC should be corrected, or therapy should be initiated under close medical supervision. When using the drug Co-Exforge, it is necessary to regularly monitor the content of blood plasma electrolytes.

Changes in the concentration of potassium in the blood plasma

In controlled trials, when using the combination of amlodipine+valsartan+hydrochlorothiazide at a maximum daily dose of 10 mg+320 mg+25 mg in patients with moderate and severe arterial hypertension, the incidence of hypokalemia (plasma potassium content less than 3.5 mmol/l) was 9.9% compared to 24.5%,6.6% and 2.7% against the background of 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 due to hypokalemia was 0.2% (one patient) in the Co-Exforge and amlodipine+hydrochlorothiazide groups. In patients treated with Co-Exforge, hyperkalemia (plasma potassium content of more than 5.7 mmol / l) was observed in 0.4% of cases (compared to 0.2-0.7% with the use of double combinations). When Co-Exforge was used in a controlled study, the opposite effects of valsartan at a dose of 320 mg / day and hydrochlorothiazide at a dose of 25 mg / day on the serum potassium content were almost balanced in many patients. In all other cases, patients had either hypo-or hyperkalemia. When using the drug Co-Exforge, it is necessary to regularly monitor the content of potassium in the blood plasma.

Systemic lupus erythematosus

Worsening of the course or development of systemic lupus erythematosus has been reported with thiazide diuretics, including hydrochlorothiazide.

Other metabolic disorders

Thiazide diuretics may impair glucose tolerance and increase plasma concentrations of cholesterol, triglycerides, and uric acid.

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

Influence on the ability to drive motor vehicles and manage mechanisms

Some side effects of the drug, including dizziness or visual disturbances, may adversely affect the ability to drive vehicles and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Form of production

Pills.

Storage conditions

In a dry place, at a temperature not exceeding 25 °C

Shelf life

18 months

Active ingredient

Amlodipine, Valsartan, Hydrochlorothiazide

Conditions of release from pharmacies

By prescription

Dosage form

Tablets