Exforge is a Swiss combination drug for hypertension. Features of using Exforge tablets according to the instructions, taking into account reviews, analogues for blood pressure Contraindications for the medicine "Co-Exforge"

There are contraindications. Before starting use, consult your doctor.

All Sartans (representatives of the same class).

All drugs used in cardiology.

You can ask a question or leave a review about the medicine (please, do not forget to indicate the name of the drug in the text of the message).

If factory combinations are unavailable, a similar effect will be achieved by the combined use of the drugs included in the combination in the same doses.

Exforge - review from a cardiologist:

A powerful drug for the treatment of severe hypertension.

Works especially well in heavier patients.

The only drawback is the price, which continues to creep up.

If the drug is not available in pharmacies or if it is impossible to purchase the drug for financial reasons, you can combine generics of the drug components, since there are many of them in pharmacies.

Exforge - official instructions for use. The drug is a prescription, the information is intended only for healthcare professionals!

Antihypertensive drug

pharmachologic effect

A combined antihypertensive drug containing active substances with a complementary mechanism for blood pressure control. Amlodipine, a dihydropyridine derivative, belongs to the class of slow calcium channel blockers (SCBCs), valsartan belongs to the class of angiotensin II receptor antagonists. The combination of these components has a mutually complementary antihypertensive effect, which leads to a more pronounced decrease in blood pressure compared to that during monotherapy with each drug.

Amlodipine

Amlodipine, which is part of Exforge, 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 peripheral vascular resistance and a decrease in blood pressure.

When taken in therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation, leading to a decrease in blood pressure (with the patient lying and standing). A decrease in blood pressure is not accompanied by a significant change in heart rate and catecholamine levels with long-term use.

Plasma concentrations of the drug correlate with the clinical effect 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 level of proteinuria.

As with the use of other BMCCs, taking amlodipine in patients with normal left ventricular function caused changes in hemodynamic parameters of cardiac function at rest and during physical activity: there was a slight increase in cardiac index without a significant effect on the maximum rate of increase in pressure in the left ventricle, end-diastolic pressure and volume of the left ventricle. Hemodynamic studies in intact animals and humans have shown 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 alter sinoatrial node function or AV conduction in intact animals or humans. 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 ECG parameters.

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

Valsartan

Valsartan is an active and specific angiotensin II receptor antagonist intended for oral administration. It acts selectively on the AT1 receptor subtype, which is responsible for the known effects of angiotensin II. An increase in plasma concentrations of free angiotensin II due to blockade of AT1 receptors 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 ACE, also known as kininase II, which converts angiotensin I to angiotensin II and causes the destruction of bradykinin.

Because When using angiotensin II antagonists, ACE inhibition and accumulation of bradykinin or substance P do not occur, and the development of a dry cough is unlikely.

<0.05) у больных, получавших валсартан (у 2.6% пациентов, получавших валсартан, и у 7.9% - получавших ингибитор АПФ). В клиническом исследовании, включавшем больных, у которых ранее при лечении ингибитором АПФ развивался сухой кашель, при лечении валсартаном это осложнение было отмечено в 19.5% случаев, при лечении тиазидным диуретиком - в 19% случаев. В то же время, в группе больных, получавших лечение ингибитором АПФ, кашель наблюдался в 68.5% случаев (р<0.05). Валсартан не вступает во взаимодействие и не блокирует рецепторы других гормонов или ионные каналы, имеющие важное значение для регуляции функций сердечно-сосудистой системы.

The antihypertensive effect appears within 2 hours in most patients after a single dose of the drug. The maximum decrease in blood pressure develops after 4-6 hours. After taking the drug, the duration of the hypotensive effect lasts 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. 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 (functional class II-IV according to the NYHA classification) leads to a significant reduction in the number of hospitalizations. This effect is most pronounced in patients not receiving ACE inhibitors or beta-blockers. When taking valsartan in patients with left ventricular failure (stable clinical course) or with impaired left ventricular function after myocardial infarction, a decrease in cardiovascular mortality is observed.

Amlodipine/valsartan

In patients with arterial hypertension who received Exforge once a day, the antihypertensive effect persisted for 24 hours.

Exforge in doses of 5/80 mg and 5/160 mg in patients with initial systolic blood pressure 153-157 mm Hg. Art. and diastolic blood pressure? 95 mm Hg. and less than 110 mm Hg. reduces blood pressure by 20-28/14-19 mm Hg. (compared to 7-13/7-9 mmHg when taking placebo).

Exforge at a dose of 10/160 mg and 5/160 mg normalizes blood pressure (decrease in diastolic blood pressure in a sitting position by less than 90 mm Hg at the end of the study) in 75% and in 62% of patients with inadequate blood pressure control during monotherapy with valsartan at a dose of 160 mg per day.

Exforge at a dose of 10/160 mg normalizes blood pressure in 78% of patients with inadequate blood pressure control during monotherapy with amlodipine at a dose of 10 mg. In patients with arterial hypertension, when combining valsartan at a dose of 160 mg with amlodipine at doses of 10 mg and 5 mg, an additional reduction in systolic and diastolic blood pressure by 6.0/4.8 mm Hg is achieved. and 3.9/2.9 mmHg. respectively, compared with patients who continued to receive valsartan 160 mg alone or amlodipine 5 and 10 mg alone.

When titrating the dose of Exforge from 5/160 mg to 10/160 mg in patients with arterial hypertension with diastolic blood pressure? 110 mm Hg. and less than 120 mm Hg. There is a decrease in blood pressure in the sitting position by 36/29 mmHg, comparable to the decrease in blood pressure when titrating the dose of a combination of an ACE inhibitor and a thiazide diuretic.

In two long-term studies with long follow-up, the effect of Exforge was maintained for 1 year. Sudden cessation of Exforge is not accompanied by a sharp increase in blood pressure.

In patients who achieved adequate blood pressure control, but developed severe edema during amlodipine monotherapy, when using combination therapy, comparable blood pressure control was achieved with a lower likelihood of developing edema.

The therapeutic effectiveness of Exforge does not depend on the age, gender and race of the patient.

Pharmacokinetics

The pharmacokinetics of valsartan and amlodipine are characterized by linearity.

Amlodipine

Suction

After oral administration of amlodipine in therapeutic doses, Cmax of amlodipine in the blood plasma is achieved after 6-12 hours. The value of absolute bioavailability averages 64-80%. Food intake does not affect the bioavailability of amlodipine.

Distribution

Metabolism

Removal

The elimination of amlodipine from plasma is biphasic with a T1/2 of approximately 30 to 50 hours. Css in blood plasma are achieved after prolonged use for 7-8 days. 10% of unchanged amlodipine and 60% of amlodipine in the form of metabolites are excreted by the kidneys.

Valsartan

Suction

After oral administration of valsartan, Cmax in blood plasma is achieved within 2-3 hours. The average absolute bioavailability is 23%. The pharmacokinetic curve of valsartan has a descending multi-exponential character (T1/2?<1 ч и T1/2? около 9 ч). При приеме валсартана с пищей отмечается снижение биодоступности (по значению AUC) на 40% и Cmax в плазме крови почти на 50%, хотя приблизительно через 8 ч после приема препарата концентрации валсартана в плазме крови в группе пациентов, принимавших его с пищей, и в группе, принимавшей натощак, выравниваются. Уменьшение AUC, однако, не сопровождается клинически значимым снижением терапевтического эффекта, поэтому валсартан можно назначать вне зависимости от времени приема пищи.

Distribution

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 active.

Removal

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/h and its renal clearance is 0.62 l/h (about 30% of the total clearance). T1/2 of valsartan is 6 hours.

Amlodipine/valsartan

After oral administration of Exforge, Cmax of valsartan and amlodipine is achieved after 3 hours and 6-8 hours, respectively. The rate and extent of absorption of Exforge is equivalent to the bioavailability of valsartan and amlodipine when taken as separate tablets.

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

The time to reach Cmax of amlodipine in blood plasma is the same in young and elderly patients. In elderly patients, the clearance of amlodipine is slightly reduced, which leads to an increase in AUC and T1/2.

In elderly patients, the systemic exposure to valsartan was slightly greater than in younger patients, but this was not clinically significant. Since the tolerability of the drug components in older and younger patients is equally good, it is recommended to use the usual dosage regimens.

In patients with impaired renal function, the pharmacokinetic parameters of amlodipine do not change significantly. There was no correlation between renal function (KF) and systemic exposure of valsartan (AUC) in patients with varying degrees of renal impairment. No change in the initial dose is required in patients with initial and moderate renal impairment (creatinine clearance 30-50 ml/min).

Patients with hepatic impairment have reduced clearance of amlodipine, resulting in an increase in AUC of approximately 40-60%. On average, in patients with mild to moderate chronic liver disease, the bioavailability (AUC) of valsartan is doubled compared to healthy volunteers (matched for age, sex and body weight).

Indications for use of the drug EXFORG

• arterial hypertension (for patients for whom combination therapy is indicated).

Dosage regimen

The drug should be taken orally with a small amount of water, 1 time per day, regardless of the time of meal.

When prescribed to elderly patients, patients with initial or moderate renal impairment (creatinine clearance>30 ml/min), with impaired liver function or liver disease, with symptoms of cholestasis, no change in dosage regimen is required.

Side effect

The safety of Exforge has been assessed in more than 2600 patients.

Criteria for assessing the frequency of adverse reactions: very often - more than 10% of cases; often - 1% -10%; sometimes - 0.1-1%; rarely - 0.001-0.1%; in some cases - less than 0.001%. Within each group, identified by frequency of occurrence, adverse reactions are distributed in decreasing order of importance.

From the respiratory system: often - nasopharyngitis, influenza; sometimes - cough, pain in the pharynx and larynx.

From the senses: rarely - visual impairment, tinnitus; sometimes - dizziness associated with dysfunction of the vestibular apparatus.

From the central nervous system and peripheral nervous system: often - headache; sometimes - dizziness, drowsiness, orthostatic dizziness, paresthesia; rarely - anxiety.

From the cardiovascular system: sometimes - tachycardia, palpitations, orthostatic hypotension; rarely - syncope, marked decrease in blood pressure.

From the digestive system: sometimes - diarrhea, nausea, abdominal pain, constipation, dry mouth.

Dermatological reactions: sometimes - skin rash, erythema; rarely - hyperhidrosis, exanthema, itching.

From the musculoskeletal system: sometimes - swelling of the joints, back pain, arthralgia; rarely - muscle spasms, a feeling of heaviness throughout the body.

From the urinary system: rarely - pollakiuria, polyuria.

From the reproductive system: rarely - erectile dysfunction.

Other: often - pastiness, facial swelling, peripheral edema, increased fatigue, flushing of the face, asthenia, feeling of heat.

In comparative and placebo-controlled clinical studies, the incidence of peripheral edema was significantly lower in patients receiving a combination of amlodipine with valsartan (5.8%) than in patients receiving amlodipine monotherapy (9%).

From the laboratory parameters: an increase in blood urea nitrogen (more than 3.1 mmol/l) was observed slightly more often in the groups receiving amlodipine/valsartan (5.5%) and valsartan as monotherapy (5.5%), compared with the group receiving placebo (4.5% ).

Allergic reactions: rarely - hypersensitivity to the components of the drug.

Adverse events previously reported with each of the components may occur with Exforge, even if they were not observed in clinical studies.

Amlodipine

In those clinical studies where amlodipine was used as monotherapy, other adverse events were also observed (regardless of their causal relationship with the drug being studied): most often - nausea; less often - alopecia, change in the frequency of defecation, dyspepsia, shortness of breath, rhinitis, gastritis, hyperplasia of the gum mucosa, gynecomastia, hyperglycemia, erectile dysfunction, increased urination, leukopenia, general malaise, mood lability, dry mouth, myalgia, peripheral neuropathy, pancreatitis, hepatitis , increased sweating, thrombocytopenia, vasculitis, angioedema, erythema multiforme.

In a long-term placebo-controlled study (PRAISE-2) in patients with heart failure of functional class III and IV according to the NYHA classification of non-ischemic etiology, an increase in the incidence of pulmonary edema was observed when using amlodipine, with no significant differences in the incidence of worsening of heart failure in comparison. with placebo.

In rare cases, at the beginning of therapy with slow calcium channel blockers (SCBC) or with an increase in the dose of SCBC, especially in patients suffering from severe coronary artery disease, an increase in the frequency, duration and severity of angina pectoris or the development of acute myocardial infarction was observed. Also, during therapy with BMCC, cases of arrhythmia (including ventricular tachycardia and atrial fibrillation) were observed. It is not possible to distinguish the occurrence of these adverse events from the natural course of the underlying disease.

Valsartan

In clinical studies when using valsartan as monotherapy, the following adverse events were noted (regardless of their causal relationship with the drug under study): viral infections, upper respiratory tract infections, sinusitis, rhinitis, neutropenia, insomnia.

In controlled clinical trials, 3.9% and 16.6% of patients with heart failure treated with valsartan experienced an increase in creatinine and blood urea nitrogen levels of more than 50%, respectively. For comparison, in patients receiving placebo, increases in creatinine and urea nitrogen were observed in 0.9% and 6.3% of cases.

In controlled clinical studies, 10% of patients with heart failure experienced an increase in serum potassium concentrations of more than 20%. For comparison, in patients receiving placebo, an increase in potassium concentration was observed in 5.1% of cases.

Contraindications to the use of the drug EXFORG

• pregnancy;
• hypersensitivity to the components of the drug.

The safety of Exforge in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, in patients after a recent kidney transplant, as well as in children and adolescents under 18 years of age has not been established.

The drug is prescribed with caution for: liver dysfunction (especially with obstructive diseases of the biliary tract); severe renal dysfunction (CK<10 мл/мин); пациентам с митральным или аортальным стенозом, гипертрофической обструктивной кардиомиопатией; при гиперкалиемии, дефиците в организме натрия и/или уменьшении ОЦК.

Use of the drug EXFORG during pregnancy and lactation

Exforge, like any other drug that directly affects the RAAS, should not be prescribed during pregnancy or to women wishing to become pregnant. If pregnancy is detected during treatment with Exforge, the drug should be discontinued as soon as possible.

Patients of childbearing age should be informed of the possible risk to the fetus associated with the use of drugs that affect the RAAS.

Given the mechanism of action of angiotensin II receptor antagonists, a risk to the fetus cannot be excluded. It is known that the administration of ACE inhibitors, which affect the RAAS, to pregnant women in the second and third trimesters leads to damage or death of the developing fetus. 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. With the unintentional use of valsartan in pregnant women, cases of spontaneous abortion, oligohydramnios and renal dysfunction in newborns have been described.

It is not known whether valsartan and/or amlodipine are excreted in breast milk. Since experimental studies have shown that valsartan is excreted in breast milk, the use of Exforge during lactation (breastfeeding) is not recommended.

Patients with initial and moderate renal impairment do not require Exforge dose adjustment. Caution should be exercised when prescribing the drug to patients with severe renal impairment (CR<10 мл/мин), так как данные по безопасности применения препарата в таких случаях не получены.

special instructions

Caution should be exercised when prescribing Exforge to patients with liver disease (especially obstructive diseases of the biliary tract). Valsartan is excreted mainly unchanged in the bile, while amlodipine is extensively metabolized in the liver.

Patients with initial and moderate renal dysfunction (creatinine clearance 30-50 ml/min) do not require Exforge dose adjustment. Caution should be exercised when prescribing the drug to patients with severe renal impairment (CR<10 мл/мин), т. к. данные по безопасности применения препарата в таких случаях не получены.

As with the use of other vasodilators, special care should be taken when prescribing the drug to patients with mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy.

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

In placebo-controlled studies in patients with uncomplicated arterial hypertension, severe arterial hypotension was observed in 0.4% of cases. In patients with activated RAAS (for example, with BCC and/or sodium deficiency in patients receiving high doses of diuretics), symptomatic arterial hypotension may develop when taking angiotensin receptor blockers. Before starting treatment with Exforge, sodium levels in the body and/or blood volume should be corrected or therapy should be initiated under close medical supervision.

If arterial hypotension develops, the patient should be placed with legs elevated and, if necessary, given an intravenous infusion of saline solution. After stabilization of blood pressure, treatment with Exforge can be continued.

When using the drug simultaneously with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other drugs that may cause an increase in the concentration of potassium in the blood (for example, with heparin), caution should be exercised and regular monitoring of the concentration of potassium in the blood should be carried out. .

There is no data on the effect of the drug on the ability to drive vehicles and operate machinery. Due to the possible occurrence of dizziness or increased fatigue, caution should be exercised when driving vehicles or operating machinery.

Overdose

There are currently no data on cases of drug overdose.

In case of an overdose of valsartan, one 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. Severe and prolonged systemic arterial hypotension has also been reported, leading to the development of shock with a fatal outcome.

Treatment: in case of accidental overdose, induce vomiting (if the drug was taken recently) or perform gastric lavage, prescribe activated charcoal. The use of activated charcoal in healthy volunteers immediately or 2 hours after taking amlodipine significantly reduced its absorption. In case of clinically significant arterial hypotension caused by Exforge, the patient should be placed with his legs elevated and active measures should be taken to maintain the activity of the cardiovascular system, including frequent monitoring of the function of the heart and respiratory system, blood volume 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. IV calcium gluconate may be effective in reversing calcium channel blockade. Removal of valsartan and amlodipine during hemodialysis is unlikely.

Drug interactions

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, Maalox (aluminum hydroxide gel, magnesium hydroxide, simethicone), cimetidine, NSAIDs, antibiotics and oral hypoglycemic drugs.

Valsartan

It has been established that with valsartan monotherapy there is no clinically significant interaction with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, 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 potassium concentrations in the blood (for example, heparin), caution should be exercised and frequent monitoring of potassium concentrations in the blood should be performed.

Conditions for dispensing from pharmacies

Storage conditions and periods

The drug should be stored out of the reach of children, in a dry place at a temperature not exceeding 30°C. Shelf life - 3 years.

Co-Exforge - official instructions for use:

Clinical and pharmacological group:

Antihypertensive drug

pharmachologic effect

Co-Exforge is a combination of three antihypertensive components with a complementary mechanism of blood pressure control: amlodipine (a dihydropyridine derivative) - a blocker of slow calcium channels, valsartan - an angiotensin II receptor antagonist (ATII) and a hydrochlorothiazide-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 Co-Exforge drug, 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 peripheral vascular resistance and a decrease in blood pressure.

When taken in therapeutic doses in patients with arterial hypertension, amlodipine 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 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 and effective renal plasma blood flow without changing the filtration fraction and the severity of proteinuria.

Also, as with the use of other slow calcium channel blockers, while taking amlodipine in patients with normal left ventricular function, changes in hemodynamic parameters of cardiac function at rest and during exercise were observed: a slight increase in the cardiac index, without a significant effect on the maximum rate of increase in pressure in the heart. left ventricle, on end-diastolic pressure and volume of the left ventricle. 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 AV 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.

In a long-term placebo-controlled study (PRAISE-2) in patients with chronic heart failure (III and IV functional class according to the NYHA classification) 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 chronic heart failure. 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 (especially in patients with hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease), an increase in the frequency, duration and severity of angina attacks occurred or acute myocardial infarction. Arrhythmia (including ventricular tachycardia and atrial fibrillation) has also been noted with the use of slow calcium channel blockers. These adverse events could not be differentiated from the natural history of the disease.

Valsartan

Valsartan is an active and specific angiotensin II receptor antagonist intended for oral administration. It acts selectively on AT1 receptors, which are responsible for the effects of angiotensin II. The 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 ACE, which converts angiotensin I to angiotensin II and causes the destruction of bradykinin. Because When using angiotensin II antagonists, ACE inhibition and accumulation of bradykinin or substance P do not occur, and 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) у больных, получавших валсартан (у 2.6% пациентов, получавших валсартан, и у 7.9% - получавших ингибитор АПФ). В клиническом исследовании, включавшем больных, у которых ранее при лечении ингибитором АПФ развивался сухой кашель, при лечении валсартаном это осложнение было отмечено в 19.5% случаев, при лечении тиазидным диуретиком - в 19.0% случаев. В то же время, в группе больных, получавших лечение ингибитором АПФ, кашель наблюдался в 68.5% случаев (р<0.05). Валсартан не вступает во взаимодействие и не блокирует рецепторы других гормонов или ионные каналы, имеющие важное значение для регуляции функций сердечно-сосудистой системы.

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 hypotensive effect lasts 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. 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 (functional class II-IV 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 (stable clinical course) or with impaired left ventricular function after myocardial infarction, a decrease in cardiovascular mortality is observed.

Hydrochlorothiazide

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 (Na+) and chlorine (Cl-) ions is suppressed. The suppression of the co-transport system of Na+ and Cl- apparently occurs due to competition for the binding sites of Cl- 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 blood volume 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.

Amlodipine + valsartan + hydrochlorothiazide

When using triple combination therapy of amlodipine + valsartan + hydrochlorothiazide, a more pronounced decrease in systolic and diastolic blood pressure was observed compared with the use of double combinations: valsartan + hydrochlorothiazide, amlodipine + valsartan and amlodipine + hydrochlorothiazide. In patients with arterial hypertension of II and III degrees (initial mean blood pressure 170/107 mm Hg), when using combination therapy 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 mm Hg. (compared to 32.0/19.7 mm Hg, 33.5/21.5 mm Hg, 31.5/19.5 mm Hg during combination therapy of 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 greatest antihypertensive effect of the drug Co-Exforge is observed 2 weeks after the start of use of the drug at the maximum individual dose orally.

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

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

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

Pharmacokinetics

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

Amlodipine

Suction

After oral administration of amlodipine in therapeutic doses, Cmax in blood plasma is achieved within 6-12 hours. Absolute bioavailability averages 64-80%. Food intake does not affect the bioavailability of amlodipine.

Distribution

Vd is approximately 21 l/kg. In vitro studies with amlodipine have shown that in patients with arterial hypertension, approximately 97.5% of the circulating drug is bound to plasma proteins.

Metabolism

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

Removal

Elimination from blood plasma is biphasic with a T1/2 of approximately 30 to 50 hours. Css in blood plasma 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%.

The pharmacokinetic curve of valsartan is descending multi-exponential (T1/2?< 1 ч и T1/2? около 9 ч). При приеме с пищей отмечается снижение биодоступности (по значению AUC) на 40% и Cmax в плазме крови почти на 50%, хотя приблизительно через 8 ч после приема препарата внутрь концентрации валсартана в плазме крови у людей, принимавших его с пищей, и в группе, получавшей препарат натощак, выравниваются. Снижение AUC, однако, не сопровождается клинически значимым уменьшением терапевтического эффекта, поэтому валсартан можно назначать вне зависимости от времени приема пищи.

Distribution

The Vd of valsartan at steady state after intravenous administration was about 17 L, indicating the absence of extensive distribution of valsartan in tissues. 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

Valsartan is excreted mainly unchanged through the intestines with feces (about 83% of the dose) and the kidneys (about 13% of the dose). After intravenous administration, 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 is 6 hours.

Hydrochlorothiazide

Suction

Absorption of hydrochlorothiazide after oral administration is rapid (time to reach Cmax is about 2 hours). On average, the increase in AUC is linear and dose proportional across the therapeutic range. When administered concomitantly with food, both increased and decreased systemic bioavailability of hydrochlorothiazide 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 hydrochlorothiazide after oral administration is 60-80%.

Distribution

The kinetics of distribution and elimination are generally described as a biexponential decreasing function, with a T1/2 of 6-15 hours. With repeated use, the kinetics of hydrochlorothiazide does not change and with 1 time of use, the accumulation is minimal. Apparent Vd - 4-8 l/kg. 40-70% of hydrochlorothiazide circulating in the blood plasma is bound to plasma proteins, mainly albumin. Hydrochlorothiazide also accumulates in erythrocytes in concentrations approximately 3 times higher than those in blood plasma.

Metabolism

Hydrochlorothiazide is excreted unchanged.

Removal

More than 95% of the absorbed dose of hydrochlorothiazide is excreted unchanged by the kidneys in the urine.

Amlodipine+valsartan+hydrochlorothiazide

After oral administration of the Co-Exforge drug, Cmax of amlodipine, valsartan and hydrochlorothiazide is achieved after 6-8, 3 and 2 hours, respectively. The rate and extent of absorption of Co-Exforge is equivalent to the bioavailability of amlodipine, valsartan and hydrochlorothiazide when taken as separate tablets.

Pharmacokinetics in special clinical situations

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

The time to reach Cmax of amlodipine in blood plasma is the same in young and elderly patients. In elderly patients, the clearance of amlodipine is slightly reduced, which leads to an increase in AUC and T1/2. In elderly patients, the systemic effect of valsartan was slightly more pronounced than in young patients, however, this was not clinically significant. There is limited data on decreased systemic clearance of hydrochlorothiazide in patients over 65 years of age (healthy or with hypertension) compared to younger patients.

In patients with impaired renal function, the pharmacokinetic parameters of amlodipine do not change significantly. There was no correlation between renal function (KF) and systemic exposure of valsartan (AUC) in patients with varying degrees of renal impairment. However, since hydrochlorothiazide is eliminated primarily through the kidneys, impaired renal function may have a significant effect on the pharmacokinetics of hydrochlorothiazide.

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 (Child-Pugh score 5-6) and moderate (Child-Pugh score 7-9) liver impairment, the bioavailability (AUC) of valsartan is doubled compared to age-matched healthy volunteers , gender and body weight).

Indications for use of the drug CO-EXFORGE

• arterial hypertension II and III degrees.

Dosage regimen

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

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 in case of insufficient blood pressure control during double combination therapy (valsartan + hydrochlorothiazide, amlodipine + valsartan and amlodipine + hydrochlorothiazide), patients can be transferred to triple combination treatment with Co-Exforge in appropriate doses.

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

• 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 per day.

In patients over 65 years of age, no dose adjustment is 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 impairment of renal function (creatinine clearance more than 30 ml/min) and liver (5-9 points on the Child-Pugh scale), no dose adjustment is required.

Side effect

Below are all the adverse events observed with the simultaneous use of amlodipine, valsartan and hydrochlorothiazide (Co-Exforge), as well as during monotherapy with amlodipine, valsartan and hydrochlorothiazide.

Co-Exforge (amlodipine + valsartan + hydrochlorothiazide)

The safety of Co-Exforge has been assessed in more than 2,200 patients. When using the drug Co-Exforge, adverse events were mostly mild or moderate. Discontinuation of drug treatment due to the development of adverse events was required in rare cases. Most often, the drug was discontinued due to the development of dizziness and a pronounced decrease in blood pressure (0.7%).

When using the drug Co-Exforge, no new adverse events were identified compared with double combination therapy and monotherapy with individual components.

As with short-term use, good tolerability of the Co-Exforge drug was observed with long-term use (for a year).

The incidence of adverse events was not associated with gender, age, or race.

When using the drug Co-Exforge, changes in laboratory parameters were minimal and did not differ from those during monotherapy with individual components. When hydrochlorothiazide is taken simultaneously with valsartan (triple combination therapy), a decrease in the hypokalemic effect of hydrochlorothiazide is observed.

The most common adverse events (incidence more than 2%) observed in clinical studies (regardless of the identification of a connection with the use of the drug Co-Exforge) were dizziness (7.7%), peripheral edema (4.5%), headache (4.3%), dyspepsia (2.2%), increased fatigue (2.2%), muscle spasms (2.2%), back pain (2.1%), nasopharyngitis (2.1%), nausea (2.1%).

<1/10); нечасто (?1/1000, <1/100); редко (?1/10 000, <1/1000); очень редко (< 1/10 000), частота неизвестна (недостаточно данных для оценки частоты развития).

Metabolism: often - hypokalemia; uncommon - anorexia, hypercalcemia, hyperlipidemia, hyponatremia.

From the nervous system: often - dizziness, headache; uncommon - insomnia/sleep disorders, coordination disorders, postural dizziness and dizziness caused by exercise, taste disturbances, lethargy, paresthesia, neuropathy, incl. peripheral, drowsiness, fainting.

From the senses: infrequently - visual disturbances, vertigo.

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

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

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

Dermatological reactions: uncommon - increased sweating, itching.

From 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; uncommon - increased plasma creatinine concentration, acute renal failure.

From the body as a whole: often - peripheral edema, increased fatigue; uncommon - abasia, gait disturbances, asthenia, general weakness, pain in the chest area.

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

Amlodipine

To assess the frequency, the following criteria were used (according to the WHO classification): very often (?1/10); often (?1/100,<1/10); нечасто (?1/1000, <1/100); редко (?1/10 000, <1/1000); очень редко (<1/10 000), частота неизвестна (недостаточно данных для оценки частоты развития).

From the hematopoietic system: very rarely - leukopenia, thrombocytopenia.

From the side of metabolism: very rarely - hyperglycemia.

From the nervous system: often - dizziness, headache, drowsiness; uncommon - insomnia/sleep disturbances, mood lability, paresthesia, fainting, tremor; very rarely - muscle hypertension, peripheral neuropathy, neuropathy; frequency unknown - extrapyramidal disorders.

From the senses: infrequently - visual disturbances, tinnitus, taste disturbances.

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

From the respiratory system: infrequently - shortness of breath, rhinitis; very rarely - cough.

From the digestive system: often - abdominal discomfort, pain in the upper abdomen, nausea; uncommon - change in frequency of bowel movements, diarrhea, dry mouth, dyspepsia, vomiting; very rarely - gastritis, gum hyperplasia, pancreatitis.

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

Dermatological reactions: uncommon - alopecia, increased sweating, itching, rash, incl. exanthema, purpura, skin discoloration; very rarely - angioedema, erythema multiforme, urticaria.

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

From the urinary system: infrequently - urinary disorders, nocturia, pollakiuria.

From the reproductive system: infrequently - erectile dysfunction, gynecomastia.

From the body as a whole: often - increased fatigue, swelling; infrequently - asthenia, discomfort, general weakness, pain in the chest, pain of various localizations.

From laboratory parameters: infrequently - increase or decrease in body weight.

Valsartan

To assess the frequency, the following criteria were used (according to the WHO classification): very often (?1/10); often (?1/100,<1/10); нечасто (? 1/1000, <1/100); редко (? 1/10 000, <1/1000); очень редко (<1/10 000), частота неизвестна (недостаточно данных для оценки частоты развития).

From the hematopoietic system: frequency unknown - decrease in hemoglobin and hematocrit, leukopenia, thrombocytopenia.

From the immune system: frequency unknown - hypersensitivity reactions.

On the part of the hearing organ: infrequently - vertigo.

From the cardiovascular system: frequency unknown - vasculitis.

From the respiratory system: infrequently - cough.

From the digestive system: infrequently - abdominal discomfort, pain in the upper abdomen.

From the liver and biliary tract: frequency unknown - increased activity of liver enzymes, increased concentration of bilirubin in the blood plasma.

Allergic reactions: frequency unknown - angioedema, itching, rash.

From the musculoskeletal system: frequency unknown - myalgia.

From the urinary system: frequency unknown - increased concentration of creatinine in the blood plasma, impaired renal function, including acute renal failure.

From the body as a whole: infrequently - increased fatigue.

From laboratory parameters: frequency unknown - increased potassium content in blood plasma.

In clinical studies when using valsartan in monotherapy, the following adverse events were noted (regardless of their causal relationship with the drug under study): 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 receiving valsartan experienced a significant decrease (more than 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 receiving valsartan and in 1.6% of patients receiving an ACE inhibitor.

In controlled studies, 3.9% and 16.6% of patients with chronic heart failure treated with valsartan experienced an increase in creatinine and blood urea nitrogen concentrations of more than 50%, respectively. For comparison, in patients receiving placebo, increases in creatinine and urea nitrogen concentrations were observed in 0.9% and 6.3% of cases.

A doubling of serum creatinine concentration was detected in 4.2% of patients after myocardial infarction receiving valsartan and in 3.4% receiving captopril.

In controlled studies, 10% of patients with chronic heart failure experienced an increase in serum potassium levels of more than 20%. For comparison, in patients receiving placebo, an increase in potassium levels was observed in 5.1% of cases.

Hydrochlorothiazide

To assess the frequency, the following criteria were used (according to the WHO classification): very often (?1/10); often (?1/100,<1/10); нечасто (?1/1000, <1/100); редко (?1/10 000, <1/1000); очень редко (<1/10 000), частота неизвестна (недостаточно данных для оценки частоты развития).

From the hematopoietic system: rarely - thrombocytopenia; very rarely - agranulocytosis, suppression of bone marrow hematopoiesis, hemolytic anemia, leukopenia.

From the immune system: very rarely - hypersensitivity reactions.

Metabolism: often - hypokalemia; uncommon - hyperuricemia, hypomagnesemia, hyponatremia; rarely - hypercalcemia, hyperglycemia; very rarely - hypochloremic alkalosis.

From the nervous system: rarely - insomnia/sleep disorders, depression, dizziness, headache, lethargy.

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

From the cardiovascular system: infrequently - orthostatic hypotension; rarely - arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation).

From the respiratory system: very rarely - respiratory distress syndrome, pulmonary edema and pneumonitis.

From the digestive system: infrequently - loss of appetite, nausea, vomiting; rarely - abdominal discomfort, pain in the upper abdomen, constipation, diarrhea; very rarely - pancreatitis.

From 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.

From the reproductive system: infrequently - erectile dysfunction.

From laboratory parameters: often - hyperlipidemia; rarely - glucosuria.

Contraindications to the use of CO-EXFORG

• severe liver dysfunction (more than 9 points on the Child-Pugh scale);
• severe renal dysfunction (creatinine clearance less than 30 ml/min), anuria;
• hypokalemia, hyponatremia, hypercalcemia, refractory to adequate therapy, as well as hyperuricemia with clinical manifestations;
• pregnancy;
• breastfeeding period;
• age under 18 years (efficacy and safety have not been established);
• hypersensitivity to amlodipine, valsartan, hydrochlorothiazide, other sulfonamide derivatives, dihydropyridine derivatives and other auxiliary components of the drug.

Caution should be exercised when prescribing the drug to patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, in conditions accompanied by a decrease in blood volume, in cases of water and electrolyte balance disorders (including hyponatremia, hyperkalemia), in patients with mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy , with mild to moderate liver dysfunction, especially against the background of biliary tract obstruction (less than 9 points on the Child-Pugh scale), with diabetes mellitus, with systemic lupus erythematosus.

The safety of the drug in patients who have recently undergone kidney transplantation, as well as in patients with heart failure or coronary artery disease, has not been established.

Use of CO-EXFORGE during pregnancy and breastfeeding

It is known that the administration of ACE inhibitors, which affect the RAAS, to pregnant women in the second and third trimesters leads to damage or death of the developing fetus. Given the mechanism of action of angiotensin II receptor antagonists, 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. Hydrochlorothiazide penetrates the placental barrier. When using thiazide diuretics, including hydrochlorothiazide, during pregnancy, the development of fetal or neonatal 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. Co-Exforge, like any other drug that directly affects the RAAS, should not be prescribed during pregnancy or to 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 treatment with Co-Exforge, the drug should be discontinued as soon as possible.

It is unknown whether valsartan and/or amlodipine passes into breast milk. In experimental studies, valsartan was excreted in breast milk. Hydrochlorothiazide is excreted into breast milk. Co-Exforge should not be used during breastfeeding.

Use for liver dysfunction

In patients with mild to moderate liver dysfunction (5-9 points on the Child-Pugh scale), no dose adjustment is required.

Contraindication: severe liver dysfunction (more than 9 points on the Child-Pugh scale).

Use for renal impairment

In patients with mild to moderate renal impairment (creatinine clearance more than 30 ml/min), no dose adjustment is required. Contraindication: severe renal dysfunction (creatinine clearance less than 30 ml/min), anuria.

special instructions

Renal dysfunction

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

Cancellation of beta blockers

If it is necessary to discontinue 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 withdrawal syndrome that occurs when beta-blocker therapy is abruptly stopped.

Marked decrease in blood pressure

In controlled studies, when using the drug Co-Exforge at the maximum daily dose (10 mg + 320 mg + 25 mg) in patients with arterial hypertension of II and III degrees, a pronounced decrease in blood pressure, including orthostatic hypotension, was observed in 1.7% of cases (compared to 1.8%, 0.4% and 0.2% against the background of combination therapy of 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 legs elevated and, if necessary, given an intravenous infusion of 0.9% sodium chloride solution. After stabilization of blood pressure, treatment with Co-Exforge can be continued.

Hyponatremia and/or decreased blood volume

In patients with activated RAAS (for example, with BCC deficiency and/or hyponatremia, as well as in patients receiving high doses of diuretics), symptomatic arterial hypotension may develop when taking angiotensin receptor antagonists. Before starting treatment with Co-Exforge, sodium levels in the body 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 electrolytes in the blood plasma.

Changes in potassium concentration in blood plasma

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

Systemic lupus erythematosus

Aggravation or development of systemic lupus erythematosus has been reported with the use of 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, it is possible to reduce calcium excretion, leading to the development of moderate hypercalcemia. Severe hypercalcemia during therapy with Co-Exforge may indicate latent hyperparathyroidism.

Impact on the ability to drive vehicles and operate machinery

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

Overdose

There are currently no data on cases of drug overdose.

In case of an overdose of valsartan, one 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. 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.

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. If there is a pronounced decrease in blood pressure, the patient should be placed with his legs elevated, active measures should be taken to increase blood pressure, maintain the activity of the cardiovascular system, including regular monitoring of the function of the heart and respiratory system, blood volume 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. Intravenous administration of calcium salt solutions may be effective in reversing calcium channel blockade. Removal of valsartan and amlodipine during hemodialysis is unlikely. Hydrochlorothiazide can be removed from the systemic circulation by hemodialysis.

Drug interactions

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, antacids (magnesium hydroxide, aluminum hydroxide gel, simethicone), cimetidine , NSAIDs, antibiotics and hypoglycemic drugs for oral administration.

Inhibitors of the CYP3A4 isoenzyme. When amlodipine is used together with diltiazem, elderly patients experience a slowdown in the metabolism of amlodipine, likely due to inhibition of the CYP3A4 isoenzyme, which leads to an increase in amlodipine plasma concentrations by approximately 50% and an increase in its systemic exposure. When amlodipine is used together with strong CYP3A4 inhibitors (for example, ketoconazole, itraconazole and ritonavir), a marked increase in the systemic exposure of amlodipine is possible.

Inducers of the isoenzyme CYP3A4. Since the use of amlodipine together with inducers of the CYP3A4 isoenzyme (for example, carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone, rifampicin, grapefruit juice, herbal preparations containing St. John's wort) can lead to a marked decrease in its concentration in the blood plasma, when amlodipine is prescribed with inducers CYP3A4, its content in the blood plasma should be monitored.

Valsartan

It has been established that with valsartan monotherapy there is no clinically significant interaction with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, 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 potassium levels in the blood (for example, heparin), caution should be exercised and regular monitoring of blood capium levels should be carried out.

When valsartan is used together with NSAIDs, the antihypertensive effect of valsartan may be reduced.

Hydrochlorothiazide

Lithium. When used simultaneously with ACE inhibitors and diuretics, cases of reversible increases in plasma lithium concentrations and its toxic effects have been reported. Therefore, when using hydrochlorothiazide and lithium preparations simultaneously, monitoring the concentration of lithium in the blood plasma is recommended.

Peripheral muscle relaxants. Thiazide diuretics, including hydrochlorothiazide, potentiate the action of peripherally acting muscle relaxants.

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

Medicines that can cause an increase in potassium levels in the blood plasma. The risk of developing hypokalemia increases with the simultaneous administration 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 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 (for example, heparin).

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

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

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

Methyldopa. Cases of hemolytic anemia have been reported with the simultaneous administration of hydrochlorothiazide and methyldopa.

Cholestyramine reduces the absorption of thiazide diuretics, including hydrochlorothiazide.

Vitamin D and calcium salts. When thiazide diuretics, including hydrochlorothiazide, are used together with vitamin D or calcium salts, an increase in serum calcium levels is possible.

Cyclosporine. Co-administration of cyclosporine may increase the risk of developing hyperuricemia and the appearance of symptoms resembling an exacerbation of gout.

Carbamazepine. Patients taking hydrochlorothiazide concomitantly with carbamazepine may develop hyponatremia. Since hyponatremia may develop in patients receiving concomitant therapy with hydrochlorothiazide and carbamazepine, appropriate monitoring of plasma sodium levels should be carried out when prescribing Co-Exforge together with carbamazepine.

Other types of interaction. Co-administration of thiazide diuretics, including hydrochlorothiazide, may lead to an increased incidence of hypersensitivity reactions to allopurinol; increased risk of developing side effects of amantadine; enhancing the hyperglycemic effect of diazoxide; reducing the excretion of cytotoxic drugs by the kidneys (for example, cyclophosphamide, methotrexate) and potentiating their myelosuppressive effect.

Conditions for dispensing from pharmacies

The drug is available with a prescription.

Storage conditions and periods

The drug should be stored in a dry place, out of reach of children, at a temperature not exceeding 25°C. Shelf life - 18 months.

Active ingredients

Valsartan
- amlodipine

Release form, composition and packaging

dark yellow, round with beveled edges, imprinted "NVR" on one side and "NV" on the other.

Excipients: microcrystalline cellulose - 54.06 mg, crospovidone - 20 mg, magnesium stearate - 4.5 mg, colloidal silicon dioxide - 1.5 mg.

Film shell composition: premix white (hypromellose, titanium dioxide, polyethylene glycol 4000, talc) - 4.4 mg, premix yellow (hypromellose, iron oxide yellow, polyethylene glycol 4000, talc) - 3.6 mg, purified water - q.s.

Film-coated tablets dark yellow, oval with beveled edges, imprinted "NVR" on one side and "ECE" on the other.

Excipients: microcrystalline cellulose - 109.06 mg, crospovidone - 40 mg, magnesium stearate - 9 mg, colloidal silicon dioxide - 3 mg.

Film shell composition: premix white (hypromellose, titanium dioxide, polyethylene glycol 4000, talc) - 7.15 mg, premix yellow (hypromellose, iron oxide yellow, polyethylene glycol 4000, talc) - 5.85 mg, purified water - q.s.

7 pcs. - blisters (2) - cardboard packs.
14 pcs. - blisters (2) - cardboard packs.

Film-coated tablets light yellow, oval with beveled edges, imprinted "NVR" on one side and "UIC" on the other.

Excipients: microcrystalline cellulose - 108.13 mg, crospovidone - 40 mg, magnesium stearate - 9 mg, colloidal silicon dioxide - 3 mg.

Film shell composition: premix white (hypromellose, titanium dioxide, polyethylene glycol 4000, talc) - 11.93 mg, premix yellow (hypromellose, yellow iron oxide, polyethylene glycol 4000, talc) - 1.04 mg, premix red (hypromellose, red iron oxide, polyethylene glycol, talc) - 0.03 mg, purified water - q.s.

7 pcs. - blisters (2) - cardboard packs.
14 pcs. - blisters (2) - cardboard packs.

pharmachologic effect

A combined antihypertensive drug containing active substances with a complementary mechanism for blood pressure control. Amlodipine, a dihydropyridine derivative, belongs to the class of slow calcium channel blockers (SCBCs), valsartan belongs to the class of angiotensin II receptor antagonists. The combination of these components has a mutually complementary antihypertensive effect, which leads to a more pronounced decrease in blood pressure compared to that during monotherapy with each drug.

Amlodipine

Amlodipine, which is part of Exforge, 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 peripheral vascular resistance and a decrease in blood pressure.

When taken in therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation, leading to a decrease in blood pressure (with the patient lying and standing). A decrease in blood pressure is not accompanied by a significant change in heart rate and catecholamine levels with long-term use.

Blood concentrations of the drug correlate with clinical effect 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 level of proteinuria.

As with the use of other BMCCs, taking amlodipine in patients with normal left ventricular function caused changes in hemodynamic parameters of cardiac function at rest and during physical activity: there was a slight increase in the index without a significant effect on the maximum rate of increase in pressure in the left ventricle, end-diastolic pressure and left ventricular volume. Hemodynamic studies in intact animals and humans have shown 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 alter sinoatrial node function or AV conduction in intact animals or humans. 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 ECG parameters.

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

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 known effects of angiotensin II. An increase in plasma concentrations of free angiotensin II due to AT 1 receptor blockade under the influence of valsartan may stimulate unblocked AT 2 receptors, which counteract the effects of AT 1 receptor stimulation. Valsartan does not have any pronounced agonistic activity against AT 1 receptors. The affinity of valsartan for receptors of the AT 1 subtype is approximately 20,000 times higher than for receptors of the AT 2 subtype.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and causes the destruction of bradykinin.

Because When using angiotensin II antagonists, ACE inhibition and accumulation of bradykinin or substance P do not occur, and 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) у больных, получавших валсартан (у 2.6% пациентов, получавших валсартан, и у 7.9% - получавших ингибитор АПФ). В клиническом исследовании, включавшем больных, у которых ранее при лечении ингибитором АПФ развивался сухой кашель, при лечении валсартаном это осложнение было отмечено в 19.5% случаев, при лечении тиазидным диуретиком - в 19% случаев. В то же время, в группе больных, получавших лечение ингибитором АПФ, кашель наблюдался в 68.5% случаев (р<0.05). Валсартан не вступает во взаимодействие и не блокирует рецепторы других гормонов или ионные каналы, имеющие важное значение для регуляции функций сердечно-сосудистой системы.

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 dose of the drug. The maximum decrease in blood pressure develops after 4-6 hours. After taking the drug, the duration of the hypotensive effect lasts 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. 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 (functional class II-IV according to the NYHA classification) leads to a significant reduction in the number of hospitalizations. This effect is most pronounced in patients not receiving ACE inhibitors or beta-blockers. When taking valsartan in patients with left ventricular failure (stable clinical course) or with impaired left ventricular function after myocardial infarction, a decrease in cardiovascular mortality is observed.

Amlodipine/valsartan

In patients with arterial hypertension who received Exforge once a day, the antihypertensive effect persisted for 24 hours.

Exforge in doses of 5/80 mg and 5/160 mg in patients with initial systolic blood pressure 153-157 mm Hg. Art. and diastolic blood pressure≥95 mm Hg. and less than 110 mm Hg. reduces blood pressure by 20-28/14-19 mm Hg. (compared to 7-13/7-9 mmHg when taking placebo).

Exforge at a dose of 10/160 mg and 5/160 mg normalizes blood pressure (decrease in diastolic blood pressure in a sitting position by less than 90 mm Hg at the end of the study) in 75% and in 62% of patients with inadequate blood pressure control during monotherapy with valsartan at a dose of 160 mg/day.

Exforge at a dose of 10/160 mg normalizes blood pressure in 78% of patients with inadequate blood pressure control during monotherapy with amlodipine at a dose of 10 mg. In patients with arterial hypertension, when combining valsartan at a dose of 160 mg with amlodipine at doses of 10 mg and 5 mg, an additional reduction in systolic and diastolic blood pressure by 6.0/4.8 mm Hg is achieved. and 3.9/2.9 mmHg. respectively, compared with patients who continued to receive valsartan 160 mg alone or amlodipine 5 and 10 mg alone.

When titrating the dose of Exforge from 5/160 mg to 10/160 mg in patients with arterial hypertension with diastolic blood pressure ≥110 mm Hg. and less than 120 mm Hg. There is a decrease in blood pressure in the sitting position by 36/29 mmHg, comparable to the decrease in blood pressure when titrating the dose of a combination of an ACE inhibitor and a thiazide diuretic.

In two long-term studies with long follow-up, the effect of Exforge was maintained for 1 year. Sudden cessation of Exforge is not accompanied by a sharp increase in blood pressure.

In patients who achieved adequate blood pressure control, but developed severe edema during amlodipine monotherapy, when using combination therapy, comparable blood pressure control was achieved with a lower likelihood of developing edema.

The therapeutic effectiveness of Exforge does not depend on the age, gender and race of the patient.

Pharmacokinetics

The pharmacokinetics of valsartan and amlodipine are characterized by linearity.

Amlodipine

Suction

After oral administration of amlodipine in therapeutic doses, the Cmax of amlodipine in the blood plasma is achieved within 6-12 hours. The absolute bioavailability averages 64-80%. Food intake does not affect the bioavailability of amlodipine.

Distribution

V d is approximately 21 l/kg. In vitro studies with amlodipine have shown that in patients with arterial hypertension, approximately 97.5% of the circulating drug is bound to plasma proteins.

Metabolism

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

Removal

The elimination of amlodipine from plasma is biphasic with T1/2 of approximately 30 to 50 hours. C ss in blood plasma are achieved after prolonged use for 7-8 days. 10% of unchanged amlodipine and 60% of amlodipine in the form of metabolites are excreted by the kidneys.

Valsartan

Suction

After oral administration of valsartan, Cmax in blood plasma is achieved within 2-3 hours. The average absolute bioavailability is 23%. The pharmacokinetic curve of valsartan has a descending multiexponential character (T 1/2α<1 ч и T 1/2β около 9 ч). При приеме валсартана с пищей отмечается снижение биодоступности (по значению AUC) на 40% и C max в плазме крови почти на 50%, хотя приблизительно через 8 ч после приема препарата концентрации валсартана в плазме крови в группе пациентов, принимавших его с пищей, и в группе, принимавшей натощак, выравниваются. Уменьшение AUC, однако, не сопровождается клинически значимым снижением терапевтического эффекта, поэтому валсартан можно назначать вне зависимости от времени приема пищи.

Distribution

V d of valsartan at steady state after intravenous administration was about 17 l, which indicates the absence of extensive distribution of valsartan in tissues. 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

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/h and its renal clearance is 0.62 l/h (about 30% of the total clearance). T1/2 of valsartan is 6 hours.

Amlodipine/valsartan

After oral administration of the drug Exforge, the Cmax of valsartan and amlodipine is achieved after 3 hours and 6-8 hours, respectively. The rate and extent of absorption of Exforge is equivalent to the bioavailability of valsartan and amlodipine when taken as separate tablets.

Pharmacokinetics in special clinical situations

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

The time to reach Cmax of amlodipine in blood plasma is the same in young and elderly patients. In elderly patients, the clearance of amlodipine is slightly reduced, which leads to an increase in AUC and T1/2.

In elderly patients, the systemic exposure to valsartan was slightly greater than in younger patients, but this was not clinically significant. Since the tolerability of the drug components in older and younger patients is equally good, it is recommended to use the usual dosage regimens.

In patients with impaired renal function, the pharmacokinetic parameters of amlodipine do not change significantly. There was no correlation between renal function (KF) and systemic exposure of valsartan (AUC) in patients with varying degrees of renal impairment. No change in the initial dose is required in patients with initial and moderate renal impairment (creatinine clearance 30-50 ml/min).

Patients with hepatic impairment have reduced clearance of amlodipine, resulting in an increase in AUC of approximately 40-60%. On average, in patients with mild to moderate chronic liver disease, the bioavailability (AUC) of valsartan is doubled compared to healthy volunteers (matched for age, sex and body weight).

Indications

• arterial hypertension (for patients for whom combination therapy is indicated).

Contraindications

• pregnancy;
• hypersensitivity to the components of the drug.

The safety of Exforge in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, in patients after a recent kidney transplant, as well as in children and adolescents under 18 years of age has not been established.

WITH caution the drug is prescribed for: liver dysfunction (especially obstructive diseases of the biliary tract); severe renal dysfunction (CK<10 мл/мин); пациентам с митральным или аортальным стенозом, гипертрофической обструктивной кардиомиопатией; при гиперкалиемии, дефиците в организме натрия и/или уменьшении ОЦК.

Dosage

The drug should be taken orally with a small amount of water, 1 time/day, regardless of the time of meal.

Upon appointment elderly patients, patients with initial or moderate renal impairment (creatinine clearance>30 ml/min), with impaired liver function or liver disease, with symptoms of cholestasis, no change in dosage regimen is required.

Side effects

The safety of Exforge has been assessed in more than 2600 patients.

Criteria for assessing the frequency of adverse reactions: very often - more than 10% of cases; often - 1-10%; sometimes - 0.1-1%; rarely - 0.001-0.1%; in some cases - less than 0.001%. Within each group, identified by frequency of occurrence, adverse reactions are distributed in decreasing order of importance.

From the respiratory system: often - nasopharyngitis, influenza; sometimes - cough, pain in the pharynx and larynx.

From the senses: rarely - visual impairment, tinnitus; sometimes - dizziness associated with dysfunction of the vestibular apparatus.

From the central nervous system and peripheral nervous system: often - headache; sometimes - dizziness, drowsiness, orthostatic dizziness, paresthesia; rarely - anxiety.

From the cardiovascular system: sometimes - tachycardia, palpitations, orthostatic hypotension; rarely - syncope, marked decrease in blood pressure.

From the digestive system: sometimes - diarrhea, nausea, abdominal pain, constipation, dry mouth.

Dermatological reactions: sometimes - skin rash, erythema; rarely - hyperhidrosis, exanthema, itching.

From the musculoskeletal system: sometimes - swelling of the joints, back pain, arthralgia; rarely - muscle spasms, a feeling of heaviness throughout the body.

From the urinary system: rarely - pollakiuria, polyuria.

From the reproductive system: rarely - erectile dysfunction.

Others: often - pastiness, facial swelling, peripheral edema, increased fatigue, flushing of the face, asthenia, feeling of heat.

In comparative and placebo-controlled clinical studies, the incidence of peripheral edema was significantly lower in patients receiving a combination of amlodipine with valsartan (5.8%) than in patients receiving amlodipine monotherapy (9%).

From the laboratory parameters: An increase in blood urea nitrogen (more than 3.1 mmol/l) was observed slightly more often in the groups receiving amlodipine/valsartan (5.5%) and valsartan monotherapy (5.5%), compared with the group receiving placebo (4.5%).

Allergic reactions: rarely - hypersensitivity to the components of the drug.

Adverse events previously reported with each of the components may occur with Exforge, even if they were not observed in clinical studies.

Amlodipine

In those clinical studies where amlodipine was used as monotherapy, other adverse events were also observed (regardless of their causal relationship with the drug being studied): most often - nausea; less often - alopecia, change in the frequency of defecation, dyspepsia, shortness of breath, rhinitis, gastritis, hyperplasia of the gum mucosa, gynecomastia, hyperglycemia, erectile dysfunction, increased urination, leukopenia, general malaise, mood lability, dry mouth, myalgia, peripheral neuropathy, pancreatitis, hepatitis , increased sweating, thrombocytopenia, vasculitis, angioedema, erythema multiforme.

In a long-term placebo-controlled study (PRAISE-2) in patients with heart failure of functional class III and IV according to the NYHA classification of non-ischemic etiology, an increase in the incidence of pulmonary edema was observed when using amlodipine, with no significant differences in the incidence of worsening of heart failure in comparison. with placebo.

In rare cases, at the beginning of therapy with slow calcium channel blockers (SCBC) or with an increase in the dose of SCBC, especially in patients suffering from severe coronary artery disease, an increase in the frequency, duration and severity of angina pectoris or the development of acute myocardial infarction was observed. Also, during therapy with BMCC, cases of arrhythmia (including ventricular tachycardia and atrial fibrillation) were observed. It is not possible to distinguish the occurrence of these adverse events from the natural course of the underlying disease.

Valsartan

In clinical studies when using valsartan as monotherapy, the following adverse events were noted (regardless of their causal relationship with the drug under study): viral infections, upper respiratory tract infections, sinusitis, rhinitis, neutropenia, insomnia.

Neutropenia was detected in 1.9% of patients receiving valsartan and in 1.6% of patients receiving an ACE inhibitor.

In controlled clinical trials, 3.9% and 16.6% of patients with heart failure treated with valsartan experienced an increase in creatinine and blood urea nitrogen levels of more than 50%, respectively. For comparison, in patients receiving placebo, increases in creatinine and urea nitrogen were observed in 0.9% and 6.3% of cases.

In controlled clinical studies, 10% of patients with heart failure experienced an increase in serum potassium concentrations of more than 20%. For comparison, in patients receiving placebo, an increase in potassium concentration was observed in 5.1% of cases.

Overdose

There are currently no data on cases of drug overdose.

In case of an overdose of valsartan, one 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. Severe and prolonged systemic arterial hypotension has also been reported, leading to the development of shock with a fatal outcome.

Treatment: in case of accidental overdose, induce vomiting (if the drug was taken recently) or perform gastric lavage, prescribe. The use of activated charcoal in healthy volunteers immediately or 2 hours after taking amlodipine significantly reduced its absorption. In case of clinically significant arterial hypotension caused by Exforge, the patient should be placed with his legs elevated and active measures should be taken to maintain the activity of the cardiovascular system, including frequent monitoring of the function of the heart and respiratory system, blood volume 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. IV administration may be effective in reversing calcium channel blockade. Removal of valsartan and amlodipine during hemodialysis is unlikely.

Drug interactions

Amlodipine

Inhibitors of the CYP3A4 isoenzyme. When amlodipine is used together with diltiazem, elderly patients experience a slowdown in the metabolism of amlodipine, probably due to inhibition of the CYP3A4 isoenzyme, which leads to an increase in the concentration of amlodipine in the blood plasma by approximately 50% and an increase in the clinical effect. When amlodipine is used together with strong CYP3A4 inhibitors (for example, ketoconazole, itraconash and ritonavir), a marked increase in the systemic exposure of amlodipine is possible.

Inducers of the CYP3A4 isoenzyme. Since the use of amlodipine together with inducers of the CYP3A4 isoenzyme (for example, carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone, rifampicin, grapefruit juice, herbal preparations containing St. John's wort) can lead to a marked decrease in its concentration in the blood plasma; When prescribing amlodipine with CYP3A4 inducers, its clinical effect should be monitored.

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, Maalox (aluminum hydroxide gel, magnesium hydroxide, simethicone), cimetidine, NSAIDs, antibiotics and oral hypoglycemic drugs.

Valsartan

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

Drugs and substances that affect the level of potassium in the blood serum: When coadministered with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other drugs that may cause an increase in potassium levels in the blood (for example, heparin), caution should be exercised and frequent monitoring of potassium levels in the blood should be performed.

NSAIDs, including selective COX-2 inhibitors: Prescribing angnotensin II receptor antagonists concomitantly with NSAIDs may lead to a weakening of the hypotensive effect. In elderly patients, patients with BCC deficiency (including those receiving diuretic therapy) or with impaired renal function, the simultaneous use of angiotensin II receptor antagonists and NSAIDs may lead to an increased risk of deterioration of renal function. When patients initiate or change a regimen of angiotensin II receptor antagonists with NSAIDs, regular monitoring of renal function is recommended.

special instructions

Patients with initial and moderate renal dysfunction (creatinine clearance 30-50 ml/min) do not require Exforge dose adjustment. Caution should be exercised when prescribing the drug to patients with severe renal impairment (CR<10 мл/мин), т.к. данные по безопасности применения препарата в таких случаях не получены.

As with the use of other vasodilators, special care should be taken when prescribing the drug to patients with mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy.

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

In placebo-controlled studies in patients with uncomplicated arterial hypertension, severe arterial hypotension was observed in 0.4% of cases. In patients with activated RAAS (for example, with BCC and/or sodium deficiency in patients receiving high doses of diuretics), symptomatic arterial hypotension may develop when taking angiotensin receptor blockers. Before starting treatment with Exforge, sodium levels in the body and/or blood volume should be corrected or therapy should be initiated under close medical supervision.

If arterial hypotension develops, the patient should be placed with legs elevated and, if necessary, given an intravenous infusion of saline solution. After stabilization of blood pressure, treatment with Exforge can be continued.

When using the drug simultaneously with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes, or with other drugs that may cause an increase in the concentration of potassium in the blood (for example, with heparin), caution should be exercised and regular monitoring of the concentration of potassium in the blood should be carried out. .

Impact on the ability to drive vehicles and operate machinery

There is no data on the effect of the drug on the ability to drive vehicles and operate machinery. Due to the possible occurrence of dizziness or increased fatigue, caution should be exercised when driving vehicles or operating machinery.

Pregnancy and lactation

Exforge, like any other drug that directly affects the RAAS, should not be prescribed during pregnancy or to women wishing to become pregnant. If pregnancy is detected during treatment with Exforge, the drug should be discontinued as soon as possible.

Patients of childbearing age should be informed of the possible risk to the fetus associated with the use of drugs that affect the RAAS.

Given the mechanism of action of angiotensin II receptor antagonists, a risk to the fetus cannot be excluded. It is known that the administration of ACE inhibitors, which affect the RAAS, to pregnant women in the second and third trimesters leads to damage or death of the developing fetus. 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. With the unintentional use of valsartan in pregnant women, cases of spontaneous abortion, oligohydramnios and renal dysfunction in newborns have been described.

It is not known whether valsartan and/or amlodipine are excreted in breast milk. Since in experimental studies Excretion of valsartan into breast milk has been noted; the use of Exforge during lactation (breastfeeding) is not recommended.

Use in childhood

The safety of Exforge in children and adolescents under 18 years of age has not been established.

For impaired renal function

Patients with initial and moderate renal impairment do not require Exforge dose adjustment. Caution should be exercised when prescribing the drug to patients with severe renal impairment (CR<10 мл/мин), так как данные по безопасности применения препарата в таких случаях не получены.

For liver dysfunction

Caution should be exercised when prescribing Exforge to patients with liver disease (especially obstructive diseases of the biliary tract). Valsartan is excreted mainly unchanged in the bile, while amlodipine is extensively metabolized in the liver.

Conditions for dispensing from pharmacies

The drug is available with a prescription.

Storage conditions and periods

The drug should be stored out of the reach of children, in a dry place at a temperature not exceeding 30°C. Shelf life - 3 years.

Exforge is a medicine to lower blood pressure. If you look at the name of its active ingredients, at least one of them will seem familiar - amlodipine.

This is a substance from the group of “calcium antagonists”, which leads to relaxation of the vascular wall. The second component, valsartan, is an angiotensin antagonist. It is able to reduce blood pressure without changing the rhythm of the heart.

In this article we will look at why doctors prescribe Exforge, including instructions for use, analogues and prices for this drug in pharmacies. Real REVIEWS of people who have already used Exforge can be read in the comments.

Composition and release form

The drugs are available in tablet form.

• Exforge tablets have active ingredients such as amlodipine and valsartan, as well as the following additional components: talc, MCC, magnesium stearate, hypromellose, colloidal silicon dioxide, titanium dioxide, crospovidone, iron oxide yellow, macrogol 4000.

Clinical and pharmacological group: antihypertensive drug

Indications for use

Exforge is indicated for patients with hypertension or hypertension of various origins for whom monotherapy has become ineffective.

pharmachologic effect

Exforge is an antihypertensive drug containing a combination of two active substances.

• Amlodipine is a representative of slow calcium channel blockers. Due to its effect on receptors, it inhibits the movement of calcium into the cell into cardiomyocytes and endothelial smooth muscle cells. Due to this, relaxation of the walls of blood vessels, their expansion, and a decrease in peripheral vascular resistance are observed.
• The second component is valsartan, which is an antagonist of the angiotensin II receptor apparatus, selectively acting on AT1 receptors. The active components in a given combination and dosage complement each other's effects. The use of Exforge is more effective than the use of amlodipine and valsartan as monotherapeutic agents.

Instructions for use

Exforge should be taken orally with a small amount of water, 1 time per day, regardless of the time of meal.

• Recommended daily dose – 1 tablet. at a dose of 5/80 mg or 5/160 mg or 10/160 mg.

The duration of treatment is determined individually.

Contraindications

The drug should not be used in the following cases:

1. His intolerance;
2. Pregnancy, lactation and children (under eighteen years of age);
3. Pathological narrowing of the renal vessels;
4. Recent kidney transplant.

Carefully:

1. Severe dysfunction of the liver or kidneys, as well as the heart;
2. Reduced blood volume;
3. Increased potassium levels in the blood;
4. Reduced sodium content in the blood.

Side effects

The most common adverse reactions from the following organ systems:

• Musculoskeletal system: swelling in the joints, muscle and back pain, cramps.
• Digestive system: dry mouth, nausea, increased frequency of bowel movements.
• Nervous system: decreased concentration, dizziness, blurred vision, disruption of the vestibular apparatus, anxiety.
• Cardiovascular system: increased heart rate, excessive drop in blood pressure, fainting.
• Respiratory system: symptoms of rhinitis, inflammation of the pharyngeal mucosa, very rarely - cough.
• Genitourinary system: increased frequency and volume of urination, erectile dysfunction.

Allergic reactions with proper use of exforge are very rare, manifesting themselves in the form of rashes or itching.

Pregnancy and lactation

Exforge, like any other drug that directly affects the RAAS, should not be prescribed during pregnancy or to women wishing to become pregnant. If pregnancy is detected during treatment with Exforge, the drug should be discontinued as soon as possible.

Exforge's analogs

Structural analogues of the active substance:

• Vamloset;
• Co-Exforge.

Attention: the use of analogues must be agreed with the attending physician.

Hypertension is a progressive disease, and over time, one antihypertensive drug becomes insufficient.

The optimal solution is a drug that combines the properties of two groups of antihypertensive drugs.

Exforge is a high-quality original Swiss-made drug that combines a calcium channel antagonist and sartan.

The components included in its composition complement and enhance each other’s action, effectively combating high blood pressure.

Amlodipine is used as a calcium channel blocker in Exforge. It prevents the entry of calcium into the cells of the muscle layer of blood vessels, thereby expanding them and lowering pressure.

An additional beneficial property of amlodipine is its positive effect on renal blood flow.

The advantages of the drug include the absence of an effect on the pulse rate and function of the sinus node, therefore the drug is effective for patients with angina pectoris and atherosclerosis of the coronary vessels.

Valsartan is an AT II receptor blocker that has a selective effect on type I receptors, effectively reducing blood pressure without reducing the number of heart contractions.

Due to the lack of influence on ACE, it has no side effects such as cough. The effect of using the drug is long-lasting and does not decrease sharply after discontinuation.

An improvement in prognosis has been proven when taking valsartan in patients with CHF and after myocardial infarction.

Indications for use

Exforge is indicated for patients with hypertension or hypertension of various origins for whom monotherapy has become ineffective.

Way

The tablets are taken orally, 1 tablet regardless of meals. The dosage is selected by a doctor, the minimum is 5 mg of ampodipine and 80 mg of valsartan.

If necessary, the dose is increased to 10 mg and 320 mg, respectively.

Release form, composition

Available in the form of film-coated tablets containing a combination of amlodipine and valsartan in dosages of 5/80 mg, 5/160, 10/160, 5/320 and 10/320.

Tablets are placed in blisters of 7, 10 or 14 pieces, which in various combinations are placed in a cardboard box.

Active substances are amlodipine besylate (6.94 or 13.87 mg per tablet), equivalent to a 5 or 10 mg dose of amlodipine. Valsartan is added in dosages of 80, 160 or 320 mg.

Additionally The tablet contains crospovidone, magnesium stearate, talc, dyes.

Absorption of the tablet components occurs in the small intestine, the maximum concentration in the blood of amlodipine occurs after 6-10 hours with a bioavailability of 70%, and valsartan after 2 hours with a bioavailability of no more than 25%. After absorption, amlodipine binds to plasma proteins and enters the liver and is excreted by the kidneys.

Valsartan combines predominantly with albumin, most of it remains unchanged and is not metabolized. 83% of the substance is excreted through the intestines, the rest in the urine.

Interaction with other drugs

When using the drug exforge together with potassium preparations or potassium-sparing diuretics, as well as with heparin, it is necessary to carefully monitor the concentration of the ion in the blood to avoid hyperkalemia.

Side effects

Allergic reactions with proper use of exforge are very rare, manifesting themselves in the form of rashes or itching.

The most common adverse reactions from the following organ systems:

Side effects

Amlodipine, in turn, can additionally cause side effects such as exacerbation of gastritis, shortness of breath, increased potassium levels in the blood, decreased levels of leukocytes and platelets.

General weakness rarely occurs, sweating increases, and mood becomes unstable. In patients with heart disease, rhythm disturbances and angina attacks have been observed, but there is no reliable connection between these events and the use of amlodipine.

Side effects of valsartan include the occurrence of upper respiratory tract infections, inflammation of the paranasal sinuses and nasal cavity. A decrease in blood neutrophils was observed in 2% of patients, and urea levels increased in 16%. Many patients during therapy with valsartan experienced an increase in creatinine and potassium in the blood.

Overdose

In case of an overdose of exforge, it is necessary to rinse the stomach and take activated charcoal.

If there is a significant drop in blood pressure, the patient should be laid down and the leg end should be raised while monitoring heart function.

Contraindications

Taking exforge is contraindicated in case of hypersensitivity to the components and during pregnancy. Use is not recommended for the following conditions:

• pathology of the liver and biliary tract;
• impaired renal function (creatinine clearance less than 10 ml per minute);
• valve defects in the form of stenosis, obstruction of the left ventricular outflow tract, hypertrophic cardiomyopathy;
• increased blood potassium level, hyponatremia, BCC deficiency.

Use during pregnancy

Exforge is contraindicated in pregnant women, since the angiotensin receptor blocker included in the composition causes miscarriage, severe fetal development disorders or serious renal pathology.

Due to the lack of reliable data on the safety of exforge, there are no recommendations for its use in nursing mothers.

Storage conditions and periods

Use within two years, store at room temperature.

Price

average cost in Russia:

• dosage 10 mg/160 mg - 14 tablets 1020 rubles, 28 tablets 1800 rubles;
• 5 mg/160 mg - 14 tablets 950 rubles, 28 tablets 1750 rubles;
• 5 mg/80 mg - 14 tablets 880 rubles, 28 tablets 1630 rubles.

average cost in Ukraine:

• dosage 10 mg/160 mg - 14 tablets 365 hryvnia, 28 tablets 590 hryvnia;
• 5 mg/160 mg - 350 hryvnia - 14 tablets, 28 tablets 580 hryvnia;
• 5 mg/80 mg - 340 hryvnia - 14 tablets, 28 tablets 520 hryvnia.

Analogues

A direct analogue of the drug exforge is vamloset. The tablets use the same concentrations of amlodipine and valsartan.

Vamloset is a Russian-made drug; its price for 28 tablets varies from 230 to 340 rubles, depending on the dosage.

There are many similar combination drugs containing a combination of antihypertensive substances:

1. Amzaar: amlodipine and an AT II receptor blocker are also combined, in this drug - losartan. Made in Russia, cost about 600 rubles.
2. Equator: the combination of amlodipine and the ACE inhibitor lisinopril, in addition to the hypotensive effect, has vasodilatory and antianginal properties. Hungarian drug, price from 500 to 700 rubles for 30 tablets.
3. Enanorm: a combination of enalapril and nitrendipine, a calcium channel blocker, made in Spain, cost 410 rubles.
4. Gizaar: losartan and the thiazide diuretic hydrochlorothiazide. Due to its diuretic effect, it is prescribed to patients with left ventricular failure. Manufacturer - the Netherlands, price on average 420 rubles for 14 tablets.

There is no shortage of good antihypertensive drugs in pharmacies today, and it would seem that this should help antihypertensive therapy become absolutely problem-free.

But with such a variety of medications, it is not so easy to choose exactly the one that is suitable for a particular patient in all respects.

The body’s reaction to the composition of a medication is in most cases unpredictable, which is why doctors are often faced with the need to abandon long-tested medications and look for others. To minimize the body’s negative reaction to the drug, you must carefully study the instructions before using it.

Let's get acquainted with the drug produced by a Swiss company - Exforge. Instructions for use of this antihypertensive drug will tell you about its most important characteristics.

Composition and description of the drug Exforge

Exforge tablets belong to the pharmacological group of combined antihypertensive medications and contain 2 active ingredients:

• (representative );
• valsartan ().

Valsartan does not block ACE (angiotensin-converting enzyme), therefore its therapeutic effect, as indicated by the instructions for use, does not provoke the appearance of a cough reflex. Exforge is produced in several versions.

5 mg + 80 mg

The drug Exforge 5 + 80 is produced in tablet form, the active composition of which includes 5 mg of amlodipine and 80 mg of valsartan.

These are dark yellow, round-shaped tablets with NV embossed on one side and NVR on the other. They most often serve as a starting agent for antihypertensive therapy, therefore, with Exforge 5/80, the instructions for use recommend starting treatment for hypertension.

5 mg + 160 mg

After 7–14 days from the start of therapy, provided that Exforge is well tolerated and if necessary, it is recommended to switch to an enhanced version of the medication. For this purpose, dark yellow Exforge pills are suitable, which, according to the instructions for use, contain double the amount of valsartan (160 mg), which enhances the antihypertensive effect with a minimum of side effects. The abbreviation ECE is imprinted on one plane of the Exforge 5/160 tablet, and NVR on the other. A medicine with this composition of active ingredients is used for maintenance antihypertensive therapy.

10 mg + 160 mg

Hypertension of 2-3 degrees of severity requires an increase in the dosage of medications taken, and in this situation it is advisable to use the Exforge 10 + 160 option. These light yellow pills with inscriptions on one and the other surface, respectively, UIC and NVR contain 10 mg of amlodipine and 160 mg of valsartan . Exforge 10/160 tablets are recommended for use in severe cases.

Mechanism of action of amlodipine and valsartan

How do the active ingredients of Exforge affect blood vessels?

1. Due to its effect on calcium channels, amlodipine prevents the influx (leakage) of Ca2 + ions into the cells of the smooth muscle layer of the arteries and heart (cardiomyocytes).
2. This has a direct relaxing effect on the blood vessels and helps reduce capillary resistance.
3. Vasodilation contributes to a drop in blood pressure without affecting heart rate.
4. Valsartan selectively acts on AT1 receptors, the blockade of which increases the amount of angiotensin II.
5. The use of valsartan does not provoke the accumulation of bradykinin (which occurs due to ACE inhibition), which makes coughing less likely to occur.
6. Due to the lack of interaction with receptors of other hormones or ion channels, when valsartan is used, their blockade does not occur, that is, the effect on the cardiovascular system is minimized.

WHO blood pressure classification

Indications

What do the instructions for use say about the use of the drug Exforge? According to this document, it is indicated for the treatment of hypertension in patients for whom it is preferable to prescribe therapy with combination medications. These, as already mentioned, are those groups of patients who:

• poorly tolerated;
• suffer from bronchial asthma or chronic lung diseases;
• prone to tachycardia (increased heart rate).

A doctor must prescribe the drug Exforge according to its indications for use; this medicine must be dispensed in pharmacies only with a prescription.

A separate group in the instructions for use of Exforge for blood pressure identifies situations where treatment with the drug is prohibited:

• with severe renal impairment or on hemodialysis;
• complex liver pathologies, cholestasis, biliary cirrhosis;
• tendency to angioedema (or other edema due to drug use);
• in the post-infarction period;
• during periods before planned conception, childbearing and breastfeeding;
• patients with type II diabetes mellitus using Aliskiren.

As in any other instructions for use, the annotation in question also mentions such a contraindication as individual intolerance to at least one ingredient in the composition of the medication.

Instructions for use

The above data on Exforge tablets does not exhaust the instructions for use. Before using the medicine, patients should read other instructions in this document.

How to take blood pressure pills?

Like most long-acting antihypertensive medications, Exforge tablets should be taken once a day. These pills do not need to be chewed, ground into powder or placed under the tongue.

To wash down the tablets, it is advisable to use ordinary drinking water - approximately 150 ml. The timing of meals does not matter when taking Exforge.

Dosages

The dosage of the drug is usually agreed with the doctor and depends on the severity of hypertension and some other factors. For example, with Exforge 5/80 tablets, the instructions for use recommend starting treatment, and from the 7th or 14th day switching to the enhanced version, if necessary.

The distribution of the amount of active ingredients is as follows:

• start of treatment - 5 mg + 80 mg 1 time per day;
• maintenance therapy - 5 mg + 160 mg or 10 mg + 160 mg once a day;
• daily maximum - 10 mg +320 mg (or 2 Exforge 5/160 tablets) at a time.

There is no need for Exforge dosage adjustment for use in people over 65 years of age with uncomplicated renal dysfunction.

special instructions

The instructions for using Exforge blood pressure tablets indicate situations when therapy is allowed only under the supervision of a physician:

• in severe cases - due to the increased likelihood of development due to treatment with amlodipine;
• with CHF of functional classes III-IV - the risk of conditions causing acute renal failure and even death increases;
• for liver diseases not listed in the contraindications, you should still ensure controlled intake of medications containing amlodipine;
• the same applies to moderate renal dysfunction, renal artery stenosis - use only under control;
• if the risk of hyperkalemia is increased (for example, against the background of potassium-sparing diuretics), monitoring the amount of potassium in the blood is mandatory;
• in case of hypovolemia or sodium deficiency in the blood - due to the increased risk of developing severe;
• If the patient has a history of Quincke's edema, as well as swelling of the vocal cords and larynx, oral organs (which is reported during treatment with valsartan), you should be extremely careful when using Exforge.

If the slightest signs of edema appear, the medication should be permanently discontinued. When working with machinery or driving vehicles, you must remember the likelihood of developing dizziness due to the use of Exforge.

Side effects

Not a single antihypertensive drug is complete without such an annoying “addition” as side effects that occur in people prone to negative reactions to medications. While taking the medication Exforge, side effects may develop in the form of:

The list of undesirable manifestations of the drug actually occupies a significant part of the instructions for use, but it is worth recognizing that their manifestations are quite rare.