Co-Diovan, 28 pcs., 80 mg+12.5 mg, film-coated tablets

Composition and release form

in blisters of 7 or 14 pcs.; in a cardboard pack 1, 2, 4, 7, 20 (7 pieces each - for a dosage of 320 mg) or 1, 2, 4, 7 (14 pieces each - for dosages 40, 80 and 160 mg) blisters, or 120 ×8 (for a dosage of 80 mg) and 45×8 (for a dosage of 160 mg) blisters; and also in GPE bottles of 56, 98 or 280 pcs. (for a dosage of 320 mg).

Description of the dosage form

Film-coated tablets, 40 mg: yellow oval with beveled edges, marked “DO” on one side and “NVR” on the other side.

Film-coated tablets, 80 mg: pale pink, round with beveled edges, scored on one side and embossed with the inscription “D/V”, on the other side “NVR”.

Film-coated tablets, 160 mg: gray-orange, oval, scored on one side and embossed with the inscription “DX/DX”, on the other side “NVR”.

Film-coated tablets, 320 mg: dark gray-violet, oval with beveled edges, scored on one side and embossed with the inscription “DXL”, on the other side “NVR”.

Pharmacodynamics

The drug Diovan® is an active specific antagonist of angiotensin II receptors, intended for oral administration. Selectively blocks receptors of the AT1 subtype, which are responsible for the effects of angiotensin II. The consequence of AT1 receptor blockade is an increase in the plasma concentration of angiotensin II, which can stimulate unblocked AT2 receptors. The drug Diovan® does not have any pronounced agonistic activity against AT1 receptors. The affinity of the drug Diovan® for receptors of the AT1 subtype is approximately 20,000 times higher than for receptors of the AT2 subtype.

The likelihood of coughing when using valsartan is very low, which is due to the lack of effect on ACE, which is responsible for the degradation of bradykinin. A comparison of the drug Diovan® with an ACE inhibitor showed that the incidence of dry cough was significantly (p<0.05) lower in patients receiving the drug Diovan® than in patients receiving an ACE inhibitor (2.6 versus 7.9%, respectively ). In the group of patients who had previously developed a dry cough during treatment with an ACE inhibitor, when treated with Diovan® this complication was noted in 19.5% of cases, in 19% of cases, while in the group of patients treated with an ACE inhibitor, cough was observed in 68.5% of cases (p<0.05). Valsartan does not interact with or block other hormone receptors or ion channels that are important for regulating the functions of the cardiovascular system. When treating patients with arterial hypertension with Diovan®, a decrease in blood pressure is observed, not accompanied by a change in heart rate.

After oral administration of a single dose of the drug, in most patients the onset of the antihypertensive effect is noted within 2 hours, and the maximum reduction in blood pressure is achieved within 4–6 hours. After taking the drug, the antihypertensive effect persists for more than 24 hours. With repeated prescriptions of the drug, the maximum decrease in blood pressure, regardless of from the dose taken, is usually achieved within 2–4 weeks and is maintained at the achieved level during long-term therapy. Sudden cessation of taking Diovan® is not accompanied by a sharp increase in blood pressure or other undesirable clinical consequences.

The mechanism of action of the drug Diovan® in chronic heart failure (CHF) is based on its ability to eliminate the negative consequences of chronic hyperactivation of the renin-angiotensin-aldosterone system (RAAS) and its main effector - angiotensin II, namely vasoconstriction, fluid retention in the body, cell proliferation , leading to remodeling of target organs (heart, kidneys, blood vessels), stimulation of excessive synthesis of hormones that act synergistically with the RAAS (catecholamines, aldosterone, vasopressin, endothelin, etc.). With the use of valsartan for CHF, preload decreases, pulmonary capillary wedge pressure (PCWP) and pulmonary artery dBP decrease, and cardiac output increases. Along with hemodynamic effects, valsartan, due to indirect blockade of aldosterone synthesis, reduces sodium and water retention in the body.

It was found that the drug did not have a significant effect on the concentration of total cholesterol, uric acid, and also, when studied on an empty stomach, on the concentration of triglycerides and glucose in the blood serum.

CHF

Hemodynamics and neurohormones. In patients with CHF (II–IV functional class according to the NYHA classification) and PCWP ≥15 mm Hg. studied hemodynamics and concentrations of neurohormones in blood serum. In patients constantly receiving ACE inhibitors, valsartan, prescribed against the background of an ACE inhibitor in single and repeated doses, led to an improvement in hemodynamic parameters, incl. to a decrease in PAWP, pulmonary artery dBP and systolic blood pressure. After 28 days of therapy, a decrease in the concentrations of aldosterone and norepinephrine in the blood was observed. In patients who had not received ACE inhibitors for at least 6 months, after 28 days of therapy, valsartan significantly reduced PCWP, systemic vascular resistance, systolic blood pressure, and cardiac output.

Morbidity and mortality. The effect of valsartan, compared with placebo, on morbidity and mortality in patients with NYHA functional class II (62%), III (36%) and IV (2%) heart failure with left ventricular ejection fraction (LVEF) <40% was studied. and left ventricular internal diastolic diameter (LVID) >2.9 cm/m2, on traditional therapy, which included ACE inhibitors (93%), diuretics (86%), digoxin (67%) and beta-blockers (36%) . The average follow-up period was almost 2 years, the average daily dose of Diovan® was 254 mg. The two primary efficacy endpoints were all-cause mortality (time to death) and heart failure-related morbidity (time to first event), assessed by the following: death, sudden death with resuscitation, hospitalization for heart failure, i.v. administration of inotropic or vasodilator drugs for 4 hours or more without hospitalization. All-cause mortality rates were comparable between the valsartan and placebo groups. Compared with the placebo group, the incidence in the group of patients receiving valsartan significantly decreased by 13.2%. The primary outcome measure was a 27.5% reduction in time to first hospitalization for heart failure. This effect was most pronounced in patients who did not receive ACE inhibitors or beta-blockers.

Exercise tolerance. In patients with chronic heart failure of functional class II–IV according to the NYHA classification with LVEF ≤40%, the effect of valsartan prescribed in addition to traditional treatment of CHF on exercise tolerance was assessed using the Modified Naughton Protocol. All treatment groups showed an increase in physical activity time compared to baseline. Compared with the placebo group, patients receiving valsartan had a greater mean increase from baseline in exercise time, although this difference was not significant. The most pronounced improvement in exercise tolerance was observed in the subgroup of patients who did not receive ACE inhibitors: the average change in exercise time in the valsartan groups was 2 times higher than that in the placebo group. The effect of valsartan on exercise capacity, compared with enalapril, according to the 6-minute walk test, was studied in patients with NYHA functional class II–IV heart failure with LVEF ≤45% who had received prior (at least 3 months) therapy ACE inhibitors. Patients were transferred from treatment with an ACE inhibitor to either valsartan or enalapril. Valsartan at doses of 80 to 160 mg once daily was at least as effective as enalapril at doses of 5 to 10 mg twice daily.

NYHA class, symptoms, quality of life, ejection fraction. In patients receiving valsartan, there was a significant improvement in the functional class of CHF according to the NYHA classification, as well as signs and symptoms of CHF, incl. such as shortness of breath, increased fatigue, peripheral edema, wheezing. Compared with the placebo group, patients taking valsartan had a significant increase in ejection fraction and a significant decrease in LVDP compared with baseline values ​​before treatment.

The use of Diovan® leads to a decrease in the number of hospitalizations for CHF, a slowdown in its progression, an improvement in NYHA functional class, an increase in ejection fraction, as well as a decrease in the severity of signs and symptoms of heart failure and an improvement in quality of life compared to placebo.

Use after acute myocardial infarction

The VALIANT study included 14,703 patients with acute myocardial infarction complicated by left ventricular failure and/or left ventricular systolic dysfunction.

Randomization was carried out 0.5–10 days after acute myocardial infarction, into groups in which, in addition to traditional treatment, treatment was started with either valsartan (4909 patients), or a combination of valsartan and captopril (4885 patients), or captopril (4909 patients). sick).

Rates of all-cause and cause-specific mortality were similar in all 3 treatment groups. A total of 979 (19.9%) patients died in the valsartan group, 941 (19.3%) in the combination therapy group, and 958 (19.5%) in the captopril group.

The hazard ratio for death from cardiovascular causes and the hazard ratio for a composite indicator that included, in addition to cardiovascular deaths, serious nonfatal cardiovascular events (recurrent myocardial infarction, hospitalization for heart failure, resuscitation after circulatory arrest, and stroke) were similar for the valsartan group and the captopril group, as well as for the combination therapy group and the captopril group.

The combination therapy group showed the highest incidence of drug-related adverse events. With monotherapy, hypotension and renal dysfunction were more often observed in the valsartan group, and cough, rash and taste disturbances were more often observed in the captopril group.

The study proved the effectiveness of valsartan, equal to that of captopril, in reducing overall and cardiovascular mortality. The calculated effectiveness of valsartan on overall mortality is 99.6% of that of captopril. An additional analysis using a placebo-assumption method showed that valsartan reduced the risk of death by 25%. Valsartan is as effective as captopril in the treatment of patients at high risk of developing cardiovascular complications after myocardial infarction. The addition of valsartan to captopril therapy leads to an increase in the incidence of adverse events without causing an additional improvement in patient survival.

Pharmacokinetics

After taking the drug orally, valsartan is rapidly absorbed, but the extent of absorption varies widely. The average absolute bioavailability of Diovan® is 23%. T1/2 is about 9 hours. In the range of doses studied, the kinetics of valsartan is linear. With repeated use of the drug, no changes in kinetic parameters were observed. When taking the drug once a day, the accumulation is insignificant. Concentrations of the drug in blood plasma were the same in women and men.

Valsartan is highly (94–97%) bound to serum proteins, predominantly albumin. VSS during the steady state period is low (about 17 L). Compared to hepatic blood flow (about 30 l/h), plasma Cl of valsartan occurs relatively slowly (about 2 l/h). The amount of valsartan excreted in feces is 70% (of the dose taken orally). About 30% is excreted in the urine, mostly unchanged. When Diovan® is administered with food, the AUC decreases by 48%, although, starting from approximately 8 hours after taking the drug, the plasma concentrations of valsartan both when taken on an empty stomach and when taken with food are the same. The decrease in AUC, however, is not accompanied by a clinically significant decrease in the therapeutic effect, so Diovan® can be taken both on an empty stomach and with food.

Pharmacokinetics in certain groups of patients

Elderly patients. In some elderly individuals, valsartan AUC values ​​were higher than those in younger individuals, however, this difference was not shown to be of any clinical significance.

Patients with impaired renal function. There was no correlation between renal function and AUC values ​​of valsartan. In patients with impaired renal function, no dose adjustment is required. There are currently no data available for hemodialysis patients. Valsartan has a high degree of binding to plasma proteins, so its elimination during hemodialysis is unlikely.

Patients with impaired liver function. About 70% of the absorbed dose of the drug is excreted in the bile, mainly unchanged. Valsartan does not undergo significant biotransformation; the AUC of valsartan does not correlate with the degree of liver dysfunction. Therefore, in patients with liver failure of non-biliary origin and in the absence of cholestasis, dose adjustment of the drug Diovan® is not required. It has been shown that in patients with biliary cirrhosis or biliary obstruction, the AUC of valsartan increases approximately 2-fold.

Pharmacological properties of the drug Diovan

Valsartan is a specific angiotensin II receptor antagonist. Acts selectively on receptors of the AT1 subtype, which are responsible for the known effects of angiotensin II. Increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor, which counterbalances the effect of the AT1 receptor. Valsartan does not exhibit pronounced agonistic activity against receptors of the AT1 subtype. 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, destroying bradykinin. As a result, the use of the drug in patients with hypertension reduces blood pressure without affecting the pulse rate. The onset of the hypotensive effect is observed within 2 hours, maximum 4–6 hours after oral administration. After taking the drug, the antihypertensive effect lasts 24 hours. The maximum therapeutic effect develops 2–4 weeks from the start of treatment and persists with long-term therapy. When the drug is combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved. Sudden cessation of taking the drug is not accompanied by the development of withdrawal syndrome. During a course of use of the drug in patients with hypertension (arterial hypertension), it was found that the drug did not have a significant effect on the level of total cholesterol, uric acid, and also, when studied on an empty stomach, on the concentration of TG and glucose in the blood serum. The use of the drug causes a decrease in the number of hospitalizations due to heart failure, a slowdown in the progression of heart failure, an improvement in NYHA functional class (New York Heart Association), an increase in ejection fraction, as well as a decrease in signs and symptoms of heart failure and an improvement in quality of life compared with placebo. The results of the VALIANT study demonstrated the effectiveness of valsartan, like captopril, in reducing overall mortality after myocardial infarction. Valsartan was also effective in reducing mortality due to cardiovascular pathology, reducing the number of hospitalizations due to heart failure and the incidence of recurrent myocardial infarction. Valsartan had a positive effect on such an indicator as the period of time after an acute myocardial infarction until the appearance of the first manifestations of cardiovascular pathology leading to death. After oral administration of the drug, valsartan is rapidly absorbed, but the extent of absorption varies significantly. The average absolute bioavailability is 23%. The pharmacokinetic curve of valsartan has a descending multi-exponential character (t1/2α≤1 hour and t1/2β about 9 hours). In the range of doses studied, the kinetics of valsartan is linear. With repeated use of the drug, no changes in kinetic parameters were observed. When taking the drug once a day, the accumulation is insignificant. Concentrations of the drug in blood plasma were the same in women and men. Valsartan is highly (94–97%) bound to serum proteins, predominantly albumin. The volume of distribution during the steady state period is low (about 17 l). Compared to hepatic blood flow (about 30 l/h), plasma clearance of valsartan occurs relatively slowly (about 2 l/h). The amount of valsartan excreted in feces is 70% (of the dose taken orally). About 30% is excreted in the urine, mostly unchanged. When valsartan is administered with food, the AUC decreases by 48%, although starting from approximately the 8th hour after taking the drug, the concentrations of valsartan in the blood plasma both when taken on an empty stomach and when taken with food are the same. A decrease in AUC, however, is not accompanied by a clinically significant decrease in the therapeutic effect, so the drug can be taken on an empty stomach or with food. The mean time to reach the highest concentration and half-life of valsartan in patients with heart failure and healthy volunteers are the same. The AUC and maximum concentrations of valsartan increase linearly and are almost proportional to increasing doses above the clinical range (40–160 mg 2 times daily). The cumulation coefficient averages 1.7. The clearance of valsartan after oral administration is approximately 4.5 l/h. Age does not affect drug clearance in patients with heart failure. Elderly patients. In some elderly patients, systemic exposure to valsartan was greater than in younger patients, but this was not shown to be of any clinical significance. Patients with impaired renal function. There was no correlation between renal function and systemic exposure to valsartan. Therefore, in patients with impaired renal function, no dose adjustment is required. There are no studies yet on the pharmacokinetics of the drug in patients on hemodialysis. However, valsartan has a high degree of binding to plasma proteins, so its elimination during hemodialysis is unlikely. Patients with impaired liver function. About 70% of the absorbed dose of the drug is excreted in the bile, mainly unchanged. Valsartan does not undergo significant biotransformation and, as would be expected, systemic exposure to valsartan does not correlate with the degree of liver dysfunction. Therefore, in patients with liver failure of non-biliary origin and in the absence of cholestasis, no dose adjustment of valsartan is required. In patients with biliary cirrhosis or biliary obstruction, the AUC of valsartan has been shown to increase approximately 2-fold.

Contraindications

hypersensitivity to any of the components of the drug Diovan®;

pregnancy;

breastfeeding period.

Carefully:

bilateral renal artery stenosis, stenosis of the artery of a single kidney;

following a sodium-restricted diet;

conditions accompanied by a decrease in blood volume (including diarrhea, vomiting);

liver failure due to biliary tract obstruction;

renal failure (creatinine Cl less than 10 ml/min), incl. patients on hemodialysis (to date, studies of the pharmacokinetics of the drug in patients on hemodialysis have not been conducted).

Use in children - since controlled studies on the effectiveness and safety of valsartan in children and adolescents (under 18 years of age) have not been conducted, it is not possible to formulate specific recommendations for use in this group of patients.

Use during pregnancy and breastfeeding

Given the mechanism of action of angiotensin II antagonists, a risk to the fetus cannot be excluded. The effect of ACE inhibitors (drugs that affect the RAAS) on the fetus, if prescribed in the second and third trimesters of pregnancy, leads to its damage and death. According to retrospective data, the use of ACE inhibitors in the first trimester of pregnancy increases the risk of having children with birth defects. There are reports of spontaneous abortions, oligohydramnios and renal dysfunction in newborns whose mothers received valsartan during pregnancy. The drug Diovan®, like any other drug that has a direct effect on the RAAS, should not be used during pregnancy, or in women planning pregnancy. When prescribing drugs that act on the RAAS, the doctor should inform women of childbearing age about the potential risk of negative effects of these drugs on the fetus during pregnancy. If pregnancy is detected during treatment with Diovan®, the drug should be discontinued as soon as possible.

It is not known whether valsartan (the active substance of Diovan®) passes into human breast milk, but valsartan has been shown to be excreted into breast milk in experimental models. Therefore, Diovan® should not be used during breastfeeding.

Special instructions for the use of Diovan

Patients with a deficiency of sodium and/or bcc in the body. In patients with a severe deficiency in the body of sodium and/or bcc, for example, receiving diuretics in high doses, in rare cases, symptomatic hypotension may occur at the beginning of treatment with Diovan. Before starting treatment with Diovan, the sodium and/or blood volume levels in the body should be corrected, for example, by reducing the dose of the diuretic. If hypotension develops, the patient should be laid down and, if necessary, given an intravenous infusion of isotonic sodium chloride solution. After blood pressure has stabilized, treatment with Diovan can be continued. Renal artery stenosis. The use of Diovan in a short course in 12 patients with renovascular hypertension, which developed secondary to unilateral renal artery stenosis, did not lead to significant changes in renal hemodynamics, serum creatinine or blood urea nitrogen levels. However, given that other drugs that affect the renin-angiotensin-aldosterone system may cause increases in serum urea and creatinine levels in patients with bilateral or unilateral renal artery stenosis, systematic monitoring of these parameters is recommended as a precaution. Renal dysfunction. Patients with impaired renal function do not require dose adjustment of the drug. However, in case of severe disorders (creatinine clearance ≤10 ml/min), caution is recommended, since there is no information on the use of the drug in such cases. Liver dysfunction. In patients with liver failure, no dose adjustment is required. Valsartan is excreted primarily unchanged in the bile, and valsartan clearance has been shown to be reduced in patients with biliary obstruction. When prescribing valsartan to patients with biliary obstruction, special caution should be exercised. Heart failure/post-infarction condition. In patients with heart failure or in the post-infarction state, taking Diovan in usual doses, there is a slight decrease in blood pressure, but discontinuation of therapy due to prolonged symptomatic therapy is usually not required if the dosage instructions are followed. When starting therapy, caution should be exercised in patients with heart failure or post-infarction. Due to inhibition of the renin-angiotensin-aldosterone system, changes in renal function are possible in sensitive patients. In patients with severe heart failure, in whom renal function depends on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors and angiotensin receptor antagonists may be accompanied by oliguria and/or increased azotemia and rarely by acute renal failure and/or death. Evaluation of patients with or post-heart failure should always include an assessment of renal function. Caution is required in patients with heart failure when using a triple combination of ACE inhibitors, beta-adrenergic blockers and valsartan. During pregnancy and breastfeeding. Given the mechanism of action of angiotensin II antagonists, a risk to the fetus cannot be excluded. The effect of ACE inhibitors on the uterus, if prescribed during pregnancy in the second and third trimester, causes damage and death of the developing fetus. There have been reports of spontaneous abortion, oligohydramnios and renal dysfunction in newborns when women accidentally took valsartan during pregnancy. Diovan, like any other drug that directly affects the renin-angiotensin-aldosterone system, should not be used during pregnancy. If pregnancy is detected during treatment with Diovan, the drug should be discontinued as soon as possible. It is not known whether valsartan passes into breast milk in humans. Therefore, it is not recommended to use Diovan during breastfeeding. Impact on the ability to drive vehicles and operate machinery. As with other antihypertensive drugs, it is advisable to exercise caution when driving or operating machinery. The safety and effectiveness of Diovan in children (under 18 years of age) have not been established.

Side effects

The incidence of any of the adverse events was not shown to depend on the dose or duration of treatment; Therefore, adverse events observed with different doses of valsartan were combined. The incidence of adverse events was also not associated with gender, age, or race. Below are all adverse events observed with a frequency of 1% or more in the group of patients receiving Diovan®, regardless of their causal relationship with the study drug, as well as post-marketing data obtained in patients with arterial hypertension.

To assess the frequency of adverse events, the following criteria were used: very often (≥1/10), often (≥1/100, <1/10), sometimes (≥1/1000, <1/100), rarely (≥1/10000 , <1/1000), very rare (<1/10000).

Infections and infestations: often - viral infections; sometimes - upper respiratory tract infections, pharyngitis, sinusitis; very rarely - rhinitis.

From the hematopoietic system: often - neutropenia; very rarely - thrombocytopenia.

From the immune system: very rarely - hypersensitivity reactions, including serum sickness.

Metabolic disorders: sometimes - hyperkalemia1,2.

From the nervous system: often - postural dizziness2; sometimes - fainting1, insomnia, decreased libido; rarely - dizziness3; very rarely - headache4.

From the organ of hearing and labyrinthine disorders: sometimes - vertigo.

From the cardiovascular system: often - orthostatic hypotension2; sometimes - hypotension1, heart failure1; very rarely - vasculitis.

From the respiratory system: sometimes - cough.

From the gastrointestinal tract: sometimes - diarrhea, abdominal pain; very rarely - nausea4.

From the skin and subcutaneous tissue: very rarely - angioedema3; rash, itching.

From the musculoskeletal system: sometimes - back pain; very rarely - arthralgia, myalgia.

From the kidneys: very rarely - renal dysfunction3,4, acute renal failure3, renal failure3.

Other: sometimes - feeling of fatigue, asthenia, swelling.

Changes in laboratory parameters: in rare cases, the use of Diovan® may be accompanied by a decrease in the concentration of hemoglobin and hematocrit. In controlled clinical studies, a significant decrease (>20%) in hematocrit and hemoglobin was observed in 0.8 and 0.4% of patients receiving Diovan®, 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 Diovan® and 1.6% of patients receiving an ACE inhibitor.

A significant increase in the concentration of creatinine, potassium and total bilirubin in the blood serum was noted, respectively, in 0.8, 4.4 and 6% of patients taking the drug Diovan®, and in 1.6, 6.4 and 12.9% of patients who were taking an ACE inhibitor. In CHF, an increase in creatinine concentration by more than 50% was observed in 3.9% of patients taking the drug Diovan®, compared to 0.9% in the placebo group. At the same time, an increase in the level of potassium in the blood serum by more than 20% was observed in 10% of patients receiving Diovan® and 5.1% receiving placebo.

When treating patients after myocardial infarction, a 2-fold increase in serum creatinine concentration was observed in 4.2% of patients receiving valsartan, 4.8% of patients receiving valsartan + captopril, and 3.4% of patients receiving captopril.

There are reports of cases of increased activity of hepatic transaminases in patients receiving the drug Diovan®.

An increase in serum urea nitrogen concentration of more than 50% was observed in 16.6% of patients treated with valsartan and 6.3% of patients in the placebo group.

Note:

- 1 these adverse events were reported in patients receiving Diovan in the period after myocardial infarction;

- 2 these adverse events were reported in patients with CHF receiving the drug Diovan®;

- 3 these adverse events have been reported with occasional frequency in patients receiving Diovan in the period after myocardial infarction;

- 4 These adverse events were reported more often in patients with CHF receiving Diovan® (often - dizziness, impaired renal function, hypotension; sometimes - headache, nausea).

All patients with CHF received traditional drug therapy for CHF, often complex therapy, which included diuretics, digitalis drugs, beta-blockers or ACE inhibitors.

With long-term use of valsartan in patients with CHF, no additional side effects were observed.

Side effects of the drug Diovan

AH (arterial hypertension). The incidence of adverse reactions is assessed as follows: very often - ≥1/10, often - from ≥1/100, ≤1/10, sometimes - from ≥1/1000, ≤1/100, rarely - from ≥1/10,000 , ≤1/1000, very rarely - ≤1/100,000. Infections and invasions: often - viral infections; rarely - upper respiratory tract infections, pharyngitis, sinusitis; very rarely - rhinitis. From the circulatory and lymphatic systems: often - neutropenia; very rarely - thrombocytopenia. From the immune system: very rarely - hypersensitivity reactions, including serum sickness. Metabolic disorders: sometimes - hyperkalemia*, #. Mental disorders: sometimes - insomnia, decreased libido. From the nervous system: often - postural dizziness#; sometimes - dizziness*; rarely - vertigo; very rarely - headache##. Visual and labyrinthine disorders: sometimes - vertigo. From the cardiovascular system: often - orthostatic hypotension; sometimes - heart failure*, hypotension*, ##; very rarely - vasculitis. From the respiratory system: sometimes - cough. From the digestive system: sometimes - diarrhea, abdominal pain; very rarely - nausea##. Skin and subcutaneous disorders: very rarely - angioedema**, rash, itching. From the musculoskeletal system: sometimes - back pain; very rarely - arthralgia, myalgia. From the urinary system: very rarely - renal dysfunction**,##, acute renal failure**, renal failure**. General disorders: sometimes - weakness, asthenia, edema. *Post-infarction condition reported; #about symptoms of heart failure; ** about the post-infarction state as a rarely observed side effect; ##about more frequent cases of heart failure (often - dizziness, impaired renal function, hypotension; sometimes - headache, nausea). Heart failure. In double-blind short-term studies in patients with heart failure, as well as in the first 4 months of the Val-HeFT study, the drug was associated with the occurrence of adverse reactions listed above, which were observed with a frequency of 1% and more often in patients taking valsartan than in patients who used a placebo. All patients received standard drug therapy for heart failure, often complex therapy that included diuretics, digitalis, beta-adrenergic blockers or ACE inhibitors. With long-term use of valsartan in patients with heart failure, no additional side effects were observed. Post-infarction state. The double-blind, randomized, parallel-group VALIANT study compared the effectiveness and safety of long-term treatment with valsartan, captopril, and their combination in high-risk patients after myocardial infarction; the safety profile of valsartan was consistent with the pharmacological properties of the drug and the etiology of the disease, cardiovascular risk factors. vascular system and clinical picture of the disease in patients receiving therapy after myocardial infarction. Serious adverse events occurred predominantly in the cardiovascular system and were in most cases related to the underlying disease, as reflected in the primary efficacy endpoint in all cases with a fatal outcome. Non-fatal adverse events thought to be related to the study substance occurred in ≥0.1% of cases. These events included hypotension and renal dysfunction. Treatment was discontinued due to side effects in 5.8% of patients taking valsartan and 7.7% taking captopril. Laboratory results. In rare cases, the use of valsartan may be accompanied by a decrease in hemoglobin and hematocrit levels. In controlled clinical studies, 0.8% and 0.4% of patients taking Diovan experienced significant reductions in hematocrit and hemoglobin (20%), respectively. For comparison, in patients receiving placebo, a decrease in both hematocrit and hemoglobin levels was noted in 0.1% of cases. Neutropenia was detected in 1.9% of patients taking valsartan, and in 1.6% taking an ACE inhibitor. In controlled clinical studies in patients with hypertension (arterial hypertension), there was a significant increase in the level of creatinine, potassium and total bilirubin in the blood serum in 0.8, 4.4 and 6% of patients taking Diovan, respectively, and in 1.6, 6. 4 and 12.9% of patients using an ACE inhibitor. There are reports of increased liver function tests in patients taking valsartan. In heart failure, an increase in creatinine levels of more than 50% was observed in 3.9% of patients taking Diovan, compared with 0.9% in the placebo group. At the same time, an increase in the level of potassium in the blood serum by more than 20% was observed in 10.0% of patients taking Diovan, and in 5.1% taking placebo. In the post-infarction period, an increase in serum creatinine levels by 2 times was noted in 4.2% of patients receiving therapy with valsartan, 4.8% - a combination of valsartan and captopril, and 3.4% - captopril. In studies on heart failure, an increase in urea nitrogen levels was observed in 16.6% of patients taking valsartan and in 6.3% of those receiving placebo.

Interaction

No clinically significant interactions with other drugs have been observed so far. Interactions with the following drugs were studied: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine and glibenclamide.

Since Diovan® does not undergo significant metabolism, it is unlikely to have clinically significant interactions with other drugs that are inducers or inhibitors of the cytochrome P450 system. Although valsartan is highly bound to plasma proteins, no interaction at this level has been observed in vitro with a number of molecules that are similarly highly bound to plasma proteins, such as diclofenac, furosemide and warfarin.

The simultaneous use of potassium-sparing diuretics (including spironolactone, triamterene, amiloride), potassium preparations or salts containing potassium may lead to an increase in the concentration of potassium in the blood serum and, in patients with heart failure, to an increase in the concentration of serum creatinine. If such combination treatment is considered necessary, caution should be exercised.

Drug interactions Diovan

Clinically significant interactions with other drugs have not yet been observed. The following drugs were studied in clinical studies: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine and glibenclamide. Because Diovan is not significantly metabolized, it is unlikely to have clinically significant interactions with other drugs at the metabolic level that result from induction or inhibition of the cytochrome P450 system. Although valsartan is highly bound to plasma proteins, in vitro have not demonstrated any interaction at this level with a number of molecules that are similarly highly bound to plasma proteins, such as diclofenac, furosemide and warfarin. The simultaneous use of potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride), potassium supplements or salts containing potassium may cause an increase in serum potassium concentrations. If such combination treatment is considered necessary, caution should be exercised. The combination of valsartan with captopril is less effective than the use of captopril alone. There were no differences in overall mortality based on age, sex, race, underlying treatment, or underlying disease. Valsartan, like captopril, reduced mortality due to any cause after myocardial infarction. These incidences were similar in the valsartan (19.9%), captopril (19.5%) and valsartan + captopril groups (19.3%). Valsartan was also effective in reducing cardiovascular mortality, hospitalization due to heart failure, recurrent myocardial infarction, and resuscitated cardiac arrest without a fatal attack (secondary composite endpoint). In addition, the benefit of treatment with the combination of valsartan + captopril, valsartan monotherapy and captopril monotherapy was confirmed in patients taking β-adrenergic blockers.

Directions for use and doses

Inside, without chewing.

Arterial hypertension. The recommended dose is 80 mg 1 time per day daily, regardless of the race, age and gender of the patient. The antihypertensive effect is observed in the first 2 weeks of treatment, the maximum effect is after 4 weeks. For those patients who fail to achieve an adequate therapeutic response, the daily dose of Diovan® can be increased to 320 mg or additionally prescribed diuretics.

Chronic heart failure. The recommended starting dose is 40 mg 2 times a day daily. The dose of Diovan® should be gradually increased to 80 mg 2 times a day, and if well tolerated - to 160 mg 2 times a day. In this case, it may be necessary to reduce the doses of concomitantly taken diuretics. The maximum daily dose is 320 mg in 2 divided doses. Assessment of the condition of patients with CHF should include an assessment of renal function.

The period after myocardial infarction. Treatment should begin within 12 hours after myocardial infarction. The initial dose is 20 mg (1/2 tablet 40 mg) 2 times a day. The dose is increased by titration (40, 80 and 160 mg 2 times a day) over the next few weeks until the target dose is reached - 160 mg 2 times a day. The maximum daily dose is 320 mg in 2 divided doses. As a rule, it is recommended to achieve a dose of up to 80 mg 2 times a day by the end of the second week of treatment. Achieving the maximum target dose of 160 mg 2 times a day is recommended by the end of the third month of therapy with Diovan®. Achievement of the target dose depends on the tolerability of valsartan during the titration period. If symptomatic hypotension or renal dysfunction occurs, dose reduction should be considered. Assessment of the condition of patients in the period after myocardial infarction should include an assessment of renal function.

Note for all indications

No adjustment of the dosage regimen is required for patients with impaired renal function and patients with liver failure of non-biliary origin without cholestasis.

Use of the drug Diovan

AH (arterial hypertension). The recommended dose of Diovan is 80 or 160 mg 1 time per day, regardless of the race, age and gender of the patient. The antihypertensive effect is achieved in the first 2 weeks of treatment; the maximum effect is observed after 4 weeks. For patients who cannot achieve an adequate reduction in blood pressure, the daily dose of Diovan can be increased to 320 mg or additionally prescribed diuretics. Diovan can also be prescribed in combination with other antihypertensive drugs. Heart failure. The recommended starting dose of Diovan is 40 mg 2 times a day daily. The dose of Diovan should be increased by titration to 80 or 160 mg 2 times a day, that is, to the maximum, well-tolerated dose. The maximum daily dose of Diovan in clinical studies, taken in several doses, was 320 mg. Evaluation of patients with heart failure should always include assessment of renal function. Post-infarction state. Treatment can be started as early as 12 hours after myocardial infarction. After an initial dose of 20 mg twice daily, the dose of valsartan should be increased to 40, 80 and 160 mg twice daily over the next few weeks. To obtain the initial dose, the 40 mg tablet is divided in half. The recommended maximum dose is 160 mg 2 times a day. It is recommended to achieve a dose of 80 mg 2 times a day for up to 2 weeks after the start of treatment and the recommended maximum dose for 3 months, based on the patient's tolerability of valsartan during the dose titration period. If symptomatic hypotension or renal dysfunction occurs, dose reduction should be considered. It is possible to use valsartan in patients receiving other drugs used after myocardial infarction, such as thrombolytics, acetylsalicylic acid, beta-adrenergic blockers and statins. When assessing the condition of patients after myocardial infarction, renal function should always be assessed. Note regarding all indications: patients with impaired renal function or hepatic insufficiency of non-bile origin and without cholestasis do not require dose adjustment.

special instructions

During treatment with Diovan® in patients with essential arterial hypertension, regular monitoring of laboratory parameters is not required.

Sodium deficiency in the body and/or decreased blood volume. In patients with a severe deficiency of sodium and/or bcc in the body, for example, those receiving high doses of diuretics, in rare cases, at the beginning of treatment with Diovan®, hypotension may occur, accompanied by clinical manifestations. Before starting treatment with Diovan®, the sodium and/or BCC levels in the body should be corrected, including by reducing the dose of the diuretic.

If hypotension develops, the patient should be laid down and legs elevated. If necessary, administer an intravenous infusion of 0.9% sodium chloride solution. After blood pressure has stabilized, treatment can be continued.

Renal artery stenosis. The use of the drug Diovan® in a short course in 12 patients with renovascular hypertension, which developed secondary to unilateral renal artery stenosis, did not lead to any significant changes in renal hemodynamics, serum creatinine concentration or blood urea nitrogen. However, given that other drugs that affect the RAAS may cause an increase in serum urea and creatinine concentrations in patients with bilateral or unilateral renal artery stenosis, monitoring these indicators is recommended as a precautionary measure.

Renal dysfunction. Patients with impaired renal function do not require dose adjustment of the drug. However, in case of severe disorders (when creatinine Cl is less than 10 ml/min), caution is recommended.

Liver dysfunction. In patients with liver failure, no dose adjustment is required, except in cases of cholestasis. Valsartan is excreted primarily unchanged in the bile, and it has been shown that valsartan Cl is reduced in patients with biliary obstruction. When prescribing valsartan to these patients, special care should be taken.

CHF/period after myocardial infarction. In patients with CHF or after a myocardial infarction who begin treatment with Diovan®, there is often a slight decrease in blood pressure, and therefore it is recommended to monitor blood pressure at the beginning of therapy. Provided that the dosage recommendations are followed, there is usually no need to discontinue Diovan® due to hypotension. Due to inhibition of the RAAS, changes in renal function are possible in sensitive patients. In patients with severe CHF, treatment with ACE inhibitors and angiotensin receptor antagonists may be accompanied by oliguria and/or increased azotemia and (rarely) acute renal failure and/or death. Therefore, assessment of renal function is necessary in patients with heart failure and patients who have suffered acute myocardial infarction.

Combination therapy. In patients with CHF, caution should be exercised when using a combination of an ACE inhibitor, beta blocker and valsartan.

For arterial hypertension, Diovan® can be prescribed both as monotherapy and in combination with other antihypertensive drugs, in particular diuretics.

For CHF, Diovan® can be prescribed both as monotherapy and in combination with other drugs - diuretics, digitalis drugs, as well as ACE inhibitors or beta-blockers.

It is possible to use the drug Diovan® in combination with other drugs prescribed after a myocardial infarction, namely thrombolytics, acetylsalicylic acid, beta-blockers and statins.

Impact on the ability to drive a car and operate machinery. Patients taking Diovan® should be careful when driving a car and operating machinery.

Indications for use of the drug Diovan

AH (arterial hypertension). Heart failure. Therapy of heart failure (class II–IV according to the NYHA classification) in patients receiving traditional therapy with diuretics, digitalis preparations, as well as other ACE inhibitors or beta-adrenergic blockers; the use of all of the listed drugs is not mandatory. Post-infarction state. Diovan is indicated for the improvement of post-myocardial infarction in clinically stable patients with signs, symptoms and radiographic findings of left ventricular failure and/or left ventricular systolic dysfunction.