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.
Instructions for use DIOVAN® (DIOVAN)
Antihypertensive drug, angiotensin II receptor antagonist.
The active hormone of the renin-angiotensin-aldosterone system is angiotensin II, which is formed from angiotensin I with the participation of ACE. Angiotensin II binds to specific receptors located on cell membranes in various tissues. It has a wide range of physiological effects, including primarily both direct and indirect participation in the regulation of blood pressure. Being a powerful vasoconstrictor, angiotensin II causes a direct pressor response. In addition, it promotes sodium retention and stimulates aldosterone secretion.
Diovan is an active, potent and specific angiotensin II receptor antagonist intended for oral administration. It antagonizes selectively the AT1 receptor subtype, which is responsible for the known effects of angiotensin II. Diovan does not exhibit any pronounced agonistic activity towards receptors of the AT1 subtype. AT2 receptors are not involved in the cardiovascular effects of angiotensin II. Diovan's affinity for AT1 subtype receptors is approximately 20,000 times higher than for AT2 subtype receptors.
Diovan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. Since there is no effect on ACE and there is no potentiation of bradykinin and substance P, it is unlikely that angiotensin II antagonists will cause cough. In clinical studies that compared Diovan with an ACE inhibitor, the incidence of dry cough was significantly (p < 0.05) lower in patients receiving Diovan than in patients receiving an ACE inhibitor (2.6% versus 7.9%, respectively). In a clinical study including patients who had previously developed a dry cough during treatment with an ACE inhibitor, this complication was noted in 19.5% of cases during treatment with Diovan, and in 19.0% of cases during treatment with a thiazide diuretic, while in the group of patients receiving treatment 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 administration of a single dose of the drug orally, in most patients, the onset of antihypertensive action is noted within 2 hours, and the peak 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 reduction in blood pressure, regardless of the dose taken, is usually achieved within 2-4 weeks and is maintained at this level during long-term therapy. When the drug is combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.
Sudden cessation of taking Diovan is not accompanied by a sharp increase in blood pressure or other undesirable clinical consequences. During a course of use of Diovan in patients with arterial hypertension, it was found that the drug did not have a significant effect on the level of total cholesterol, uric acid, or, when examined on an empty stomach, on the concentration of triglycerides and glucose in the blood serum.
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.
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.
Diovan®
Valsartan is an active specific angiotensin II receptor antagonist 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. 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 interact with or block other hormone receptors or ion channels that are important in regulating the functions of the cardiovascular system.
The likelihood of coughing when using valsartan is very low, which is due to the lack of effect on angiotensin-converting enzyme (ACE), which is responsible for the degradation of bradykinin. A comparison of valsartan with an ACE inhibitor demonstrates that the incidence of dry cough is significantly (p < 0.05) lower in patients taking the drug than in patients taking an ACE inhibitor (2.6% versus 7.9%, respectively). In the group of patients who previously developed a dry cough during treatment with an ACE inhibitor, this adverse event (AE) was observed in 19.5% of cases during treatment with valsartan, and in 19.0% of cases during treatment with a thiazide diuretic, while in In the group of patients treated with an ACE inhibitor, cough was observed in 68.5% of cases (p < 0.05).
Use for arterial hypertension in patients over 18 years of age
When treating patients with arterial hypertension with valsartan, a decrease in blood pressure (BP) is observed, not accompanied by a change in heart rate (HR).
After oral administration of a single dose of the drug in most patients, the onset of the antihypertensive effect is observed within 2 hours, and the maximum reduction in blood pressure is achieved within 4-6 hours, lasting more than 24 hours. With repeated use of the drug, the maximum reduction 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.
In case of simultaneous use of the drug with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.
Abrupt cessation of valsartan use is not accompanied by a significant increase in blood pressure or other adverse events.
In patients with arterial hypertension, type 2 diabetes mellitus and nephropathy, taking valsartan at a dose of 160-320 mg, there is a significant decrease in proteinuria (36-44%).
Use after acute myocardial infarction in patients over 18 years of age
When using the drug for 2 years in patients who began taking it from 12 hours to 10 days after acute myocardial infarction (complicated by left ventricular failure and/or left ventricular systolic dysfunction), the rates of overall mortality and cardiovascular mortality are reduced and the time until the first hospitalization for exacerbation of chronic heart failure, repeated myocardial infarction, sudden cardiac arrest and stroke (without death) increases. The safety profile of valsartan in patients with acute myocardial infarction is similar to that in other conditions.
Chronic heart failure (CHF) in patients over 18 years of age
When using valsartan (in an average daily dose of 254 mg) for 2 years in patients with CHF II (62%), III (36%) and IV (2%) functional class according to the NYHA classification with left ventricular ejection fraction (LV) less than 40% and LV internal diastolic diameter more than 2.9 cm/m2, receiving standard therapy, including ACE inhibitors (93%), diuretics (86%), digoxin (67%) and beta-blockers (36%) there is a significant decrease (by 27.5%) risk of hospitalization due to exacerbation of CHF.
In patients not receiving ACE inhibitors, there was a significant reduction in overall mortality (by 33%), cardiovascular mortality and CHF-related morbidity (time to first cardiovascular event), assessed by the following indicators: death, sudden death with resuscitation, hospitalization for exacerbation of CHF, intravenous administration of inotropic or vasodilator drugs for 4 or more hours without hospitalization (44%). In the group of patients receiving ACE inhibitors (without beta-blockers), during treatment with valsartan there is no reduction in overall mortality, but cardiovascular mortality and morbidity associated with CHF decrease by 18.3%.
In general, the use of valsartan leads to a decrease in the number of hospitalizations for CHF, a slowdown in the progression of CHF, an improvement in the functional class of CHF according to the NYHA classification, an increase in left ventricular 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 in patients over 18 years of age with arterial hypertension and impaired
glucose tolerance
When using valsartan and changing lifestyle, there was a statistically significant reduction in the risk of developing diabetes mellitus in this category of patients. Valsartan had no effect on the incidence of deaths due to cardiovascular events, myocardial infarction and non-fatal ischemic attacks, hospitalizations due to heart failure or unstable angina, arterial revascularization, in patients with impaired glucose tolerance and arterial hypertension, differing in age, gender and race.
In patients receiving valsartan, the risk of developing microalbuminuria was significantly lower than in patients not receiving this therapy. The recommended starting dose of Diovan® in patients with arterial hypertension and impaired glucose tolerance is 80 mg once daily. If necessary, the dose can be increased to 160 mg.
Use in children and adolescents from 6 to 18 years of age with arterial hypertension
In children and adolescents from 6 to 18 years of age, valsartan provides a dose-dependent, smooth reduction in blood pressure. When using valsartan, the maximum reduction in blood pressure, regardless of the dose taken, is usually achieved within 2 weeks and is maintained at this level during long-term therapy.
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.
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.
Co-Diovan, 28 pcs., 80 mg+12.5 mg, film-coated tablets
Valsartan
Suction
After oral administration of valsartan, its maximum plasma concentrations are reached within 2-4 hours. The average bioavailability is 23%.
When taking valsartan with food, the area under the concentration-time curve (AUC) decreases by 48%, although, starting from approximately the 8th hour after taking the drug, the concentration of valsartan in the blood plasma both when taken on an empty stomach and when taken on an empty stomach with food, the same. The decrease in AUC, however, is not accompanied by a clinically significant decrease in the therapeutic effect.
Distribution
Valsartan is highly (94-97%) bound to serum proteins, mainly albumin.
Biotransformation/metabolism
Valsartan does not undergo significant biotransformation; only about 20% of the dose is excreted in the form of metabolites. Valeryl-4-hydroxy valsartan is found in plasma in low concentrations (less than 10% of AUC). This metabolite is pharmacologically inactive.
Removal
The pharmacokinetic curve of valsartan has a descending multi-exponential character: (half-life - T1/2α < 1 hour and T1/2β about 9 hours). Valsartan is excreted through the intestines (about 83% of the dose) and by the kidneys (about 13% of the dose), mainly unchanged. The half-life of valsartan is 6 hours.
In the range of doses studied, the kinetics of valsartan is linear. With repeated use of valsartan, no changes in kinetic parameters were observed. When taking valsartan once a day, the accumulation is insignificant.
Plasma concentrations of valsartan were similar in women and men.
Hydrochlorothiazide (HCTZ)
Suction
After oral administration, absorption of hydrochlorothiazide occurs quickly, the time to reach maximum concentration (tcmax) is about 2 hours.
Over the therapeutic dose range, the mean AUC increases in direct proportion to the dose. Concomitant administration of HCTZ with food may result in either increased or decreased systemic availability compared with fasting, but the magnitude of these effects is small and of little clinical significance. When taken orally, the absolute bioavailability of hydrochlorothiazide is 70%.
Distribution
The pharmacokinetics of hydrochlorothiazide during the distribution and elimination phases is generally described by a biexponential descending curve. The apparent volume of distribution is 4-8 l/kg. Binding to plasma proteins (mainly albumin) is 40-70%. Hydrochlorothiazide also accumulates in erythrocytes at concentrations approximately three times higher than plasma concentrations.
Biotransformation
HCTZ is eliminated virtually unchanged.
Removal
The half-life of the terminal phase is 6-15 hours. With repeated use of the drug, the kinetics of hydrochlorothiazide does not change; when the drug is prescribed once a day, the accumulation of the drug is minimal. More than 95% of the absorbed dose is excreted unchanged by the kidneys.
Valsartan/hydrochlorothiazide
When used together with valsartan, the systemic bioavailability of HCTZ is reduced by approximately 30%. Simultaneous administration of GTZ, for its part, does not have a significant effect on the kinetics of valsartan. The observed interaction does not affect the effectiveness of the combined use of valsartan and GTZ. In controlled clinical studies, a clear antihypertensive effect of this combination was revealed, which exceeded the effect of each component separately, as well as the placebo effect.
Pharmacokinetics in selected patient groups
Patients aged ≥65 years
In some elderly patients, the AUC of valsartan was slightly greater than in younger patients, but this was not clinically significant.
Limited data suggest that the systemic clearance of HCTZ is lower in elderly patients (both healthy and hypertensive) than in healthy young volunteers.
Patients with impaired renal function
No dose adjustment is required in patients with a glomerular filtration rate of 30-70 ml/min.
Currently, there is no data on the use of Co-Diovan® in patients with severely impaired renal function (glomerular filtration rate <30 ml/min) and in patients receiving hemodialysis. Valsartan is not eliminated by hemodialysis due to significant binding to plasma proteins. At the same time, hemodialysis makes it possible to effectively remove HCTZ from the body.
In the presence of renal failure, mean peak plasma concentrations and AUC values of hydrochlorothiazide increase and the rate of excretion decreases. In patients with mild to moderate renal impairment, the half-life is almost doubled.
Patients with liver dysfunction
The AUC of valsartan in patients with mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale) liver dysfunction was 2 times greater than in healthy volunteers. Currently, there is no data on the use of Co-Diovan® in patients with severe (more than 9 points on the Child-Pugh scale) liver dysfunction.
Since liver dysfunction does not have a clinically significant effect on the pharmacokinetics of HCTZ, no dosage adjustment is required in patients with liver dysfunction.
The use of Co-Diovan® is contraindicated in patients with severe (more than 9 points on the Child-Pugh scale) liver dysfunction. In patients with biliary obstruction, Co-Diovan® should be used with caution.
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.
