Pharmacological properties of the drug Valsacor
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 that are located on the cell membranes of various tissues. It has a whole range of physiological effects, exhibiting both direct and indirect effects on the regulation of blood pressure. As a powerful vasoconstrictor, angiotensin II has a direct pressor effect. In addition, it promotes sodium retention and aldosterone secretion. Valsartan is an oral, potent and specific angiotensin II receptor antagonist. Selectively acts on receptors of the AT1 subtype, which are responsible for the action of angiotensin II. When the concentration of angiotensin II in the blood plasma increases after blockade of AT1 receptors by valsartan, stimulation of unblocked AT2 receptors occurs, which regulate the action of AT1 receptors. Valsartan does not exhibit any agonistic activity towards AT1 receptors and has a significantly greater affinity (approximately 20,000 times) for AT1 receptors than for AT2 receptors. Valsartan does not inhibit the activity of ACE, also known as kininase II, an enzyme that converts angiotensin I into angiotensin II and catalyzes the breakdown of bradykinin. Angiotensin II antagonists do not cause cough because they do not affect the activity of ACE and do not increase the production of bradykinin and substance P. In clinical studies in which valsartan was compared with other ACE inhibitors, the incidence of dry cough in patients taking valsartan was significantly lower (P ≤0.05) than in patients using an ACE inhibitor (2.6% compared with 7.9%). In a clinical trial, dry cough was reported in 19.5% of patients taking valsartan, 19.0% of patients taking a thiazide diuretic, compared with 68.5% of patients taking an ACE inhibitor (P≤0.05). Valsartan does not bind to or block other hormonal receptors or ion channels important for the regulation of the cardiovascular system. Treatment of patients with hypertension (arterial hypertension) with valsartan helped reduce blood pressure without affecting heart rate. In most patients, the hypotensive effect develops within 2 hours after a single oral dose, and the maximum effect on blood pressure is observed after 4–6 hours and lasts 24 hours. With repeated administration of the drug at any dose, the maximum reduction in blood pressure is achieved after 2–4 weeks and persists throughout the entire treatment period. With the combined use of hydrochlorothiazide, a significant additional reduction in blood pressure occurs. Discontinuation of valsartan does not cause a sudden increase in blood pressure and other undesirable clinical events in patients. In a long-term study of the use of valsartan in patients with heart failure, it was noted that in patients taking valsartan, there was a decrease in plasma norepinephrine and brain natriuretic peptide levels compared to the initial level. Valsartan produced significant improvements in pulmonary capillary wedge pressure, systemic vascular resistance, cardiac output, and systolic blood pressure. Patients using valsartan experience a significant increase in ejection fraction and a decrease in the internal diameter of the left ventricle compared to the initial state, and a significant decrease in the severity of symptoms of heart failure, including shortness of breath, fatigue, swelling and breath sounds. Valsartan is rapidly absorbed after oral administration, but the amount absorbed varies significantly. The average absolute bioavailability of valsartan is 23%. Valsartan is characterized by multi-exponential elimination kinetics (half-life in the α phase ≤1 hour and half-life in the β phase ≈9 hours). The pharmacokinetics of valsartan in the studied dose range is linear. With repeated administration of the drug, the pharmacokinetic parameters do not change; When the drug is administered once a day, only a slight accumulation of valsartan is observed. Valsartan binds well to serum proteins (94–97%), mostly to albumin. The volume of distribution at steady state is low (≈17 l). Plasma clearance occurs relatively slowly (≈2 L/h) compared to hepatic blood flow (≈30 L/h). The drug is excreted mainly unchanged: 70% of the absorbed amount is in feces, 30% in urine. When valsartan is taken with food, AUC decreases by 48%; however, after 8 hours, the concentration of valsartan in the blood plasma is the same both when taken on an empty stomach and when taken with food. This indicates the possibility of using valsartan regardless of food intake.
Instructions for use VALSACOR® H160
Combined antihypertensive drug.
Valsartan/hydrochlorothiazide
In a double-blind, randomized, active-controlled study, patients who failed to achieve adequate BP control with hydrochlorothiazide 12.5 mg received a combination of valsartan/hydrochlorothiazide 160/12.5 mg had a decrease in mean BP (12.4/7.5 mmHg). ) compared with patients receiving only hydrochlorothiazide at a dose of 25 mg (5.2/2.1 mmHg). In addition, a greater number of patients (%) experienced a hypotensive effect on therapy with the combination of valsartan/hydrochlorothiazide 160/12.5 mg (diastolic blood pressure <140/90 mm Hg or a decrease in SBP ≥20 mm Hg or DBP ≥10 mm Hg .st.) (50%) compared to taking hydrochlorothiazide at a dose of 25 mg (25%).
In a double-blind, randomized, active-controlled study, patients who failed to achieve adequate BP control with valsartan 160 mg received a combination of valsartan/hydrochlorothiazide 160/12.5 mg had a decrease in mean BP (14.6/11.9 mmHg). ) compared with patients receiving only valsartan at a dose of 160 mg (8.7/8.8 mmHg). The difference in blood pressure reduction when comparing doses of 160/25 mg and 160/12.5 mg reached statistical significance. In addition, a greater number of patients (%) experienced a hypotensive effect (diastolic blood pressure <90 mmHg or decrease ≥10 mmHg) to therapy with the combination of valsartan/hydrochlorothiazide 160/25 mg (68%) and 160/ 12.5 mg compared to valsartan 160 mg (49%).
A double-blind, randomized, placebo-controlled, factorial design study compared different doses of valsartan/hydrochlorothiazide combinations with their respective components. When comparing placebo (1.9/4.1 mmHg), hydrochlorothiazide at a dose of 12.5 mg (7.3/7.2 mmHg), hydrochlorothiazide at a dose of 25 mg (12.7/9.3 mmHg) and valsartan at a dose of 160 mg (12.1/9.4 mmHg) the greatest decrease in mean blood pressure was observed when taking the combination of valsartan/hydrochlorothiazide 160/12.5 mg (17.8/13.5 mmHg) and 160/25 mg (22.5/15.3 mmHg) . In addition, a greater number of patients (%) experienced a hypotensive effect (diastolic blood pressure <90 mmHg or a decrease ≥10 mmHg) to therapy with the combination of valsartan/hydrochlorothiazide 160/12.5 mg (81%) and 160/ 12.5 mg (76%) compared with placebo (29%) and corresponding monotherapy with hydrochlorothiazide 12.5 mg (41%), 25 mg (54%), valsartan 160 mg (59%).
In controlled clinical studies of the combination of valsartan/hydrochlorothiazide, a dose-dependent decrease in serum potassium was observed. A decrease in serum potassium was observed more often in patients receiving hydrochlorothiazide at a dose of 25 mg than in patients receiving hydrochlorothiazide at a dose of 12.5 mg.
In controlled clinical trials of the valsartan/hydrochlorothiazide combination, the hypokalemic effect of hydrochlorothiazide was reduced as a result of the potassium-sparing effect of valsartan.
The beneficial effects of valsartan in combination with hydrochlorothiazide on cardiovascular mortality and morbidity are currently unknown. Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
Valsartan
Valsartan is a selective angiotensin II receptor antagonist for oral administration. It has a selective antagonistic effect on receptors of the AT1 subtype. A consequence of AT1 receptor blockade is an increase in plasma concentrations of angiotensin II, which can stimulate unblocked AT2 receptors, which is believed to regulate the effects of AT1 receptors. Valsartan does not have agonist activity against AT1 receptors. Its affinity for receptors of the AT1 subtype is approximately 20,000 times greater than for receptors of the AT2 subtype. Valsartan does not interact with or block other hormone receptors or ion channels involved in regulating the function of the cardiovascular system.
Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. Due to the lack of influence on ACE, the effects of bradykinin and substance P are not potentiated, therefore, when taking angiotensin II receptor antagonists, the development of a dry cough is unlikely.
Clinical studies in which valsartan was compared with an ACE inhibitor showed that the incidence of dry cough was significantly lower in patients receiving valsartan compared to patients receiving an ACE inhibitor (2.6% versus 7.9%, respectively, p>0.05). In clinical trials in patients with a history of cough during ACE inhibitor therapy, dry cough was observed in 19.5% of patients switched to valsartan and 19% of patients treated with thiazide diuretics, compared with 68.5% of patients treated with an ACE inhibitor (p>0.05).
In the treatment of arterial hypertension, valsartan reduces blood pressure without affecting heart rate.
In most patients, after oral administration of a single dose of valsartan, the antihypertensive effect develops within 2 hours, and the maximum reduction in blood pressure is achieved within 4-6 hours. The antihypertensive effect of valsartan persists for 24 hours. With repeated prescriptions of valsartan, the maximum decrease in blood pressure is achieved, regardless of the dose , is achieved after 2-4 weeks and remains at the achieved level during long-term therapy. In combination with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.
Abrupt withdrawal of valsartan is not accompanied by rebound hypertension or other adverse clinical events.
During observations, it was revealed that as a result of the use of valsartan in patients with type 2 diabetes mellitus and microalbuminuria, protein excretion in the urine decreases. The MARVAL (Microalbuminuria Reduction with Valsartan) study assessed the reduction in urinary protein excretion with valsartan (80-160 mg once daily) compared with amlodipine (5-10 mg once daily) in 332 patients with type 2 diabetes mellitus (average age 58 years; 265 male patients) with microalbuminuria (valsartan - 58 mcg/min; amlodipine - 55.4 mcg/min), normal or elevated blood pressure and preserved renal function (blood creatinine <120 μmol/l) . At 24 weeks, urinary protein excretion decreased (p<0.001) by 42% (-24.2 μg/min; 95% CI:
- -40.4 to -19.1) when using valsartan and approximately 3% (-1.7 mcg/min;
- 95% CI: -5.5 to 14.9) with amlodipine, despite the same level of blood pressure reduction in both groups.
The DROP (The Diovan Reduction of Proteinuria) study continued to study the effectiveness of valsartan in reducing urinary protein excretion in 391 patients with arterial hypertension (BP 150/88 mm Hg) and type 2 diabetes mellitus, albuminuria (mean value - 102 µg/min; 20-700 µg/min) and preserved renal function (mean serum creatinine = 80 µmol/L). Patients were randomized to receive one of 3 doses of valsartan (160, 320, and 640 mg once daily) and were treated for 30 weeks. The purpose of the study was to establish the optimal dose of valsartan to reduce urinary protein excretion in hypertensive patients with type 2 diabetes mellitus. At 30 weeks, the percentage change in urinary protein excretion was significantly reduced by 36% from baseline with valsartan 160 mg (95% CI: 22 to 47%), with a 44% reduction with valsartan 320 mg. (95% CI:
- 31 to 54%). It was concluded that the use of valsartan 160-320 mg caused a clinically significant reduction in urinary protein excretion in patients with hypertension and type 2 diabetes mellitus.
Two large randomized controlled trials, ONTARGET (ONgoing Telmisartan Alone and incombination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes), examined the use of ACE inhibitors in combination with angiotensin II receptor antagonists.
The ONTARGET study was conducted in patients with cardiovascular disease, cerebrovascular disease, or type 2 diabetes with evidence of end-organ damage.
The VA NEPHRON-D study was conducted in patients suffering from type 2 diabetes mellitus and diabetic nephropathy.
Compared with monotherapy, these studies did not show significant beneficial effects on renal function and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalemia, acute renal failure and/or hypotension was observed. Due to similar pharmacodynamic properties, these results are relevant to other ACE inhibitors and angiotensin II receptor antagonists. Therefore, ACE inhibitors and angiotensin II receptor antagonists should not be used simultaneously in patients with diabetic nephropathy.
The ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease End points) study was designed to determine the benefits of adding aliskiren to standard ACE inhibitor or angiotensin II receptor antagonist therapy in patients with type 2 diabetes mellitus, chronic renal failure, cardiovascular diseases. The study was stopped early due to an increased risk of adverse outcomes. Stroke and cardiovascular mortality were observed more often in the aliskiren group than in the placebo group. Also, in the group taking aliskiren, undesirable side effects (hyperkalemia, hypotension, renal dysfunction) were more often observed.
Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic whose site of action is primarily in the distal renal tubules. In the renal cortex there are receptors that have high affinity and are the main binding site for thiazide diuretics, where the transport of NaCl into the distal tubules is suppressed. The mechanism of action of thiazides is due to inhibition of the cotransport of Na+ and Cl- ions, possibly due to competition for Cl- transport sites, which affects the mechanisms of electrolyte reabsorption:
- the excretion of sodium and chloride ions increases approximately equally in direct proportion. Indirectly, as a result of this diuretic effect, there is a decrease in plasma volume, resulting in increased renin activity, aldosterone secretion, and urinary excretion of potassium, resulting in a decrease in serum potassium concentration.
The relationship between renin and aldosterone is mediated by angiotensin II, therefore, with simultaneous use of valsartan, the decrease in serum potassium concentration is less pronounced than with the use of hydrochlorothiazide as monotherapy.
Non-melanoma skin cancer (NMSC)
Based on available data from epidemiological studies, there is a cumulative dose-dependent association between hydrochlorothiazide and NMSC. One study included a population of 71,533 cases of basal cell carcinoma and 8,629 cases of squamous cell carcinoma matched to 1,430,833 and 172,462 control populations, respectively. High-dose hydrochlorothiazide (cumulative ≥50,000 mg) was associated with an adjusted OR of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A clear dose-response relationship was observed for both basal cell carcinoma and squamous cell carcinoma. Another study showed a possible association between lip cancer (SCC) and HCTZ exposure: 633 cases of lip cancer were matched to 63,067 population controls using a risk-adjusted sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI:
- 1.7-2.6), increasing to OR 3.9 (3.0-4.9) for the highest cumulative dose (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg).
Use of the drug Valsacor
AH (arterial hypertension) The recommended dose of Valsacor is 80 mg 1 time per day, regardless of the patient’s age, gender or race. The hypotensive effect is achieved after 2 weeks, and the maximum antihypertensive effect is achieved after 4 weeks of treatment. For patients who do not achieve an adequate reduction in blood pressure, the daily dose can be increased to 160 mg or supplemented with diuretic therapy. There is no need to change the dose in patients with impaired renal or hepatic function of non-biliary origin in the absence of cholestasis. Valsacor can also be taken in combination with other antihypertensive drugs. Heart failure The recommended initial dose is 40 mg 2 times a day. This dose is gradually increased to 80 mg twice daily and then to 160 mg twice daily, the highest dose the patient can tolerate. The maximum daily dose of valsartan is 320 mg. For patients who are simultaneously treated with a diuretic, it is recommended to reduce the dose of Valsacor. Post-myocardial infarction Treatment with the drug can begin 12 hours after myocardial infarction. The initial dose of Valsacor is 20 mg 2 times a day. At the beginning of treatment, it is recommended to use Valsacor 40 mg tablets with a notch on one side. After a few weeks, the dose should be gradually increased to 40, 80 and 160 mg 2 times a day, depending on the patient’s tolerance to treatment. If symptomatic hypotension or renal failure occurs, the dose should be reduced.
Mechanism of action of drugs
Valsacor provides a long-term reduction in the resistance of vascular walls, prevents their spasms, improves myocardial contractility, and increases the volume of blood pumped by the heart. As a result, unfavorable symptoms of deficiency disappear:
- think in your ears and head;
- swelling;
- dyspnea;
- physical weakness;
- dizziness.
Valsacor N maintains normal blood pressure, reduces the likelihood of valsartan side effects, and helps hypertensive patients maintain good health. Hydrochlorothiazide in its composition has a diuretic effect, stimulates the excretion of excess sodium and chlorine.
The medicine quickly dissolves in the stomach after administration and is absorbed into the blood. The effect of one dose of tablets develops over 30–60 minutes, reaches a maximum after 4–5 hours and lasts up to a day. With regular use, Valsacor provides an increasing antihypertensive effect after 3-4 weeks - it prevents the development of high blood pressure.
About 60% of hydrochlorothiazide ingested interacts with blood proteins; in combination with valsartan, it is less bioavailable. The components of the drugs do not accumulate in the body. Metabolism occurs in the liver, then the remaining substances are excreted through the intestinal contents and through the kidneys. Disintegration and release occur approximately 9 hours after the dose of the drug.
Side effects of the drug Valsacor
During treatment with the drug, viral infections, upper respiratory tract infections, rhinitis, sinusitis, and pharyngitis often occurred (≥1%). Nervous system and mental disorders; headache, dizziness; cough; nausea, diarrhea, abdominal pain; back pain and arthralgia; hyperkalemia; fatigue. Rarely (≤1%) rash, itching, insomnia, and swelling were noted; isolated cases of hypersensitivity reactions; very rarely - renal function disorders. The frequency of side effects does not depend on the dose and period of treatment, as well as the gender, race and age of the patient.
Precautions and contraindications
Valsacor requires careful use and constant monitoring of well-being in cases of impaired renal and liver function during treatment after a heart attack. The drug enhances the toxic effect of medications containing acetylsalicylic acid. It is not advisable to take Valsacor simultaneously with cardiac glycosides, anti-gout medications, or potassium-sparing agents.
When combined with barbiturates, adrenergic blockers, vasodilators, the diuretic and hypotensive effect of Valsacor is enhanced. It is important to remember this when choosing dosages.
The medicine affects psychomotor reactions, so during the treatment period caution is required when creating vehicles and operating special equipment.
The drug is incompatible with alcohol and can provoke a sharp drop in blood pressure, hypoxia and vascular collapse.
It is necessary to refuse therapy with Valsacor:
- with renal artery stenosis, not on hemodialysis, with severe renal failure;
- with cirrhosis, severe hepatosis;
- acute dehydration;
- during pregnancy and lactation;
- in case of individual intolerance to the components.
Caution is required in various forms of cardiomyopathy, stenosis of the mitral valve or aorta.
Special instructions for the use of the drug Valsacor
Caution should be exercised when starting treatment in patients with heart failure after myocardial infarction. They often initially experience a slight decrease in blood pressure, however, if dosing instructions are properly followed, such symptomatic hypotension for the most part does not cause discontinuation of treatment. During treatment with Valsacor, renal function should be regularly checked in patients with heart failure and special caution should be exercised with the combined use of ACE inhibitors, beta-adrenergic blockers and angiotensin II receptor antagonists (AT1 subtype). In debilitated patients and/or with significantly reduced sodium levels (for example, those taking high doses of diuretics), symptomatic hypotension may rarely occur when starting treatment with Valsacor. Before starting therapy, it is necessary to restore the amount of water and sodium in the body (for example, by reducing the dose of the diuretic). If arterial hypotension occurs, the patient should be placed in a horizontal position and, if necessary, given an intravenous infusion of 0.9% sodium chloride solution. After stabilization of blood pressure, treatment with Valsacor can be continued. During therapy, it is recommended to carefully evaluate patients with unilateral or bilateral renal artery stenosis, since drugs that affect the activity of the renin-angiotensin-aldosterone system can cause an increase in serum urea and creatinine levels. The drug should be used with caution in patients with impaired renal function and obstructive diseases of the biliary tract. In this case, the dose should not be reduced. Since Valsacor contains lactose, the drug is not recommended for use in patients with galactosemia, lactase deficiency or impaired glucose/galactose absorption. In patients with hypersensitivity, changes in the functional activity of the kidneys may occur, which are caused by inhibition of the activity of the renin-angiotensin system. Treatment with ACE inhibitors and angiotensin II receptor antagonists (AT1 subtype) should not be carried out in patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system. This can cause oliguria, progressive azotemia, and sometimes acute renal failure or death. Children. The safety and effectiveness of the drug in treating children has not been established. Period of pregnancy or breastfeeding. Given the mechanism of action of angiotensin II receptor antagonists, a risk to the fetus cannot be excluded. It has been shown that the use of ACE inhibitors in the second and third trimester of pregnancy can cause damage and death of the fetus. Like other drugs that act directly on the renin-angiotensin-aldosterone system, Valsacor is not recommended for use during pregnancy. It is not known whether valsartan passes into breast milk, so Valsacor is not recommended for use during breastfeeding. The ability to influence reaction speed when driving vehicles or working with other mechanisms. As with the use of other antihypertensive drugs, during treatment with Valsacor it is recommended to exercise caution when driving vehicles and operating machinery.
Dosage form and composition
The medication is intended for oral administration and is available in the form of yellow film-coated tablets:
- Valsacor: contains the active substance valsartan - an antagonist of hormone receptors that provokes an increase in pressure in blood vessels, prevents the development of hypertensive attacks;
- Valsacor N80, ND160: a combination drug containing two active ingredients: valsartan and hydrochlorothiazide, has a more pronounced and long-lasting therapeutic effect, reduces blood pressure.
In addition to active compounds, pills contain auxiliary components: MCC, lactose, silicon dioxide, stabilizing and form-building additives.
Interactions of the drug Valsacor
For patients after myocardial infarction, Valsacor can be taken in combination with other drugs, such as thrombolytics, acetylsalicylic acid, beta-adrenergic blockers or statins. When Valsacor is used in combination with potassium-sparing diuretics (such as spironolactone, triamterene, amiloride), potassium preparations or salt substitutes that contain potassium, an increase in the concentration of potassium in the blood serum may occur. There were no signs of clinically significant interaction between Valsacor and other drugs. In clinical studies, drugs such as cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, and glibenclamide were studied. Since Valsacor does not undergo significant metabolism, it is unlikely that clinically significant interactions in the form of metabolic induction or inhibition of the cytochrome P450 system will occur. Valsartan binds well to plasma proteins, but in vitro did not indicate any interactions at this level with molecules that are also highly protein bound (diclofenac, furosemide or warfarin).
VALSAKOR N80
Interaction
Common drug interactions for valsartan and hydrochlorothiazide
Concomitant use is not recommended
Lithium preparations
With the simultaneous use of ACE inhibitors, AR II or thiazide diuretics with lithium preparations, a reversible increase in the concentration of lithium in the blood plasma and the development of intoxication were observed. The risk of toxic effects associated with the use of lithium preparations may further increase when used simultaneously with Valsacor® N 80, since the renal clearance of lithium preparations is reduced by the influence of thiazide diuretics. If simultaneous use with lithium preparations is necessary, the concentration of lithium in the blood plasma should be carefully monitored.
Concomitant use with caution
Other antihypertensive drugs
The antihypertensive effect may be enhanced when used simultaneously with other drugs that lower blood pressure (for example, ACE inhibitors, beta-blockers, slow calcium channel blockers (SCBCs), guanethidine, methyldopa, vasodilators, direct renin inhibitors, ARA II).
Pressor amines (eg, norepinephrine and epinephrine)
The effect of pressor amines may be weakened, which does not require discontinuation of the simultaneous use of valsartan and HCTZ.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors
With simultaneous use of ARA II and HCTZ with NSAIDs, the diuretic and antihypertensive effects may be weakened. In conditions of hypovolemia, the development of acute renal failure (ARF) is possible; it is recommended to monitor renal function at the beginning of therapy, as well as adequate replenishment of the patient's blood volume.
Drug interactions for valsartan
Concomitant use is contraindicated
Concomitant use of ARB II, including valsartan, with aliskiren is contraindicated in patients with diabetes or moderate to severe renal impairment (creatinine clearance less than 60 ml/min).
Concomitant use is not recommended
Potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium supplements, potassium-containing table salt substitutes and other drugs and substances that can cause an increase in serum potassium (for example, heparin)
If simultaneous use with drugs that affect potassium levels is necessary, it is recommended to monitor the potassium content in the blood plasma.
Concomitant use with caution
With simultaneous use of ARA II, including valsartan, with drugs that affect the renin-angiotensin-aldosterone system (RAAS), such as ACE inhibitors or aliskiren, the incidence of cases of arterial hypotension, hyperkalemia, and renal dysfunction increases.
It is necessary to monitor blood pressure, renal function, and electrolyte levels in the blood plasma in such patients.
Transport proteins
In vitro studies
using liver cultures showed that valsartan is a substrate for the transporter proteins OATP1B1/OATP1B3 and MRP2. Concomitant use of valsartan with inhibitors of the transport protein OATP1B1/OATP1B3 (rifampicin, cyclosporine) or MRP2 (ritonavir) may increase the systemic exposure of valsartan (Cmax and AUC). Caution must be exercised when starting simultaneous use with the above drugs or after their discontinuation.
No drug interactions
No clinically significant interactions have been identified with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, HCTZ, amlodipine and glibenclamide.
Drug interactions for HCTZ
Concomitant use with caution
Medicines that affect potassium levels in blood plasma
When used simultaneously with loop diuretics, glucocorticosteroids (GCS), adrenocorticotropic hormone (ACTH), amphotericin B, benzathine benzylpenicillin, carbenoxolone, laxatives, acetylsalicylic acid or its derivatives, the risk of a decrease in plasma potassium and hypokalemia increases. In this case, it is recommended to monitor the potassium content in the blood plasma.
Drugs that can cause polymorphic ventricular tachycardia of the torsade de pointes type
When using antiarrhythmic drugs of classes IA and III and some antipsychotic drugs (neuroleptics) with HCTZ, caution should be exercised, as there is a risk of developing arrhythmias against the background of possible hypokalemia. Monitoring of potassium levels in blood plasma is recommended.
Non-depolarizing peripheral muscle relaxants (tubocurarine)
HCTZ potentiates the action of muscle relaxants.
Hypoglycemic agents (oral and insulin)
With simultaneous use, dose adjustment of hypoglycemic agents may be required.
Metformin
should be taken with caution, as the development of lactic acidosis induced by renal failure while taking HCTZ is possible.
Medicines that affect plasma sodium levels
With long-term simultaneous use with antidepressants, anticonvulsants, antipsychotic (neuroleptic) drugs (for example, carbamazepine), etc., caution should be exercised, as the risk of developing hyponatremia increases. It is recommended to regularly monitor the sodium content in the blood plasma.
Cardiac glycosides
Hypokalemia and hypomagnesemia while taking thiazide diuretics may contribute to the development of cardiac arrhythmias in patients receiving cardiac glycosides.
N- and m-cholinergic blockers
H- and m-anticholinergic agents (atropine, biperiden) can increase the bioavailability of thiazide diuretics by reducing the peristaltic activity of the gastrointestinal tract (GIT) and slowing gastric emptying. Accordingly, gastrointestinal motility stimulants (cisapride) may reduce the bioavailability of thiazide diuretics.
Anion exchange resins (colestyramine and colestipol)
The absorption of thiazide diuretics, including HCTZ, is reduced with simultaneous use of cholestyramine and colestipol. Therefore, HCTZ should be taken 4 hours before or 4-6 hours after taking anion exchange resins.
Methyldopa
Isolated cases of the development of hemolytic anemia have been described with the simultaneous use of methyldopa and HCTZ.
Vitamin D and calcium salts
The simultaneous use of thiazide diuretics, including HCTZ, with vitamin D or calcium salts can lead to an increase in calcium levels in the blood plasma as a result of increased calcium reabsorption.
Cyclosporine
With simultaneous use of HCTZ and cyclosporine, the risk of developing hyperuricemia and symptoms similar to exacerbation of gout increases.
Radiocontrast agents containing iodine
Hypovolemia that develops while taking diuretics increases the risk of developing acute renal failure. It is necessary to replenish the blood volume before using products with a high iodine content (for example, radiocontrast agents containing iodine).
Medicines to treat gout (probenecid, sulfinpyrazone and allopurinol)
When using HCTZ, it is possible to increase the concentration of uric acid in the blood plasma, which may require dose adjustment of drugs for the treatment of gout (for example, increasing the dose of sulfinpyrazone and probenecid). Concomitant use with thiazide diuretics, including HCTZ, may lead to an increased incidence of hypersensitivity reactions to allopurinol.
Amantadine
Concomitant use with thiazide diuretics, including HCTZ, increases the risk of side effects from amantadine.
Beta blockers and diazoxide
Concomitant use with thiazide diuretics, including HCTZ, increases the risk of developing hyperglycemia.
Cytotoxic drugs (cyclophosphamide, methotrexate)
Concomitant use with thiazide diuretics, including HCTZ, reduces the excretion of cytotoxic drugs by the kidneys, which leads to potentiation of their myelosuppressive effect.
Ethanol, barbiturates and narcotic drugs
Concomitant use with thiazide diuretics, including HCTZ, may potentiate the development of orthostatic hypotension.
