Valz N, 160 mg+12, 5 mg 28 pcs.

Pharmacotherapeutic group: combined hypotensive agent (angiotensin II receptor antagonist + diuretic).

The ATX code: C09DA03

Pharmacological properties

Pharmacodynamics

Valz N is a combination hypotensive drug consisting of an angiotensin II receptor antagonist (ARAII) and a thiazide diuretic.

Angiotensin II is the active hormone of the renin-angiotensin-aldosterone system (RAAS) and is formed from angiotensin I with the participation of angiotensin-converting enzyme (ACE). Angiotensin II binds to specific receptors located on cell membranes in various tissues. It has a wide range of physiological effects, including both direct and indirect involvement in blood pressure (BP) regulation. As an active vasoconstrictor, angiotensin II induces a direct pressor response. In addition, it stimulates the secretion of aldosterone and promotes the retention of sodium ions.

Valsartan is an active specific APAII. It selectively blocks AT₁ subtype receptors, which are responsible for the vasopressor effect of angiotensin II. Increased serum concentrations of angiotensin II due to blockade of AT₁ receptors by valsartan may result in stimulation of unblocked AT₂ receptors, which partially counterbalances the vasopressor effects associated with AT₁-receptor activation.

Valsartan has no agonist activity against AT₁ receptors. The affinity of valsartan for AT₁ receptors is about 20,000 times higher than for AT₂ receptors.

Since valsartan does not inhibit ACE, which converts angiotensin I to angiotensin II and causes bradykinin degradation, the development of side effects associated with bradykinin accumulation is unlikely.

When comparing valsartan with an ACE inhibitor, the incidence of dry cough was significantly (p < 0.05) lower in patients receiving valsartan than in patients taking an ACE inhibitor (2.6% versus 7.9%, respectively).

Valsartan does not interact with or block other hormone receptors or ion channels involved in the regulation of cardiovascular function.

The site of action of thiazide diuretics is the distal convoluted renal tubules. When thiazide diuretics act on the highly sensitive receptors of the distal tubules of the cortical layer of the kidney, the reabsorption of sodium ions (Na⁺) and chlorine ions (Cl^–) is suppressed. The suppression of the Na⁺ and Cl^– co-transport system appears to occur through competition for the Cl^– ion binding sites in this system. As a result, the excretion of sodium and chlorine ions increases to about the same extent. As a result of the diuretic action, there is a decrease in circulating blood volume, resulting in increased renin activity, aldosterone secretion, renal excretion of potassium and, consequently, decreased serum potassium content.

Pharmacokinetics

. Valsartan

Assimilation

After oral administration of valsartan, its maximum plasma concentration (C_max) is reached within 2-4 hours. The average absolute bioavailability is 23%. When valsartan is taken with food, the area under the curve “concentration-time” (AUC) is reduced by 48%, although starting about 8 hours after taking the drug, its plasma concentrations, both when taken on an empty stomach and simultaneously with food, are the same. The decrease in AUC, however, is not accompanied by a clinically significant decrease in therapeutic effect, so valsartan can be taken regardless of the time of ingestion.

Distribution

The volume of distribution (V_d) of valsartan at equilibrium after intravenous (IV) administration was approximately 17 liters, indicating that it has no marked distribution in tissues. Valsartan is largely bound to serum proteins (94-97%), predominantly to albumin.

Metabolism

Valsartan is not significantly biotransformed (only about 20% of the ingested dose is excreted as metabolites). A pharmacologically inactive hydroxyl metabolite is detected in plasma at low concentrations (less than 10% of the AUC of valsartan).

Elevation

The pharmacokinetic curve of valsartan has a descending multiexponential character (the elimination half-life of the initial phase (T_1/2α) less than 1 hour and the final phase (T_1/2β) about 9 hours). Valsartan is excreted mainly unchanged through the intestine (about 83%) and the kidneys (about 13%). After IV administration, plasma clearance of valsartan is about 2 l/h, and its renal clearance is 0.62 l/h (about 30% of total clearance). The half-life (T_1/2) is 6 hours.

In the range of doses studied, the kinetics of valsartan is linear. No changes in pharmacokinetic parameters were observed with its repeated administration. When valsartan is administered once daily, cumulation is insignificant. Plasma concentrations of valsartan do not differ between women and men.

Hydrochlorothiazide

Extraction

. After oral administration, absorption of hydrochlorothiazide is rapid, with a time to reach maximum concentration (T_max) of about 2 hours.

In the therapeutic dose range, the average AUC increases in direct proportion to increasing the dose. Concomitant ingestion of hydrochlorothiazide with food may result in both increased and decreased systemic availability compared to fasting, but the magnitude of these effects is small and of little clinical significance. When oral administration the absolute bioavailability of hydrochlorothiazide is 70%.

Distribution

The pharmacokinetics of hydrochlorothiazide in the distribution and excretion phases is described in general by a biexponential downward curve. Apparent volume of distribution is 4-8 l/kg. Binding to plasma proteins (predominantly to albumin) is 40-70%. Hydrochlorothiazide also accumulates in erythrocytes at a concentration approximately three times higher than the plasma concentration.

Metabolism

Hydrochlorothiazide is excreted almost unchanged.

Evolution

The elimination half-life of the end phase is 6-15 hours. The kinetics of hydrochlorothiazide does not change with repeated administration; when the drug is administered once daily its accumulation is minimal. More than 95% of the absorbed dose is excreted unchanged by the kidneys.

Valsartan/hydrochlorothiazide

The systemic bioavailability of hydrochlorothiazide is reduced by approximately 30% when co-administered with valsartan. Concomitant use with hydrochlorothiazide has no significant effect on the pharmacokinetics of valsartan. This interaction has no effect on the efficacy of the combined use of valsartan and hydrochlorothiazide. Controlled clinical studies have demonstrated a significant antihypertensive effect of this combination that exceeded the effect of each component alone as well as the placebo effect.

Pharmacokinetics in selected patient groups

p> Elderly patients (> 65 years)

. Some elderly patients have higher systemic bioavailability of valsartan than younger patients; however, this has not been found to be clinically relevant.

Separate clinical data suggest that in elderly patients (both healthy and arterial hypertensive patients) the systemic clearance of hydrochlorothiazide is lower than in healthy young volunteers.

Patients with impaired renal function

There is no need to adjust the drug dose in patients with glomerular filtration rate (GFR) 30-70 ml/min/1.73 m² body surface area.

There are currently no data on the use of the valsartan/hydrochlorothiazide combination in patients with severe renal impairment (GFR < 30 mL/min/1.73 m² body surface area) and in patients receiving hemodialysis. Valsartan is not excreted by hemodialysis due to significant binding to plasma proteins. At the same time, hemodialysis allows efficient excretion of hydrochlorothiazide.

In the presence of renal failure, the mean peak plasma concentrations and AUC values of hydrochlorothiazide are increased and the excretion rate is decreased. In patients with mild to moderate renal impairment the half-life is almost doubled.

Patients with impaired liver function

The AUC of valsartan in patients with mild (Child-Pugh score 5-6) and moderate (Child-Pugh score 7-9) impaired liver function was 2 times greater than in healthy volunteers. There are currently no data on the use of the valsartan/hydrochlorothiazide combination in patients with severe (greater than 9 Child-Pugh points) hepatic impairment.

As hepatic impairment has no clinically significant effect on the pharmacokinetics of hydrochlorothiazide, no dose adjustment is required in patients with hepatic impairment.

The use of Valz H is contraindicated in patients with severe (greater than 9 points by Child-Pugh score) liver dysfunction, biliary obstruction (biliary cirrhosis and cholestasis).

Indications

Active ingredient

Composition

Effective ingredients: valsartan 160.00 mg, hydrochlorothiazide 12.50 mg;

excipients: microcrystalline cellulose pH 102 – 72.00 mg, lactose monohydrate – 71.94 mg, croscarmellose sodium – 21.60 mg, povidone K29/32 – 14.40 mg, talc – 3.60 mg, magnesium stearate – 2.52 mg, colloidal silicon dioxide – 1.44 mg;

coat film: Opadray II 85G25455 Red 14.40 mg (polyvinyl alcohol – 6.34 mg, talc – 2.88 mg, macrogol 3350 – 1.78 mg, titanium dioxide – 1.57 mg, iron oxide red dye – 0.78 mg, sunset yellow aluminum dye – 0.56 mg, lecithin – 0.50 mg).

How to take, the dosage

Before starting therapy with Valz N, water-electrolyte disorders must be corrected (see sections “Caution” and “Special Precautions”).

The drug is taken orally, without chewing, with water, regardless of the time of meals.

The drug Valz N is prescribed 1 tablet once a day.

The dose of the drug is recommended depending on the individual antihypertensive effect. It is recommended to gradually increase the dose of Valz N at each step of dose selection to reduce the likelihood of significant BP decrease and other adverse events. Valz N is available in the following fixed doses of the active components valsartan + hydrochlorothiazide – 80 mg + 12.5 mg, 160 mg + 12.5 mg, 160 mg + 25 mg, 320 mg + 12.5 mg or 320 mg + 25 mg.

In cases where acceptable, patients with inadequate BP control on monotherapy with valsartan or hydrochlorothiazide may switch to the combination drug Valz N with fixed doses of active ingredients with a preceding step of titration of doses of valsartan and hydrochlorothiazide.

The BP should be monitored after initiation of treatment. In the absence of adequate hypotensive effect, the dose of Valz N may be gradually increased to maximum daily doses of valsartan and hydrochlorothiazide of 320 mg+25 mg or 320 mg+12.5 mg.

The maximum BP reduction is usually achieved over 2-4 weeks of therapy. However, some patients may require 4 to 8 weeks of therapy to achieve adequate BP control, which should be taken into account during dose titration.

If the expected BP lowering effect is not achieved within 8 weeks of therapy with Valz N 320 mg + 25 mg, the physician should consider another regimen (prescribe an additional hypertensive drug or change to another hypertensive drug).

Patientswith mild to moderately expressed renal dysfunction (FFR > 30 ml/min/1.73 m2 body surface area) do not require the drug dose change. Due to the fact that one of the active substances is hydrochlorothiazide, Valz H is contraindicated for patients with severe renal dysfunction (FFR < 30 ml/min/1.73 m2 body surface area).

In patients with mild (5-6 points on the Child-Pugh scale) and moderate(7-9 points on the Child-Pugh scale)disorders without concomitant cholestasis, the dose of valsartan should not exceed 80 mg. Valz H is contraindicated in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale).

Dose adjustment is not required in older patients.

The drug Valz N is contraindicated in children and adolescents under 18 years due to lack of efficacy and safety data.

Interaction

Common drug interactions for valsartan and hydrochlorothiazide

Drugs with which co-administration should be avoided:

Lithium preparations

The concomitant use of lithium preparations with ACE inhibitors and ARAII or thiazide diuretics has reported a reversible increase in plasma lithium concentration and an associated increase in toxic manifestations. The risk of toxic manifestations associated with the use of lithium drugs may further increase with concomitant use of Valz H because renal clearance of lithium drugs is reduced by thiazide diuretics.

Drugs with which concomitant use requires caution:

Hypotensive drugs

. Increased antihypertensive effect is possible when combined with other blood pressure lowering agents (ACE inhibitors, beta-adrenoblockers, “slow” calcium channel blockers, guanethidine, methyldopa, vasodilators, direct renin inhibitors, ARAII).

Pressor amines

The effects of pressor amines (norepinephrine, epinephrine) may be attenuated without requiring discontinuation of co-administration.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors

. Concomitant use of NSAIDs may impair the antihypertensive effect of both angiotensin II receptor antagonists and hydrochlorothiazide. Simultaneous use of Valz H and NSAIDs may result in impaired renal function and increased serum potassium. If concomitant use of Valz H and NSAIDs is necessary, renal function should be evaluated and water-electrolyte disturbances corrected before starting treatment.

Drug interactions for Valsartan

Drugs with which co-administration should be avoided:

The concomitant use of potassium-saving diuretics, potassium-containing supplements; potassium-containing salt substitutes; and other drugs that increase serum potassium levels (such as heparin) requires precautions, (including frequent blood potassium testing).

Double blockade of the RAAS

When treated with drugs affecting the RAAS, especially in combination, severe BP decrease, syncope, stroke, hyperkalemia, and impaired renal function (including acute renal failure) have been reported in sensitive patients.

Caution is required when combining APAII, including valsartan, with other drugs that block the RAAS, such as ACE inhibitors or aliskiren.

The concomitant use of APAII, including valsartan, with drugs containing aliskiren is contraindicated in patients with diabetes and/or with moderate to severe renal impairment (FFR < 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

The concomitant use of APAII with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Protein carriers

According to the results of the invitro on liver cultures, valsartan is a substrate for the transfer proteins OATP1B1 and MRP2. Concomitant administration of valsartan with OATP1B1 transporter protein inhibitors (rifampicin, cyclosporine) and MRP2 transporter protein inhibitor (ritonavir) may increase systemic exposure to valsartan (Cmax and AUC).

No drug interactions:

No clinically significant interactions have been noted with valsartan monotherapy with the following medications: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.

Drug interactions for hydrochlorothiazide

Lithium

Concomitant use with ACE inhibitors and diuretics has reported cases of reversible increases in plasma lithium concentration and its toxic effects. There have been no studies of concomitant use of hydrochlorothiazide with valsartan and lithium preparations. Therefore, when concomitant use of hydrochlorothiazide and drugs containing lithium, it is recommended to monitor blood lithium concentration.

Other hypotensive drugs

. Thiazide diuretics increase the antihypertensive effect of other hypotensive drugs (including guanethidine, methyldopa, beta-adrenoblockers, vasodilators, slow calcium channel blockers, ACE inhibitors, angiotensin receptor antagonists, renin inhibitors).

Curare-like myorelaxants

Thiazide diuretics, including hydrochlorothiazide, potentiate the effects of nondepolarizing myorelaxants.

Drugs that affect blood potassium

The risk of hypokalemia caused by diuretics may be increased with concomitant use of glucocorticosteroids (GCS), laxatives, adrenocorticotropic hormone (ACTH), amphotericin B, carbenoxolone, penicillin, acetylsalicylic acid or its derivatives and antiarrhythmic drugs.

Drugs affecting blood sodium

The hyponatremic effect caused by diuretics may be increased with concomitant use with antidepressants, antipsychotics, anticonvulsants (carbamazepine), etc. Caution should be exercised if hydrochlorothiazide is coadministered with the above drugs for a long time.

Drugs that may provoke pirouette-type polymorphic ventricular tachycardia:

Because of the risk of hypokalemia, hydrochlorothiazide should be used with caution concomitantly with drugs that can cause pirouette-type polymorphic ventricular tachycardia.

Hypoglycemic agents

Thiazide diuretics may alter glucose tolerance, and doses of insulin and oral hypoglycemic agents may need to be adjusted.

Metformin should be used with caution because of the risk of lactic acidosis caused by possible renal dysfunction associated with hydrochlorothiazide.

Beta-adrenoblockers and diazoxide

The simultaneous use of thiazide diuretics, including hydrochlorothiazide, with beta-adrenoblockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may increase the hyperglycemic effect of diazoxide.

Drugs intended to treat gout (probenecid, sulfinpyrazone, and allopurinol)

. It may be necessary to adjust the dose of uricosuric drugs (probenecid or sulfinpyrazone), because hydrochlorothiazide may increase the concentration of uric acid in the blood serum. Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol.

Heart glycosides

Hypokalemia and hypomagnesemia (unwanted effects of thiazide diuretics) may contribute to cardiac rhythm disturbances in patients receiving cardiac glycosides.

NSAIDs

The concomitant use of NSAIDs and hydrochlorothiazide may decrease the diuretic and antihypertensive effects of the latter. Concomitant hypovolemia may provoke acute renal failure.

H- and m-cholinoblockers

H- and m-cholinoblockers (including atropine, biperiden) may increase bioavailability of hydrochlorothiazide, which is associated with decreased peristalsis and gastric emptying rate. Accordingly, gastrointestinal motility stimulators (cisapride) may decrease the bioavailability of hydrochlorothiazide.

Anion exchange resins

Hydrochlorothiazide absorption is impaired in the presence of colestyramine and colestipol. Hydrochlorothiazide should be taken either 4 hours or 4-6 hours after taking these compounds.

Vitamin D and calcium salts

The simultaneous use of hydrochlorothiazide with vitamin D or calcium preparations may lead to hypercalcemia due to increased calcium reabsorption.

Cyclosporine

The simultaneous use of hydrochlorothiazide and cyclosporine increases the risk of hyperuricemia and gout exacerbation.

Methyldopa

Hemolytic anemia has been reported with concomitant administration of hydrochlorothiazide and methyldopa.

Other interactions

The concomitant administration of thiazide diuretics, including hydrochlorothiazide, may increase the risk of amantadine side effects; decreased renal excretion of drugs with cytotoxic effects (e.g., cyclophosphamide, methotrexate) and potentiation of their myelosuppressive effects.

Ethanol, barbiturates and narcotics

Their combined use with hydrochlorothiazide may potentiate orthostatic hypotension.

Iodocontrast agents

Iodocontrast agents used at high doses against reduced blood pressure due to diuretics may increase the risk of acute renal failure. The blood circulatory capacity should be restored before starting Valz H.

Special Instructions

Changes in serum electrolytes

Valsartan

. Care should be taken with potassium supplements, potassium-saving diuretics, potassium-containing salt substitutes, or other drugs that may cause an increase in blood potassium (e.g., heparin) when used concomitantly.

Hydrochlorothiazide

Thiazide diuretics should be used with caution in patients with conditions with electrolyte disturbances because of their ability to decrease serum potassium and magnesium: Nephropathy accompanied by loss of salts, and prerenal (cardiogenic) renal dysfunction. If clinical manifestations of hypokalemia occur (muscle weakness, paresis, ECG changes), Valz N treatment should be discontinued. Hypokalemia and hypomagnesemia should be corrected before starting the drug administration. All patients taking thiazide diuretics require regular monitoring of plasma electrolytes, especially potassium.

When using Valz H, the ability of thiazide diuretics to cause hyponatremia and hypochloremic alkalosis as well as to aggravate existing hyponatremia should be considered. Hyponatremia in these cases is rarely accompanied by neurological symptoms. Regular monitoring of plasma sodium is necessary.

Deficiency of sodium in the body and/or decrease of the blood circulation volume

In patients receiving thiazide diuretics, including hydrochlorothiazide, the appearance of clinical symptoms of sodium deficiency in the body and/or decrease of the blood circulation volume should be observed.

In patients with severe sodium deficiency in the body and/or decreased RBC, e.g. those receiving high doses of diuretics, in rare cases after initiation of Valz H therapy, a marked BP decrease accompanied by clinical manifestations may develop. Before starting treatment with Valz H it is necessary to correct the sodium content in the body and/or replenish the BOD, otherwise the treatment should be started under close medical supervision.

In case of pronounced BP decrease the patient should be laid down and, if necessary, an intravenous infusion of 0.9% sodium chloride solution should be performed. After BP stabilization, treatment with Valz H can be continued.

Renal artery stenosis

. In patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of the sole kidney, taking Valz H may be accompanied by increased serum concentrations of urea and creatinine; therefore, Valz H should be used with caution in these patients.

Primary hyperaldosteronism

The drug is not effective in treating arterial hypertension in patients with primary hyperaldosteronism because there is no activation of RAAS in this category of patients.

Aortic and mitral stenosis, obstructive hypertrophic cardiomyopathy

. As with other vasodilating agents, caution should be exercised when taking Valz N in patients with aortic or mitral stenosis and obstructive hypertrophic cardiomyopathy.

Renal function impairment

Patientswith mild to moderately impaired renal function

Synopsis

Contraindications

Side effects

In clinical and post-marketing studies, adverse reactions (ARs) have been reported more frequently with Valsartan and hydrochlorothiazide compared to placebo.

The occurrence of HF is possible with Valz H therapy, both as observed with Valsartan and hydrochlorothiazide alone and not identified in clinical studies of Valz H.

The following criteria (according to the World Health Organization (WHO) classification) were used to assess the incidence of HF: Very frequently (>10%); frequently (>1% and < 10%); infrequently (>0.1% and < 1%); rarely (>0.01% and <0.1%); very rare (<0.01%); frequency unknown (frequency of development cannot be determined from available data).

.System-organ class

Adverse reactions

Valsartan+

Hydrochlorothiazide

Valsartan

Hydrochloro-thiazide

Benign, malignant and unspecified neoplasms (including cysts and polyps)

nonmelanoma skin cancer (basal cell carcinoma of the skin and squamous cell carcinoma of the skin)

nonmelanoma skin cancer (basal cell carcinoma of the skin and squamous cell carcinoma of the skin)/p>

–

–

frequency unknown

Overdose

Symptoms: in valsartan overdose, severe hypotension may be expected, accompanied by depressed consciousness, vascular collapse and/or fatal shock. In case of overdose of hydrochlorothiazide the following symptoms may occur: nausea, somnolence, hypovolemia, heart rhythm disorders and muscle cramps caused by disturbed water-electrolyte balance.

The treatment: symptomatic, the nature of which depends on the time elapsed since taking the drug and the severity of symptoms. In case of early detection of overdose of the drug it is recommended to induce vomiting. In case of pronounced BP decrease, intravenous infusion of 0.9% sodium chloride solution is recommended, accompanied by regular monitoring of heart and respiratory system activity, CIC and the amount of urine excreted. Valsartan is not excreted by hemodialysis due to significant binding to plasma proteins. At the same time, hemodialysis allows effective excretion of hydrochlorothiazide.

Pregnancy use

Pregnancy

Risk summary

As for any other drug affecting the RAAS, the use of Valz H in pregnancy is contraindicated. Given the mechanism of action of APAII, risks to the fetus cannot be excluded. It is known that the use of ACE inhibitors (a class of specific drugs acting on the RAAS) in the second and third trimesters of pregnancy leads to fetal damage and death. According to a retrospective analysis, the use of ACE inhibitors in the first trimester of pregnancy is associated with a potential risk of fetal malformations.

Hydrochlorothiazide penetrates the placenta. Inadvertent administration of valsartan in pregnancy has been associated with spontaneous miscarriage, low water content, and impaired renal function in the newborn.

Intrauterine exposure to thiazide diuretics, including hydrochlorothiazide, has been associated with the development of fetal or neonatal jaundice or thrombocytopenia and may also be associated with other adverse reactions seen in adults. If pregnancy is diagnosed during treatment with Valz N, the drug should be discontinued as soon as possible.

Clinical aspects

Maternal and/or fetal risks associated with the disease

Arterial hypertension in pregnancy increases the risk of pre-eclampsia, gestational diabetes mellitus, premature delivery, and complications in labor (e.g., need for a cesarean section, development of postpartum bleeding). Arterial hypertension increases the risk of delayed intrauterine development of the fetus and intrauterine fetal death.

Risk from the fetus/newborn

Malovody in pregnant women taking drugs that affect the RAAS in the second and third trimesters may lead to impaired fetal renal function, resulting in anuria and renal failure, fetal lung hypoplasia, fetal skeletal deformities, including skull bone hypoplasia, arterial hypotension and fetal death.

Inadvertent administration of ARAs during pregnancy should consider the need for appropriate fetal monitoring.

Newborns whose mothers have received APA therapy should be closely monitored with respect to the development of arterial hypotension.

Valsartan

. Fetotoxicity was observed in fetal development studies in mice, rabbits, and rats and was associated with maternal toxicity in rats when valsartan was administered at a daily dose of 600 mg/kg per day, approximately 6 times the maximum recommended daily dose for a 60 kg patient), and rabbits at a daily dose of 10 mg/kg of valsartan, which is approximately 0.6 times the maximum recommended daily dose for humans based on mg/kg body weight (calculation assumes a daily oral dose of 320 mg for a human patient weighing 60 kg). No events of maternal toxicity or fetotoxicity were noted when administered in mice at daily doses of up to 600 mg/kg, which is approximately 9 times the maximum recommended daily dose for humans at mg/kg of body weight (calculation assumes a daily dose of 320 mg orally for a patient with a body weight of 60 kg).

Hydrochlorothiazide

There was no teratogenicity or effect of hydrochlorothiazide on fertility or fertility in a study in 3 animal species that received oral hydrochlorothiazide. No dose-dependent fetotoxicity was observed in rats when administered orally at doses of 0, 100, 300, and 1000 mg/kg. Lack of weight gain in dairy rats was attributed to the high dose and diuretic effects of hydrochlorothiazide and the corresponding effects on milk production.

Breastfeeding

It is not known whether valsartan penetrates into breast milk. In preclinical studies, valsartan has been shown to be excreted with the milk of lactating rats. Hydrochlorothiazide is excreted with breast milk. The use of the drug during breastfeeding is contraindicated.

Patients and patients with preserved reproductive potential

Like any other drug with a direct effect on the RAAS, Valz N should not be used in women planning pregnancy. When choosing any drug that acts on the RAAS, the physician should inform the patient with preserved reproductive potential about the possible risk of using the drug during pregnancy.

Fertility

There are no data on the effect of valsartan or hydrochlorothiazide on fertility in humans. No effect of valsartan or hydrochlorothiazide on fertility in rats has been reported in preclinical studies.

Similarities