Valsartan h
Ukraine
Table of Contents
INSTRUCTIONS for medical use of the medicinal product Valmisar H (Valmisar H)
Composition:
Active substances: valsartan and hydrochlorothiazide;
One tablet contains 80 mg of valsartan and 12.5 mg of hydrochlorothiazide, or 160 mg of valsartan and 12.5 mg of hydrochlorothiazide, or 160 mg of valsartan and 25 mg of hydrochlorothiazide, or 320 mg of valsartan and 12.5 mg of hydrochlorothiazide, or 320 mg of valsartan and 25 mg of hydrochlorothiazide;
Excipients:
Dosage 80/12.5 mg: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating Opadry Pink 03F84641: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide red pigment (E 172), iron oxide yellow pigment (E 172);
Dosage 160/12.5 mg: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating Opadry Brown 03F565001: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide red pigment (E 172);
Dosage 160/25 mg: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating Opadry Brown 03F57311: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide red pigment (E 172), iron oxide yellow pigment (E 172), iron oxide black pigment (E 172);
Dosage 320/12.5 mg: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating Opadry Pink 03F540000: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide red pigment (E 172), iron oxide black pigment (E 172);
Dosage 320/25 mg: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating Opadry Yellow 03F82329: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide yellow pigment (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
Valmisar H 80 mg/12.5 mg: biconvex oval-shaped film-coated tablets of light orange color, with "L16" embossed on one side and smooth on the other side;
Valmisar H 160 mg/12.5 mg: biconvex oval-shaped film-coated tablets of dark red color, with "L17" embossed on one side and smooth on the other side;
Valmisar H 160 mg/25 mg: biconvex oval-shaped film-coated tablets of brown color, with "L18" embossed on one side and smooth on the other side;
Valmisar H 320 mg/12.5 mg: biconvex oval-shaped film-coated tablets of pink color, with "L19" embossed on one side and smooth on the other side;
Valmisar H 320 mg/25 mg: biconvex oval-shaped film-coated tablets of yellow color, with "L20" embossed on one side and smooth on the other side.
Pharmacotherapeutic group. Angiotensin II antagonists and diuretics. Valsartan and diuretics. ATC code C09DA03.
Pharmacological properties.
Pharmacodynamics.
Valsartan
Valsartan is an active and specific angiotensin II receptor antagonist intended for oral administration. It selectively acts on AT1 subtype receptors, which are responsible for the effects of angiotensin II. Increased levels of angiotensin II resulting from AT1 receptor blockade by valsartan may stimulate unopposed AT2 receptors, counterbalancing the effects mediated by AT1 receptors. Valsartan has no partial agonist activity at AT1 receptors and exhibits much greater affinity (approximately 20,000 times higher) for AT1 receptors than for AT2 receptors.
Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. No side effects related to bradykinin have been observed. In clinical studies comparing valsartan with ACE inhibitors, the incidence of dry cough was significantly lower (P < 0.05) in patients treated with valsartan compared to those receiving an ACE inhibitor (2.6% vs. 7.9%, respectively). In patients who previously experienced dry cough during ACE inhibitor therapy, this adverse effect occurred in 19.5% of cases during treatment with valsartan and in 19% of cases during treatment with a thiazide diuretic, whereas cough was observed in 68.5% of patients in the group receiving ACE inhibitors (P < 0.05).
In controlled clinical trials, the incidence of cough in patients receiving the combination of valsartan and hydrochlorothiazide was 2.9%.
Valsartan does not interact with or block receptors of other hormones or ion channels that play an important role in cardiovascular regulation.
Administration of the drug to patients with hypertension results in a reduction of arterial blood pressure without affecting pulse rate.
In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and maximal reduction in blood pressure is achieved within 4–6 hours. The antihypertensive effect persists for more than 24 hours after a single dose. With regular administration, the maximal therapeutic effect is usually achieved within 2–4 weeks and is maintained at this level during long-term therapy. The combination with hydrochlorothiazide reduces arterial blood pressure more effectively.
Discontinuation of valsartan does not lead to a sudden increase in arterial blood pressure (rebound syndrome) or other adverse effects.
Valsartan does not affect total cholesterol, triglycerides, serum glucose, or uric acid levels in patients with arterial hypertension.
The site of action of thiazide diuretics is the cortical segment of the distal convoluted renal tubules, where receptors highly sensitive to diuretic action are located, and where Na+ and Cl- ion transport is inhibited. The mechanism of action of thiazides is associated with inhibition of the Na+Cl- cotransporter, presumably due to competition for Cl- transport sites. As a result, excretion of sodium and chloride ions increases to a similar extent. Due to the diuretic effect, a reduction in plasma volume occurs, leading to increased renin activity, aldosterone secretion, and potassium excretion in urine, resulting in decreased serum potassium concentration. The renin-aldosterone relationship is mediated by angiotensin II; therefore, administration of an angiotensin II receptor antagonist reduces potassium loss associated with the use of a thiazide diuretic.
Pharmacokinetics.
Valsartan/hydrochlorothiazide
Systemic availability of hydrochlorothiazide decreases by approximately 30% when co-administered with valsartan. The pharmacokinetics of valsartan are not significantly altered when co-administered with hydrochlorothiazide. This interaction does not affect the combined use of valsartan and hydrochlorothiazide, as the clear antihypertensive effect of the combination exceeds the effect achieved with monotherapy using either active substance or placebo.
Valsartan
Absorption. After oral administration, peak plasma concentration of valsartan is reached within 2–4 hours. Mean absolute bioavailability is 23%. Food intake reduces the exposure (as measured by AUC) of valsartan by approximately 40% and peak plasma concentration (Cmax) by approximately 50%, although about 8 hours after administration, plasma valsartan concentrations are similar whether administered with or without food. This reduction in AUC, however, is not associated with clinically significant reduction in therapeutic effect; therefore, valsartan can be taken regardless of food intake.
Distribution. The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 liters, indicating that valsartan is minimally distributed into tissues. Valsartan is highly bound to serum proteins (94–97%), primarily to serum albumin.
Metabolism. Valsartan undergoes minimal biotransformation, as only about 20% of the dose is recovered as metabolites. A hydroxylated metabolite has been detected in plasma at low concentrations (less than 10% of the AUC for valsartan). This metabolite is pharmacologically inactive.
Elimination. Valsartan exhibits multi-exponential elimination kinetics (t½α <1 hour and t½ß approximately 9 hours). Valsartan is primarily eliminated via feces (approximately 83% of the dose) and urine (approximately 13% of the dose), mostly in unchanged form.
Following intravenous administration, plasma clearance of valsartan is approximately 2 L/h, and renal clearance is 0.62 L/h (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.
Hydrochlorothiazide
Absorption. After oral administration, hydrochlorothiazide is rapidly absorbed (tmax approximately 2 hours). The increase in mean AUC is linear and dose-proportional within the therapeutic range. The effect of food on hydrochlorothiazide absorption is not clinically significant. Absolute bioavailability of hydrochlorothiazide after oral administration is 70%.
Distribution. Apparent volume of distribution is 4–8 L/kg. Circulating hydrochlorothiazide is bound to plasma proteins (40–70%), primarily to serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at concentrations approximately three times higher than in plasma.
Elimination. Hydrochlorothiazide is primarily excreted unchanged. Terminal elimination half-life in plasma averages between 6 and 15 hours. No changes in hydrochlorothiazide kinetics occur with repeated dosing, and accumulation is minimal with once-daily administration. More than 95% of the absorbed dose is excreted unchanged in urine. Renal clearance involves passive filtration and active tubular secretion.
Pharmacokinetics in specific patient populations
Elderly patients. In some elderly patients, systemic exposure to valsartan was slightly higher than in younger patients, although this was not clinically significant. Limited data suggest that systemic clearance of hydrochlorothiazide is lower in elderly patients—both healthy and those with arterial hypertension—compared to healthy young volunteers.
Patients with renal impairment. Dose adjustment is not required in patients with creatinine clearance of 30–70 mL/min.
There are no data on the use of Valmisar H in patients with severe renal impairment (creatinine clearance < 30 mL/min) or in patients undergoing hemodialysis. Valsartan is highly protein-bound and is not removed by hemodialysis; hydrochlorothiazide, in contrast, is eliminated during hemodialysis. In renal insufficiency, mean peak plasma levels and AUC values of hydrochlorothiazide increase, while urinary excretion rate decreases. In patients with mild to moderate renal impairment, AUC of hydrochlorothiazide increases by 3-fold. In patients with severe renal impairment, AUC increases by 8-fold. Hydrochlorothiazide is contraindicated in patients with severe renal impairment (see section "Contraindications").
Hepatic impairment. Systemic exposure to valsartan is approximately twice as high in patients with mild (n = 6) and moderate (n = 5) hepatic impairment compared to healthy volunteers. There are no data on the use of valsartan in patients with severe hepatic impairment. Liver disease does not significantly affect the pharmacokinetics of hydrochlorothiazide, and therefore dose reduction is not required.
Non-melanoma skin cancer (NMSC)
Available epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of NMSC. One study included 71,533 cases of basal cell carcinoma (with 1,430,833 individuals in the control group) and 8,629 cases of squamous cell carcinoma (with 172,462 individuals in the control group). High-dose hydrochlorothiazide (≥ 50,000 mg cumulative) was associated with an adjusted odds ratio (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 cumulative dose-response relationship was observed for both basal cell and squamous cell carcinoma. Another study showed a possible association between lip cancer and hydrochlorothiazide use: 633 cases of lip cancer were matched with 63,067 population-based controls using a risk-set 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) with high-dose use (~25,000 mg) and OR 7.7 (5.7–10.5) with the highest dose (~100,000 mg). For example, a cumulative dose of 100,000 mg corresponds to daily use of a defined daily dose of 25 mg over a period exceeding 10 years.
Clinical characteristics.
Indications.
Arterial hypertension in patients whose blood pressure is not adequately controlled with monotherapy.
Contraindications.
- Hypersensitivity to any component of the medicinal product or to other sulfonamide derivatives.
- Severe impairment of liver function, liver cirrhosis, and cholestasis.
- Anuria.
- Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
- Concomitant use of angiotensin receptor antagonists (ARA), including valsartan, or angiotensin-converting enzyme inhibitors (ACE inhibitors) with aliskiren in patients with diabetes mellitus (type I and II) or renal impairment (eGFR < 60 mL/min/1.73 m²).
- Pregnancy, planned pregnancy (see "Use during pregnancy or breastfeeding").
- Hereditary angioedema or angioedema during previous treatment with angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin receptor antagonists (ARA).
Interaction with other medicinal products and other forms of interaction.
Interactions with the combination of valsartan and hydrochlorothiazide
Concomitant use not recommended
Lithium
Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of ACE inhibitors and thiazide diuretics, including hydrochlorothiazide. Due to lack of experience with concomitant use of valsartan and lithium, this combination is not recommended. If such combination is necessary, careful monitoring of plasma lithium levels is recommended.
Concomitant use requiring special caution
Other antihypertensive medicinal products
The medicinal product may enhance the hypotensive effect of other antihypertensive agents (such as guanethidine, methyldopa, vasodilators, ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, direct renin inhibitors, and dopamine reuptake inhibitors).
Pressor amines (e.g., noradrenaline, adrenaline)
Reduced response to pressor amines is possible. The clinical significance of this effect is not well established and insufficient to preclude their use.
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and non-selective NSAIDs
NSAIDs may reduce the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when used concomitantly. Additionally, concomitant use of valsartan/hydrochlorothiazide and NSAIDs may lead to worsening of renal function and increased serum potassium levels. Therefore, monitoring of renal function at the beginning of treatment and adequate fluid replacement are recommended.
In elderly patients, patients with reduced blood volume (including those receiving diuretic therapy), or patients with impaired renal function, concomitant use of NSAIDs (or COX-2 inhibitors) with angiotensin II receptor blockers (ARBs) increases the risk of worsening renal function, including acute renal failure. Combined use of these medicinal products requires caution and monitoring of renal function.
Interactions related to valsartan
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ARA, ACE inhibitors, or aliskiren
Caution is required when ARAs, including valsartan, are used concomitantly with other agents that block the RAAS, such as ACE inhibitors or aliskiren.
This is due to an increased incidence of hypotension, syncope, hyperkalemia, and renal dysfunction (including acute renal failure) compared to monotherapy. Therefore, dual blockade of the RAAS by combined use of ACE inhibitors, angiotensin receptor blockers, or aliskiren is not recommended. If dual RAAS blockade is considered absolutely necessary, treatment should be under specialist supervision and accompanied by monitoring of renal function, electrolyte levels, and blood pressure.
Concomitant use of angiotensin receptor antagonists (ARA), including valsartan, or angiotensin-converting enzyme inhibitors (ACE inhibitors) with aliskiren in patients with diabetes mellitus (type I and II), diabetic nephropathy, or renal impairment (eGFR < 60 mL/min/1.73 m²) is contraindicated (see section "Contraindications" and "Adverse reactions").
Concomitant use not recommended
Potassium-sparing diuretics, potassium-containing dietary supplements, potassium-containing salt substitutes, and other substances that may increase potassium levels
If use of a medicinal product affecting potassium levels is necessary in combination with valsartan, monitoring of plasma potassium levels is recommended.
Concomitant use of angiotensin II receptor antagonists with other medicinal products capable of increasing serum potassium levels (e.g., potassium-sparing diuretics, potassium-containing medicinal products, heparin) increases the risk of hyperkalemia. In such cases, Valmisar N should be used with caution and potassium levels should be monitored.
Transporters
In vitro studies show that valsartan is a substrate for the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical significance of these findings is unknown. Concomitant use of inhibitors of uptake transporters (e.g., rifampicin, cyclosporine) or efflux transporters (e.g., ritonavir) may increase systemic exposure to valsartan. Appropriate precautions should be taken at the initiation or discontinuation of concomitant use of these medicinal products.
Absence of interactions
No clinically significant interactions were observed in studies with valsartan when administered with any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glyburide. Digoxin and indomethacin may interact with hydrochlorothiazide (see interactions related to hydrochlorothiazide).
Interactions related to hydrochlorothiazide
Concomitant use requiring special caution
MEDICINAL PRODUCTS ASSOCIATED WITH POTASSIUM LOSS AND HYPokalemia
The hypokalemic effect of hydrochlorothiazide may be enhanced when used concomitantly with potassium-wasting diuretics, corticosteroids, laxatives, adrenocorticotropic hormones (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid and its derivatives, antiarrhythmic agents.
If the above medicinal products are prescribed in combination with valsartan/hydrochlorothiazide, monitoring of serum potassium levels is recommended (see section "Special precautions for use").
MEDICINAL PRODUCTS CAPABLE OF INDUCING TORSADES DE POINTES VENTRICULAR TACHYCARDIA
Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution when administered concomitantly with medicinal products that may induce torsades de pointes ventricular tachycardia, particularly class Ia and III antiarrhythmics, as well as certain antipsychotics.
MEDICINAL PRODUCTS AFFECTING SERUM SODIUM LEVELS
The hyponatremic effect of diuretics may be enhanced when used concomitantly with medicinal products such as antidepressants, antipsychotics, antiepileptics, etc. Long-term use of these medicinal products should be prescribed with caution.
MEDICINAL PRODUCTS THAT MAY CAUSE TORSADES DE POINTES ARRHYTHMIA
- Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide)
- Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide)
- Certain neuroleptics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)
- Others (e.g., bepridil, cisapride, diphenylhydantoin, intravenous erythromycin, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vincamine)
Due to the risk of developing hypokalemia, hydrochlorothiazide should be used with caution when administered concomitantly with medicinal products that may cause torsades de pointes arrhythmia.
Cardiac glycosides
Hypokalemia or hypomagnesemia induced by thiazides may occur as an adverse effect promoting cardiac arrhythmias induced by digitalis preparations (see section "Special precautions for use").
Calcium salts and vitamin D
Administration of thiazide diuretics, including hydrochlorothiazide, in combination with vitamin D or calcium salts may lead to increased serum calcium levels. Concomitant use of thiazide diuretics with calcium salts may cause hypercalcemia in patients predisposed to hypercalcemia (e.g., patients with hyperparathyroidism, malignancies, or conditions associated with vitamin D deficiency) due to enhanced tubular reabsorption of calcium.
Antidiabetic medicinal products (oral agents and insulin)
Thiazides may alter glucose tolerance. Adjustment of antidiabetic agent dosage may be necessary.
Metformin should be used with caution due to the risk of lactic acidosis, possibly caused by functional renal impairment associated with hydrochlorothiazide use.
Beta-blockers and diazoxide
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.
MEDICINAL PRODUCTS USED IN THE TREATMENT OF GOUT (probenecid, sulfinpyrazone, and allopurinol)
Dosage adjustment of gout medications may be necessary because hydrochlorothiazide may increase serum uric acid levels. Dose increases of probenecid or sulfinpyrazone may be required if needed. Concomitant use of thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol.
Anticholinergic agents and other medicinal products affecting gastrointestinal motility
The bioavailability of thiazide diuretics may increase when administered with anticholinergic agents (e.g., atropine, biperiden), particularly due to reduced gastrointestinal motility and delayed gastric emptying. Conversely, prokinetic agents such as cisapride may reduce the bioavailability of thiazide diuretics.
Amantadine
Thiazides, including hydrochlorothiazide, increase the risk of adverse effects caused by amantadine.
Ion-exchange resins
Absorption of thiazide diuretics, including hydrochlorothiazide, is impaired when administered concomitantly with cholestyramine or colestipol.
This may lead to subtherapeutic effects of thiazide diuretics. To minimize interaction, hydrochlorothiazide should be administered at least 4 hours before or 4–6 hours after resin intake.
Cytotoxic agents (e.g., cyclophosphamide, methotrexate)
Thiazides may reduce renal excretion of cytotoxic agents and potentiate their myelosuppressive effect.
Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine)
Thiazides, including hydrochlorothiazide, enhance the effect of skeletal muscle relaxants such as curare derivatives.
Cyclosporine
Concomitant use with cyclosporine may increase the risk of hyperuricemia and symptoms resembling gout flare-ups.
Alcohol, anesthetics, and sedatives
Concomitant use of thiazide diuretics with medicinal products that may also lower blood pressure (e.g., due to reduced activity of the central sympathetic nervous system or direct vasodilatory effects) may potentiate orthostatic hypotension.
Methyldopa
Cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.
Carbamazepine
Hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Such patients should be informed about the possibility of hyponatremic reactions and appropriately monitored.
Iodine-containing contrast agents
In cases of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine-containing agents. Adequate fluid replacement should be provided prior to administration.
Special precautions for use.
Changes in serum electrolyte balance
Potassium
Thiazide diuretics may cause hypokalemia or exacerbate existing hypokalemia.
Correction of hypokalemia is recommended prior to initiating thiazide therapy. Concomitant hypomagnesemia may contribute to hypokalemia that is difficult to correct.
Since Valmisar N contains an angiotensin II receptor antagonist, caution should be exercised when Valmisar N is used concomitantly with potassium salts, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin). Cases of hypokalemia have been reported during treatment with thiazide diuretics. Regular monitoring of serum potassium and magnesium levels is recommended in patients with conditions involving increased potassium loss. Electrolyte balance should be monitored in all patients receiving thiazide diuretics.
Patients with sodium and/or circulating blood volume deficiency
Treatment with thiazide diuretics is often associated with the development of hyponatremia or worsening of existing hyponatremia and hypochloremic alkalosis. This may be accompanied by neurological symptoms (e.g., vomiting, confusion, apathy). Thiazide diuretics should be administered only after correction of hyponatremia. Serum sodium concentration should be monitored regularly.
Thiazides enhance urinary magnesium excretion, which may lead to hypomagnesemia.
In patients with marked sodium and/or circulating blood volume deficiency (e.g., those receiving high-dose diuretic therapy), symptomatic arterial hypotension may occur after initiation of treatment with the drug. Sodium and/or circulating blood volume should be corrected prior to starting therapy.
In case of hypotension, the patient should be placed in a supine position and, if necessary, receive intravenous saline infusion. Treatment may be continued immediately after stabilization of blood pressure.
Calcium
Thiazide diuretics reduce calcium excretion in urine and may cause elevated serum calcium levels. Thiazide diuretics should be used only after correction of hypercalcemia or treatment of conditions causing it. Serum calcium concentration should be monitored regularly.
Patients with severe chronic heart failure with congestion or other conditions with activation of the renin-angiotensin-aldosterone system (RAAS)
In patients whose renal function primarily depends on RAAS activity (e.g., patients with severe congestive heart failure), treatment with agents acting on RAAS may cause oliguria and/or progressive azotemia, and rarely, acute renal failure. The use of Valmisar N in patients with severe chronic heart failure is not justified.
Since it cannot be excluded that suppression of the renin-angiotensin-aldosterone system may also be associated with impaired renal function, the drug should not be used in such patients.
Renal artery stenosis
Since serum urea and creatinine levels may increase, patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney should not take the drug.
Primary hyperaldosteronism
The drug is not recommended for use in patients with primary hyperaldosteronism, as their RAAS is not activated.
Aortic or mitral valve stenosis, hypertrophic obstructive cardiomyopathy
As with other vasodilators, particular caution is required in patients with aortic or mitral valve stenosis or hypertrophic obstructive cardiomyopathy (HOCM).
Intestinal angioedema
Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers, including valsartan (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, the drug should be discontinued and appropriate monitoring initiated until symptoms completely resolve.
Renal impairment
Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 mL/min).
Valmisar N should be used with caution in patients with severe renal impairment (creatinine clearance < 30 mL/min). Thiazide diuretics may provoke azotemia in patients with chronic renal impairment. They are ineffective as monotherapy in severe renal impairment (creatinine clearance < 30 mL/min), but may be used with appropriate caution in combination with loop diuretics, even in patients with creatinine clearance < 30 mL/min.
Concomitant use of angiotensin receptor blockers, including Valmisar N, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren is contraindicated in patients with renal impairment (creatinine clearance < 60 mL/min).
There is no experience with the use of valsartan in patients with end-stage renal disease (creatinine clearance < 10 mL/min) or in patients undergoing dialysis.
Kidney transplantation
Currently, there are no data on the safety of using the drug in patients who have recently undergone kidney transplantation.
Hepatic impairment
Caution is required when treating patients with hepatic impairment. Dose adjustment is not required in patients with mild to moderate hepatic impairment without cholestasis. Liver disease does not significantly alter the pharmacokinetic parameters of hydrochlorothiazide.
Thiazides may cause electrolyte imbalances, hepatic encephalopathy, and hepatorenal syndrome. Therefore, Valmisar N should be prescribed to such patients only after careful assessment of risk versus benefit and with monitoring of clinical and laboratory parameters. Valmisar N is contraindicated in patients with biliary cirrhosis or cholestasis.
Systemic lupus erythematosus
Thiazide diuretics, including hydrochlorothiazide, may exacerbate or activate systemic lupus erythematosus.
Other metabolic disorders
Thiazide diuretics may affect glucose tolerance and increase serum cholesterol, triglycerides, and uric acid levels, potentially exacerbating hyperuricemia and leading to gout. Therefore, Valmisar N is not recommended for use in patients with hyperuricemia and/or gout. Diabetic patients may require adjustment of insulin or oral hypoglycemic agent doses.
Thiazides may reduce urinary calcium excretion and cause transient and slight increases in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate the presence of hyperparathyroidism. Thiazide use should be discontinued prior to testing parathyroid function.
Photosensitivity
Cases of photosensitivity reactions have been reported with thiazide diuretics (see section "Adverse reactions"). If a photosensitivity reaction occurs during treatment, drug use should be discontinued. If re-administration of the diuretic is necessary, protection of exposed areas from sunlight or artificial UV radiation is recommended.
Pregnancy
Angiotensin II receptor antagonists should not be initiated during pregnancy. Women planning pregnancy should be switched to alternative antihypertensive treatments with established safety profiles for use during pregnancy, unless continued therapy with angiotensin II receptor antagonists is considered necessary. If pregnancy is detected, treatment with angiotensin II receptor antagonists should be stopped immediately, and alternative therapy initiated if needed.
General disorders
Caution should be exercised when administering the drug to patients with a history of hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies and asthma.
Angioedema
Angioedema (including laryngeal and glottal edema leading to airway obstruction, and/or facial, lip, pharyngeal, and/or tongue swelling) has been observed in patients receiving valsartan. Some of these patients had a history of angioedema with other drugs, including other angiotensin II receptor antagonists and ACE inhibitors. If angioedema occurs, treatment with angiotensin II receptor antagonists should be stopped immediately. Re-administration of the drug is contraindicated.
Choroidal effusion, acute myopia, and secondary acute angle-closure glaucoma
Hydrochlorothiazide, a sulfonamide, has been associated with idiosyncratic reactions that may lead to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma. Symptoms include acute decrease in visual acuity or eye pain, typically occurring within hours to a week after drug administration. Untreated acute angle-closure glaucoma may lead to permanent vision loss.
Treatment with hydrochlorothiazide should be discontinued as soon as possible. Emergency medical or surgical intervention may be required. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Patients with heart failure, previous myocardial infarction
In patients whose renal function depends on renin-angiotensin-aldosterone system (RAAS) activity (e.g., patients with severe heart failure), treatment with ACE inhibitors or angiotensin receptor antagonists may be associated with oliguria and/or progressive azotemia, and in some cases, acute renal failure and fatal outcomes. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.
Non-melanoma skin cancer (NMSC)
An increased risk of NMSC (basal cell carcinoma and squamous cell carcinoma) with increasing cumulative dose of hydrochlorothiazide was observed in two epidemiological studies based on the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be a potential mechanism for NMSC development.
Patients taking hydrochlorothiazide should be informed about the risk of NMSC. Regular skin examinations for new lesions are recommended, and any suspicious skin changes should be reported immediately. Preventive measures to minimize skin cancer risk, such as limiting exposure to sunlight and UV radiation and using adequate sun protection, are advised. Suspicious skin lesions should be promptly evaluated, including histological examination and biopsies. The use of hydrochlorothiazide should also be reconsidered in patients who have experienced NMSC.
Fertility
There is no information on the effect of valsartan on human fertility. Animal studies in rats showed no effect of valsartan on fertility.
Dose adjustment is not required in elderly patients.
Hydrochlorothiazide may reduce plasma protein-bound iodine levels. Hydrochlorothiazide may increase free bilirubin concentration in serum.
Acute respiratory toxicity
There have been reports of very rare cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), following hydrochlorothiazide administration. Pulmonary edema usually develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening pulmonary function, and hypotension. If ARDS is suspected, the drug should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after taking hydrochlorothiazide.
Use during pregnancy or breastfeeding
Pregnancy
Valsartan
The drug should not be used during pregnancy or in women planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use must be stopped immediately and replaced with another medicinal product approved for use in pregnant women.
It is known that angiotensin II receptor antagonists used during the second and third trimesters cause fetotoxicity (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia) in humans.
If angiotensin II receptor antagonists were used from the second trimester of pregnancy, ultrasound monitoring of fetal kidneys and skull is recommended.
Infants born to mothers who took angiotensin II receptor antagonists require careful monitoring for hypotension.
Hydrochlorothiazide
Experience with hydrochlorothiazide use during pregnancy is limited, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters of pregnancy may impair fetoplacental circulation and cause effects in the fetus and newborn such as jaundice, electrolyte imbalance, and thrombocytopenia.
The physician prescribing a drug acting on RAAS should inform the woman about the potential risks during pregnancy.
Due to the mechanism of action of angiotensin II receptor antagonists, the risk of embryopathy and fetal disease cannot be excluded. According to retrospective data, the use of ACE inhibitors in the first trimester is associated with a potential risk of congenital defects. Moreover, fetal injury and fatal outcomes have been reported with drugs directly affecting the renin-angiotensin-aldosterone system (RAAS) during the second and third trimesters. Fetal renal perfusion, dependent on RAAS development, begins during the second trimester. Therefore, the risk associated with valsartan treatment is higher during the second and third trimesters. Spontaneous abortions, oligohydramnios, and neonatal renal dysfunction have been reported when pregnant women inadvertently took valsartan.
Newborns exposed to the drug in utero should be carefully examined for adequate urine output, hyperkalemia, and blood pressure. If necessary, appropriate medical measures (e.g., rehydration) should be taken to remove the drug from the circulation.
Intrauterine exposure to thiazide diuretics, including hydrochlorothiazide, may cause jaundice or thrombocytopenia in the fetus and newborn or other adverse reactions observed in adults.
Lactation
If use of the drug is essential, breastfeeding should be discontinued. There is no information on the use of valsartan during lactation. Hydrochlorothiazide passes into human milk in small amounts. Thiazides in high doses cause diuresis, which may suppress milk production. During lactation, alternative treatment options with better-established safety profiles are preferred, especially when nursing a newborn or preterm infant.
Ability to affect reaction speed when driving or operating machinery
No studies on the effect on the ability to drive or operate machinery have been conducted. It should be noted that dizziness or weakness may occur while driving or operating machinery.
Method of Administration and Dosage
Valmisar N can be taken with or without food, swallowed with water.
The recommended dose of Valmisar N is 1 tablet of 80 mg/12.5 mg once daily. If blood pressure is not adequately controlled after 3–4 weeks of treatment, consider increasing to a dose of 1 tablet of 160 mg/12.5 mg once daily. Tablets of 160 mg/25 mg should be prescribed to patients in whom adequate blood pressure reduction is not achieved with 160 mg/12.5 mg tablets. If blood pressure remains insufficiently controlled with 160 mg/25 mg tablets, consider increasing to a dose of 320 mg/12.5 mg. Tablets of 320 mg/25 mg should be prescribed to patients in whom adequate blood pressure reduction is not achieved with 320 mg/12.5 mg tablets.
The maximum daily dose is 320 mg/25 mg.
If there is no response to Valmisar N treatment after 8 weeks, consider using an additional or alternative antihypertensive agent.
Maximum antihypertensive effect is achieved within 2–4 weeks. Some patients may require 4–8 weeks of treatment. This should be taken into account during dose titration.
Use in elderly patients (over 65 years of age)
Valmisar N can be used in patients of any age.
Use in patients with renal impairment
Dose reduction may be necessary in patients with renal impairment. Since Valmisar N contains hydrochlorothiazide, it is contraindicated in patients with anuria, and special caution is required when used in patients with severe renal impairment (creatinine clearance < 30 mL/min).
There are no data on the use of valsartan in patients with end-stage renal disease (creatinine clearance < 10 mL/min) or in patients undergoing dialysis.
Hepatic impairment
Dose reduction may be necessary in patients with hepatic impairment. Since Valmisar N contains hydrochlorothiazide, it should be used with caution in patients with hepatic impairment. Since Valmisar N contains valsartan, it is contraindicated in patients with biliary cirrhosis or cholestasis.
The dose of valsartan in patients with mild to moderate non-biliary hepatic impairment without cholestasis should not exceed 80 mg.
Children
Valmisar N is not recommended for use in children due to lack of data on safety and efficacy.
Overdose
Symptoms
Overdose may lead to pronounced arterial hypotension, which can result in decreased level of consciousness, vascular collapse, and/or shock. In addition, hydrochlorothiazide overdose may cause symptoms such as nausea, drowsiness, hypovolemia, and electrolyte imbalance, leading to cardiac arrhythmias and muscle spasms. The most characteristic signs of overdose also include tachycardia, arterial hypotension, shock, weakness, confusion, dizziness, muscle cramps, paresthesia, exhaustion, disturbances of consciousness, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, elevated blood urea nitrogen levels (primarily due to renal failure).
Treatment
In all cases of overdose, general supportive measures should be implemented, including continuous monitoring of the patient and measures to stabilize cardiovascular function.
Therapeutic interventions depend on the time of ingestion and the type and severity of symptoms; stabilization of circulation is of primary importance.
If the drug was ingested recently, induce vomiting. If a significant amount of time has passed since ingestion, administer a sufficient quantity of activated charcoal.
In case of arterial hypotension, the patient should be placed in a supine position and immediate restoration of fluid and electrolyte balance should be achieved by intravenous administration of isotonic saline solution. Valsartan cannot be removed by hemodialysis due to its high plasma protein binding; however, hemodialysis is effective in removing hydrochlorothiazide from the body.
Adverse reactions
The frequency of adverse reactions is assessed as follows, starting with the most common: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000), including isolated reports.
Frequency of adverse reactions during administration of valsartan/hydrochlorothiazide
Table 1
| Infections and infestations |
|
| Uncommon |
viral infections, fever |
| Metabolism and nutrition disorders |
|
| Uncommon |
dehydration |
| Not known |
hypokalemia, hyponatremia |
| Nervous system disorders |
|
| Common |
headache, fatigue, dizziness |
| Uncommon |
asthenia, dizziness, insomnia, anxiety, paresthesia |
| Rare |
depression |
| Not known |
syncope |
| Eye disorders |
|
| Uncommon |
blurred vision |
| Rare |
conjunctivitis |
| Ear and labyrinth disorders |
|
| Uncommon |
otitis media, tinnitus |
| Cardiac disorders |
|
| Uncommon |
palpitations, tachycardia |
| Vascular disorders |
|
| Uncommon |
edema, arterial hypotension, hyperhidrosis |
| Respiratory, thoracic and mediastinal disorders |
|
| Common |
cough, rhinitis, pharyngitis, upper respiratory tract infections |
| Uncommon |
bronchitis, dyspnea, sinusitis, pharyngolaryngeal pain, dry mouth |
| Very rare |
epistaxis |
| Not known |
non-cardiogenic pulmonary edema |
| Gastrointestinal disorders |
|
| Common |
diarrhea |
| Uncommon |
abdominal pain, dyspepsia, nausea, gastroenteritis |
| Musculoskeletal and connective tissue disorders |
|
| Common |
back pain, arthralgia |
| Uncommon |
limb pain, chest pain, neck pain, arthritis, sprains and deformities, muscle cramps, myalgia |
| Renal and urinary disorders |
|
| Uncommon |
frequency of urination, urinary tract infections |
| Very rare |
renal function impairment |
| Reproductive system disorders |
|
| Common |
erectile dysfunction |
| General disorders |
|
| Uncommon |
increased fatigue |
| Investigations |
|
| Not known |
elevated plasma uric acid levels, elevated plasma bilirubin and creatinine levels, hypokalemia, hyponatremia, increased blood urea nitrogen, neutropenia |
Additional information on individual components
Adverse reactions observed with the use of valsartan and hydrochlorothiazide individually may also be potential adverse effects of the medicinal product Valmisar N, even if they were not observed in clinical trials or during the post-marketing period.
Frequency of adverse reactions during the use of valsartan
Table 2
| From the blood and lymphatic system |
|
| Unknown |
decreased hemoglobin levels, decreased hematocrit, thrombocytopenia |
| From the immune system |
|
| Unknown |
other hypersensitivity reactions/allergic reactions, including serum sickness |
| Metabolism and nutritional disorders |
|
| Unknown |
increased plasma potassium levels, hyponatremia |
| From the ear and labyrinth disorders |
|
| Uncommon |
vestibular vertigo |
| Vascular disorders |
|
| Unknown |
vasculitis |
| Gastrointestinal disorders |
|
| Uncommon |
abdominal pain, gastroenteritis |
| Very rare |
Angioneurotic edema of the intestine |
| Hepatobiliary disorders |
|
| Unknown |
elevated liver function parameters |
| From the skin and subcutaneous tissue |
|
| Unknown |
edema, angioneurotic edema, rash, pruritus, bullous dermatitis |
| From the urinary system |
|
| Unknown |
renal failure, acute renal failure |
| Musculoskeletal and connective tissue disorders |
|
| Common |
arthralgia |
| Neurological disorders |
|
| Uncommon |
asthenia, insomnia, dizziness |
| Rare |
neuralgia |
| From the reproductive system |
|
| Uncommon |
decreased libido |
| Cardiac disorders |
|
| Very rare |
cardiac arrhythmia |
There has been one reported case of angioneurotic edema.
Undesirable effects associated with the use of hydrochlorothiazide
Hydrochlorothiazide has been widely used for many years, often at doses higher than those contained in the medicinal product Valmisar H. The adverse reactions listed below have been observed in patients receiving thiazide diuretics, including hydrochlorothiazide as monotherapy.
Frequency of adverse reactions during the use of hydrochlorothiazide
Table 3
| From the metabolism and metabolic disorders |
|
| Very common |
with high-dose administration – increased blood lipid levels, hypokalemia |
| Common |
hyponatremia, hypomagnesemia, hyperuricemia |
| Rare |
hypercalcemia, hyperglycemia, glucosuria, and worsening of metabolism in patients with diabetes mellitus |
| Very rare |
hypochloremic alkalosis |
| From the blood and lymphatic system |
|
| Rare |
thrombocytopenia, sometimes with purpura |
| Very rare |
agranulocytosis, leukopenia, hemolytic anemia, bone marrow suppression |
| Unknown |
aplastic anemia |
| From the immune system |
|
| Very rare |
hypersensitivity reactions |
| Psychiatric disorders |
|
| Rare |
depression, sleep disturbances |
| Neurological disorders |
|
| Rare |
headache, dizziness, paresthesia |
| Eye disorders |
|
| Rare |
blurred vision during the first few weeks after starting treatment |
| Unknown |
choroidal effusion, acute angle-closure glaucoma |
| Cardiac disorders |
|
| Rare |
arrhythmia |
| Vascular disorders |
|
| Common |
postural hypotension, which may be intensified by alcohol, anesthetics, or sedatives |
| Respiratory, thoracic and mediastinal disorders |
|
| Very rare |
acute respiratory distress syndrome (ARDS), respiratory failure including pneumonia and pulmonary edema |
| Gastrointestinal disorders |
|
| Common |
loss of appetite, mild nausea and vomiting |
| Rare |
constipation, gastrointestinal discomfort, diarrhea |
| Very rare |
pancreatitis |
| Hepatobiliary disorders |
|
| Rare |
intrahepatic cholestasis or jaundice |
| Skin and subcutaneous tissue disorders |
|
| Common |
urticaria and other types of rash |
| Rare |
photosensitization |
| Very rare |
necrotic vasculitis and toxic epidermal necrolysis, skin reactions resembling lupus erythematosus, reactivation of cutaneous lupus |
| Unknown |
multiform erythema |
| Reproductive system disorders |
|
| Common |
impotence |
| Renal and urinary disorders |
|
| Unknown |
acute renal failure, renal dysfunction |
| General disorders |
|
| Unknown |
fever, fatigue |
| Musculoskeletal and connective tissue disorders |
|
| Unknown |
muscle spasms |
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
|
| Unknown |
non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) |
Reporting of suspected adverse reactions
Reporting of adverse reactions following the registration of a medicinal product is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Storage conditions.
Store at a temperature not exceeding 25 °C in the original packaging.
Keep out of reach and sight of children.
Packaging.
10 tablets per blister; 3 or 9 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
MACLEODS PHARMACEUTICALS LIMITED.
Manufacturer's address and site of operations.
Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India.