Vanatex an
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICINAL USE OF THE MEDICINAL PRODUCT VANAHEX AH
Composition:
Active substances: amlodipine in the form of amlodipine maleate, valsartan, hydrochlorothiazide;
One film-coated tablet contains amlodipine in the form of amlodipine maleate 5 mg or 10 mg, valsartan 160 mg, hydrochlorothiazide 12.5 mg;
Excipients:
Core: microcrystalline cellulose, crospovidone (type A), colloidal anhydrous silicon dioxide, magnesium stearate;
Coating: hypromellose 2910, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), macrogol 6000.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
Film-coated tablets of 5 mg/160 mg/12.5 mg: oval, biconvex, white or almost white film-coated tablets; after breaking the tablet, the core color is white or almost white;
Film-coated tablets of 10 mg/160 mg/12.5 mg: oval, biconvex, yellow film-coated tablets; after breaking the tablet, the core color is white or almost white.
Pharmacotherapeutic group. Angiotensin II antagonists, other combinations. Valsartan, amlodipine and hydrochlorothiazide. ATC code C09DX01.
Pharmacological Properties.
Pharmacodynamics.
The medicinal product Vanatex AH contains three antihypertensive agents with complementary mechanisms of blood pressure control in patients with essential hypertension: amlodipine, belonging to the class of calcium channel antagonists; valsartan, belonging to the class of angiotensin II antagonists; and hydrochlorothiazide, belonging to the class of thiazide diuretics. The combination of these three components demonstrates mutually reinforcing antihypertensive effects.
Amlodipine
Amlodipine, included in the medicinal product Vanatex AH, inhibits transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. The antihypertensive mechanism of action of amlodipine occurs via direct vasodilatory action on vascular smooth muscle, resulting in reduced peripheral vascular resistance and arterial blood pressure.
In therapeutic doses, amlodipine reduces arterial blood pressure in both supine and standing positions in patients with arterial hypertension. This reduction in arterial blood pressure is not accompanied by significant changes in heart rate or plasma catecholamine levels during long-term treatment.
Plasma concentration correlates with effect in both young and elderly patients.
In patients with arterial hypertension and normal renal function, amlodipine at therapeutic doses reduces renal vascular resistance and increases glomerular filtration rate (GFR) and effective renal plasma flow without altering filtration fraction or proteinuria.
Valsartan
Valsartan is an orally active, potent, and specific angiotensin II receptor antagonist (ARB II). Valsartan acts selectively on the AT1 receptor subtype, which mediates the known effects of angiotensin II.
Administration of valsartan to patients with arterial hypertension leads to reduction in arterial blood pressure without affecting pulse rate.
In most patients, after oral administration of a single dose, the onset of hypotensive effect occurs within 2 hours, and maximum reduction in blood pressure is achieved within 4–6 hours. The antihypertensive effect persists for 24 hours after dosing. With repeated administration, maximum blood pressure reduction (at all dosage regimens) is usually achieved within 2–4 weeks.
Hydrochlorothiazide
The primary site of action of thiazide diuretics is the distal convoluted tubules of the kidneys. High-affinity binding sites in the renal cortex have been identified as the main site for thiazide diuretic binding and inhibition of NaCl transport in the distal convoluted tubules. The mechanism of action of thiazides involves inhibition of Na+Cl– cotransporters, possibly through competition at Cl– binding sites, thereby affecting electrolyte reabsorption: directly increasing excretion of sodium and chloride to approximately equivalent degrees, and indirectly, via diuretic effect, reducing plasma volume, leading to increased plasma renin activity, aldosterone secretion, and potassium excretion in urine, as well as decreased serum potassium levels.
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 dose-response relationship was observed for both basal cell and squamous cell carcinomas. Another study showed a possible association between lip cancer and hydrochlorothiazide use: 633 cases of lip cancer were matched with 63,067 population 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) for high dose (~25,000 mg) and OR 7.7 (5.7–10.5) for the highest dose (~100,000 mg).
Other: Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Two large randomized controlled trials, ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (a study of diabetic nephropathy conducted by the Department of Veterans Affairs), evaluated the concomitant use of an angiotensin-converting enzyme inhibitor (ACE inhibitor) with an ARB II.
The ONTARGET trial included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.
These studies did not demonstrate significant beneficial effects on renal and/or cardiovascular function or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or arterial hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these findings are also relevant to other ACE inhibitors and ARBs II.
Therefore, concomitant use of ACE inhibitors and ARBs II is not recommended in patients with diabetic nephropathy (see section "Special precautions for use").
Additionally, the ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Endpoints), which evaluated the benefits of adding aliskiren to standard therapy (an ACE inhibitor or ARB II) in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both, was prematurely terminated due to an increased risk of adverse outcomes. Cardiovascular death and stroke occurred more frequently in the aliskiren group than in the placebo group; furthermore, adverse reactions, including serious ones (hyperkalemia, arterial hypotension, and renal function impairment), were more frequent in the aliskiren group than in the placebo group.
Pharmacokinetics.
Linearity
Amlodipine, valsartan, and hydrochlorothiazide exhibit linear pharmacokinetics.
Amlodipine/valsartan/hydrochlorothiazide
After oral administration of Vanatex AH to healthy adult volunteers, maximum plasma concentrations (Cmax) of amlodipine, valsartan, and hydrochlorothiazide were reached within 6–8 hours, 3 hours, and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan, and hydrochlorothiazide following administration of Vanatex AH are similar to those observed when the components are administered as individual agents.
Amlodipine
Absorption. After oral administration of amlodipine alone at therapeutic doses, Cmax is reached within 6–12 hours. Absolute bioavailability ranges from 64% to 80%. Food intake does not affect the bioavailability of amlodipine.
Distribution. The volume of distribution is approximately 21 L/kg. In vitro studies show that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Metabolism. Amlodipine is extensively metabolized (approximately 90%) in the liver to inactive metabolites.
Elimination. Amlodipine is eliminated from plasma in a biphasic manner, with a terminal half-life of approximately 30–50 hours. Steady-state plasma levels are achieved after 7–8 days of continuous dosing. About 10% of unchanged amlodipine and 60% of its metabolites are excreted in urine.
Valsartan
Absorption. After oral administration of valsartan alone, Cmax is reached within 2–4 hours. Mean absolute bioavailability is 23%. Food intake reduces the area under the plasma concentration-time curve (AUC) by approximately 40% and Cmax by approximately 50%, although valsartan concentrations 8 hours after dosing are similar in fasting and postprandial groups. However, this reduction in AUC does not result in clinically significant reduction in therapeutic effect; therefore, valsartan may be administered regardless of food intake.
Distribution. The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 liters, indicating limited tissue distribution. Valsartan is highly bound to serum proteins (94–97%), primarily to serum albumin.
Metabolism. Valsartan undergoes minimal transformation, with only about 20% of the dose excreted as metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of valsartan AUC). This metabolite is pharmacologically inactive.
Elimination. Valsartan is primarily excreted via feces (approximately 83% of dose) and urine (approximately 13% of dose), mainly as unchanged drug. After intravenous administration, plasma clearance of valsartan is approximately 2 L/hour, and renal clearance is 0.62 L/hour (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.
Hydrochlorothiazide
Absorption. Absorption of hydrochlorothiazide after oral administration is rapid (time to maximum concentration (Tmax) is approximately 2 hours). The increase in mean AUC is linear and proportional to dose within the therapeutic dose range. No changes in hydrochlorothiazide kinetics are observed upon repeated dosing, and accumulation is minimal with once-daily administration. Concurrent food intake may either increase or decrease systemic availability of hydrochlorothiazide compared to fasting, but the magnitude of these effects is minor and of limited clinical significance. Absolute bioavailability of hydrochlorothiazide after oral administration is 60–80%.
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 levels 1.8 times higher than in plasma.
Metabolism. Hydrochlorothiazide is excreted unchanged.
Elimination. More than 95% of the absorbed dose is excreted unchanged in urine. Renal clearance involves passive filtration and active tubular secretion. Elimination half-life ranges from 6 to 15 hours.
Special patient populations
Children (under 18 years of age)
There are no pharmacokinetic data available in children.
Elderly patients (aged 65 years and older)
Tmax of amlodipine is similar in younger and elderly patients. In elderly patients, amlodipine clearance tends to decrease, resulting in increased AUC and half-life. Mean systemic AUC of valsartan is 70% higher in elderly patients than in younger patients; therefore, dose escalation should be performed with caution in the elderly.
Valsartan AUC is slightly higher in elderly patients compared to younger patients, but this difference is not clinically significant.
Limited data suggest that systemic clearance of hydrochlorothiazide is reduced in both healthy elderly volunteers and elderly hypertensive patients compared to younger healthy volunteers.
Since all three components of the drug are similarly well tolerated in younger and elderly patients, the standard dosing regimen is recommended.
Renal impairment
Renal impairment does not significantly affect the pharmacokinetics of amlodipine. As expected for a drug with only 30% of total plasma clearance being renal, no correlation was observed between renal function and valsartan AUC. Therefore, patients with mild to moderate renal impairment may use the drug at the standard initial dose.
Hepatic impairment
In patients with hepatic impairment, amlodipine clearance is reduced, leading to an increase in AUC by approximately 40–60%. On average, valsartan AUC is twice as high in patients with mild to moderate chronic liver disease compared to healthy adult volunteers (matched for age, sex, and body weight). The drug should be used with caution in patients with hepatic disease.
The combination amlodipine/valsartan/hydrochlorothiazide has not been tested for genotoxicity and carcinogenicity, as no interaction signals were observed between these long-marketed agents. However, amlodipine, valsartan, and hydrochlorothiazide have each been individually tested for genotoxicity and carcinogenicity, yielding negative results.
Clinical characteristics.
Indications.
Treatment of essential hypertension in adult patients whose blood pressure is adequately controlled with the combination of amlodipine, valsartan, and hydrochlorothiazide, administered either as three separate medicinal products or as two medicinal products, one of which is a combination.
Contraindications.
- Hypersensitivity to the active substances, to other sulfonamides, to dihydropyridine derivatives, or to any excipient of the medicinal product.
- Pregnancy or planning pregnancy (see section "Use in pregnancy or breast-feeding").
- Hepatic impairment, biliary cirrhosis, or cholestasis.
- Severe renal impairment (GFR < 30 mL/min/1.73 m²), anuria, as well as dialysis.
- Concomitant use of the medicinal product Vanatex AH with medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²).
- Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
- Severe hypotension.
- Shock (including cardiogenic shock).
- Obstruction of the left ventricular outflow tract (e.g., hypertrophic obstructive cardiomyopathy and severe aortic stenosis).
- Hemodynamically unstable heart failure following acute myocardial infarction.
Interaction with other medicinal products and other forms of interaction.
Studies on the interaction of the medicinal product Vanatex AH with other medicinal products have not been conducted. Table 1 provides information only on interactions with other medicinal products known for each individual active substance.
However, it is important to consider that Vanatex AH may enhance the hypotensive effect of other antihypertensive medicinal products.
Table 1
| Concomitant use not recommended |
||
| Components of Vanatex AN |
Medicinal products and substances with which interactions exist |
Effect of interaction |
| Valsartan and hydrochlorothiazide |
Lithium |
Reversible increases in serum lithium concentration and toxicity have been reported during concomitant use of lithium with ACE inhibitors, angiotensin II receptor antagonists (including valsartan), or thiazides such as hydrochlorothiazide. Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may increase with Vanatex AN use. Therefore, careful monitoring of serum lithium levels is recommended during concomitant therapy. |
| Valasartan |
Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, and other medicinal products that may increase potassium levels |
If concomitant use of a medicinal product affecting potassium levels with valsartan is required, frequent monitoring of plasma potassium levels is recommended. |
| Amlodipine |
Grapefruit or grapefruit juice |
Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as bioavailability may increase in some patients, leading to enhanced antihypertensive effect. |
| Concomitant use requires caution |
||
| Components of Vanatex AN |
Medicinal products and substances with which interactions exist |
Effect of interaction |
| Amlodipine |
CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir) |
Studies in elderly patients have shown that diltiazem inhibits amlodipine metabolism, possibly via CYP3A4 (plasma concentration increases by approximately 50% and amlodipine effect is enhanced). It cannot be excluded that stronger CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir) may increase amlodipine plasma concentration more than diltiazem. Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in amlodipine exposure. Clinical manifestations of these pharmacokinetic changes may be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be required. |
| CYP3A4 inducers (anticonvulsants [e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone], rifampicin, St. John's wort) |
There are no data on the effect of CYP3A4 inducers on amlodipine. Concomitant use of CYP3A4 inducers (e.g., rifampicin, St. John's wort) may reduce amlodipine plasma concentration. Clinical monitoring with possible dose adjustment of amlodipine during and after treatment with an inducer is advised. Amlodipine should be used with caution together with CYP3A4 inducers. |
|
| Simvastatin |
Repeated doses of 10 mg amlodipine with 80 mg simvastatin increase simvastatin AUC by 77% compared to simvastatin alone. The daily dose of simvastatin should be reduced to 20 mg in patients taking amlodipine. |
|
| Dantrolene (infusions) |
Lethal cases due to ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed in animals after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and during treatment of malignant hyperthermia. |
|
| Valasartan and hydrochlorothiazide |
NSAIDs, including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and non-selective NSAIDs |
Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when used concomitantly. Additionally, concomitant use of Vanatex AN and NSAIDs may lead to worsening renal function and increased serum potassium levels. Therefore, monitoring of renal function at the start of treatment and adequate patient hydration are recommended. |
| Valasartan |
Uptake transporter inhibitors (rifampicin, cyclosporine) or efflux transporter inhibitors (ritonavir) |
In vitro studies using human liver tissue have shown that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Concomitant use of uptake transporter inhibitors (rifampicin, cyclosporine) or efflux transporter inhibitors (ritonavir) may increase valsartan AUC. |
| Hydrochlorothiazide |
Alcohol, barbiturates, or narcotic drugs |
Concomitant use of thiazide diuretics with substances that also lower blood pressure (e.g., those reducing central sympathetic activity or causing direct vasodilation) may enhance orthostatic hypotension. |
| Amantadine |
Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions caused by amantadine. |
|
| Anticholinergic drugs and other drugs affecting gastrointestinal motility |
Bioavailability of thiazide diuretics may be increased by anticholinergic drugs (e.g., atropine, biperiden), likely due to reduced gastrointestinal motility and delayed gastric emptying. Conversely, prokinetic agents such as cisapride may reduce bioavailability of thiazide diuretics. |
|
| Antidiabetic drugs (e.g., insulin and oral antidiabetics) |
Thiazides may alter glucose tolerance. Dose adjustments of insulin and oral hypoglycemic agents may be necessary. Metformin should be used with caution due to the risk of lactic acidosis potentially induced by functional renal impairment associated with hydrochlorothiazide use. |
|
| Beta-blockers and diazoxide |
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may enhance the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide. |
|
| Carbamazepine |
Hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Patients should be warned about the possibility of hyponatremic reactions and monitored accordingly. |
|
| Cyclosporine |
Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and complications of gouty type. |
|
| Cytotoxic drugs (e.g., cyclophosphamide, methotrexate) |
Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic drugs (e.g., cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects. |
|
| Cardiac glycosides |
Thiazide-induced hypokalemia or hypomagnesemia may lead to digoxin-induced cardiac arrhythmias as an adverse effect. |
|
| Iodine-containing contrast agents |
In cases of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high iodine doses. Rehydration should be performed before administration. |
|
| Ion-exchange resins |
Absorption of thiazide diuretics, including hydrochlorothiazide, is reduced by cholestyramine or colestipol. This may lead to subtherapeutic effects of thiazide diuretics. However, due to the interaction, hydrochlorothiazide should be administered at least 4 hours before or 4–6 hours after the resin to potentially minimize the interaction. |
|
| Medicinal products affecting potassium levels (potassium-wasting diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylate derivatives) and antiarrhythmic drugs |
The hypokalemic effect of hydrochlorothiazide may be enhanced by potassium-wasting diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylate derivatives, and antiarrhythmic drugs. If such drugs are prescribed with the amlodipine/valsartan/hydrochlorothiazide combination, monitoring of plasma potassium levels is recommended. |
|
| Medicinal products affecting sodium levels |
The hyponatremic effect of diuretics may be enhanced by antidepressants, antipsychotics, and antiepileptics when used concomitantly. Caution is required during prolonged use of these medicinal products. |
|
| Medicinal products that may cause torsades de pointes |
Due to the risk of hypokalemia, hydrochlorothiazide should be used cautiously with medicinal products that may cause torsades de pointes, particularly class Ia and class III antiarrhythmics, and some antipsychotics. |
|
| Medicinal products used to treat gout (probenecid, sulfinpyrazone, and allopurinol) |
Dose adjustment of uricosuric drugs may be necessary, as hydrochlorothiazide may increase serum uric acid levels. Dose increases of probenecid or sulfinpyrazone may be required. Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol. |
|
| Methyldopa |
Isolated reports of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa. |
|
| Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine) |
Thiazides, including hydrochlorothiazide, potentiate the effect of curare derivatives. |
|
| Other antihypertensive drugs |
Thiazides potentiate the antihypertensive effect of other antihypertensive drugs (e.g., guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers, and direct renin inhibitors). |
|
| Pressor amines (e.g., noradrenaline, adrenaline) |
Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is uncertain and insufficient to warrant discontinuation of their use. |
|
| Vitamin D and calcium salts |
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may potentiate increased serum calcium levels. Concomitant use of thiazide diuretics may lead to hypercalcemia (e.g., in hyperparathyroidism, malignancies, or vitamin D-mediated states) in susceptible patients due to increased tubular reabsorption of calcium. |
|
Dual blockade of the RAS with ACE inhibitors, ARAs II, or aliskiren
Clinical data have shown that dual blockade of the RAS by concomitant use of ACE inhibitors, ARAs II, or aliskiren is associated with an increased risk of adverse reactions such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to monotherapy with a RAS-acting agent.
Special precautions for use.
The safety and efficacy of amlodipine in hypertensive crisis have not been studied.
Patients with sodium deficiency and dehydration
Excessive hypotension, including orthostatic hypotension, was observed in 1.7% of patients receiving the maximum dose of Vanatex AH (10 mg/320 mg/25 mg), compared to 1.8% of patients receiving valsartan/hydrochlorothiazide (320 mg/25 mg), 0.4% of patients receiving amlodipine/valsartan (10 mg/320 mg), and 0.2% of patients receiving hydrochlorothiazide/amlodipine (25 mg/10 mg) in a controlled study involving patients with moderate or severe uncomplicated hypertension.
Symptomatic arterial hypotension may occur in patients with salt depletion and/or dehydration, particularly those on high-dose diuretic therapy, after initiation of Vanatex AH. Therefore, correction of such conditions is recommended prior to starting this medication, or careful monitoring is required at the beginning of treatment.
If pronounced arterial hypotension occurs during treatment with Vanatex AH, the patient should be placed in a supine position with elevated lower limbs. Intravenous infusion of physiological saline may be administered if necessary. Treatment may be continued once blood pressure has stabilized.
Changes in serum electrolyte levels
Amlodipine/valsartan/hydrochlorothiazide
In a controlled study of Vanatex AH, the opposing effects of 320 mg valsartan and 25 mg hydrochlorothiazide on serum potassium levels approximately balanced each other in many patients. In others, one or more of these effects may predominate.
Serum electrolyte levels should be periodically monitored to detect potential electrolyte imbalances.
Periodic assessment of serum electrolytes and potassium levels should be performed at appropriate intervals to prevent possible electrolyte imbalance, especially in patients with risk factors such as impaired renal function, concomitant medication use, or history of electrolyte imbalance.
Valsartan
Concomitant use with potassium-containing supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other drugs that may increase potassium levels (e.g., heparin) is not recommended. Serum potassium levels should be monitored if such combination therapy is necessary.
Hydrochlorothiazide
Hypokalemia has been reported during treatment with thiazide diuretics, including hydrochlorothiazide.
Initiation of Vanatex AH should occur only after correction of hypokalemia and any coexisting hypomagnesemia. Thiazide diuretics may cause or exacerbate hypokalemia and should therefore be used cautiously in patients with conditions involving potassium loss, such as salt-wasting nephropathy or prerenal (cardiogenic) renal dysfunction. If hypokalemia develops during hydrochlorothiazide therapy, Vanatex AH should be discontinued until potassium balance is stably corrected.
Treatment with thiazide diuretics, including hydrochlorothiazide, is associated with the development of hyponatremia and hypochloremic alkalosis or worsening of pre-existing hyponatremia. Hyponatremia may present with neurological symptoms (nausea, progressive disorientation, apathy). Treatment with hydrochlorothiazide should only be initiated after correction of existing hyponatremia. In cases of severe or rapidly developing hyponatremia during Vanatex AH therapy, treatment should be discontinued until sodium levels normalize. Thiazides, including hydrochlorothiazide, increase urinary magnesium excretion, potentially leading to hypomagnesemia. Thiazide diuretics reduce calcium excretion, which may result in hypercalcemia.
All patients receiving thiazide diuretics should undergo periodic monitoring of electrolyte levels, particularly potassium, sodium, and magnesium.
Renal impairment
Thiazide diuretics may accelerate azotemia in patients with chronic kidney disease.
Periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended in patients with renal impairment receiving Vanatex AH. This medicinal product is contraindicated in patients with severe renal impairment, anuria, and those undergoing dialysis.
Dose adjustment of Vanatex AH is not required in patients with mild to moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m²).
Renal artery stenosis
Vanatex AH should be used with caution in the treatment of arterial hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, as serum urea and creatinine levels may increase.
Kidney transplantation
There is currently no information on the safety of Vanatex AH in patients who have recently undergone kidney transplantation.
Hepatic impairment
Valsartan is primarily excreted unchanged in bile. The elimination half-life of amlodipine is prolonged and AUC increased in patients with hepatic impairment; dosing recommendations are not established. For patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose of valsartan is 80 mg. Therefore, Vanatex AH is not indicated for this patient group.
Angioedema
Angioedema, including laryngeal and glottal edema that may lead 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 ACE inhibitors. If angioedema occurs, Vanatex AH should be discontinued immediately and re-administration is not recommended.
Intestinal angioedema
Intestinal angioedema has been reported in patients receiving angiotensin II receptor antagonists, including valsartan (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, valsartan should be discontinued and appropriate monitoring initiated until symptoms completely resolve.
Heart failure and coronary artery disease/post-myocardial infarction state
Due to suppression of the RAAS, renal dysfunction may be expected in sensitive patients. In patients with severe heart failure, in whom renal function may depend on RAAS activity, treatment with ACE inhibitors and angiotensin receptor antagonists may lead to oliguria and/or progressive azotemia (rarely) with acute renal failure and/or fatal outcomes. Similar outcomes have been reported with valsartan. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.
In a long-term placebo-controlled study of amlodipine (PRAISE-2) in patients with NYHA (New York Heart Association) class III and IV non-ischemic heart failure, the incidence of pulmonary edema was higher with amlodipine, despite a minimal difference in the development or worsening of heart failure compared to placebo.
Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular events and mortality.
Vanatex AH should be prescribed with caution, particularly at the maximum dose of 10 mg/320 mg/25 mg, in patients with heart failure and coronary artery disease, as data on use in this patient group are limited.
Aortic and mitral valve stenosis
As with other vasodilators, Vanatex AH should be used with particular caution in patients with low-grade aortic or mitral valve stenosis.
Pregnancy
Treatment with ARAs II should not be initiated during pregnancy. If continued ARAs II therapy is necessary, patients planning pregnancy should switch to alternative antihypertensive agents with established safety profiles during pregnancy. If pregnancy occurs, ARAs II therapy should be discontinued immediately and alternative therapy initiated if needed.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan, as the renin-angiotensin system is not activated in these patients. Therefore, Vanatex AH is not recommended for this patient group.
Systemic lupus erythematosus
Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.
Other metabolic disturbances
Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and increase serum cholesterol, triglycerides, and uric acid levels. Dose adjustments of insulin or oral hypoglycemic agents may be necessary in patients with diabetes.
Since Vanatex AH contains hydrochlorothiazide, it is contraindicated in systemic hyperuricemia. Hydrochlorothiazide may increase serum uric acid levels due to reduced uric acid clearance and may precipitate hyperuricemia or acute gout attacks in susceptible patients.
Thiazides may reduce calcium excretion in urine and cause transient, mild increases in serum calcium levels in the absence of known calcium metabolism disorders. Vanatex AH should be discontinued if hypercalcemia develops during treatment. Serum calcium levels should be monitored periodically during thiazide therapy. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide therapy should be discontinued before parathyroid function testing.
Photosensitivity
Cases of photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reactions occur during Vanatex AH therapy, discontinuation is recommended. If resumption of diuretic therapy is considered necessary, protection of exposed skin from sunlight or artificial ultraviolet radiation is advised.
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma
Sulfonamide-containing or sulfonamide-derivative drugs may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and typically occur within hours to weeks of starting therapy.
Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, medical or surgical intervention may be required. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
General
Vanatex AH should be prescribed with caution in patients with a history of hypersensitivity to other ARAs II. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies or asthma.
Elderly patients (aged 65 years and older)
Vanatex AH should be prescribed with caution, particularly with frequent blood pressure monitoring, in elderly patients, especially at the maximum dose of 10 mg/320 mg/25 mg, as data on use in this patient group are limited.
Dual blockade of the RAAS
Evidence indicates that concomitant use of ACE inhibitors, ARAs II, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure).
Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, ARAs II, or aliskiren is not recommended.
If dual RAAS blockade is required, it should be performed under close specialist supervision with continuous monitoring of renal function, electrolyte levels, and blood pressure. Concomitant use of ACE inhibitors and ARAs II is not recommended in patients with diabetic nephropathy.
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. These patients should regularly examine their skin for new lesions and promptly report any suspicious changes. Preventive measures to minimize skin cancer risk, such as limiting sun and ultraviolet exposure and using adequate protection when exposed to sunlight, should be considered. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsies. The use of hydrochlorothiazide should also be reconsidered in patients with a history of NMSC.
Acute respiratory toxicity
Very rare, severe cases of acute respiratory toxicity, sometimes progressing to acute respiratory distress syndrome (ARDS), have been reported during hydrochlorothiazide therapy. Pulmonary edema may develop within minutes or hours after hydrochlorothiazide administration. Precursor symptoms include dyspnea, fever, and worsening pulmonary function. In such cases, hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients with a history of ARDS following hydrochlorothiazide use.
Use during pregnancy or breastfeeding
Pregnancy
Amlodipine
Studies on the safety of amlodipine during pregnancy have not been conducted. Reproductive toxicity was observed in animal studies at high doses. Use during pregnancy is recommended only if no safer alternative is available and if the condition poses greater risk to the mother and fetus.
Valsartan
This medicinal product is contraindicated in pregnant women and women planning pregnancy. If pregnancy is confirmed during treatment, the drug should be discontinued immediately and replaced with another agent approved for use in pregnancy.
Hydrochlorothiazide
Experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Animal data are insufficient.
Hydrochlorothiazide crosses the placenta. Its pharmacological mechanism suggests that use during the second and third trimesters may impair fetoplacental perfusion and cause fetal and neonatal adverse effects such as jaundice, electrolyte imbalances, and thrombocytopenia, and may be associated with other adverse reactions observed in adults.
Amlodipine/valsartan/hydrochlorothiazide
There is no experience with Vanatex AH use in pregnant women. Based on available data on the components, use of this medicinal product is contraindicated.
Breastfeeding period
Amlodipine is excreted in breast milk. The fraction of maternal dose received by the infant is estimated at an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on the infant is unknown. Information on valsartan use during breastfeeding is lacking. Hydrochlorothiazide is detected in breast milk in small amounts. High-dose thiazides causing strong diuresis may interfere with breast milk production.
The use of Vanatex AH is contraindicated during breastfeeding.
Fertility
No clinical studies on the effect of Vanatex AH on fertility have been conducted.
Valsartan
Valsartan had no adverse effect on reproductive function in male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose based on mg/m² (calculations assume an oral dose of 320 mg daily for a 60 kg patient).
Amlodipine
Reversible biochemical changes in sperm heads have been reported in some patients receiving calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. An adverse effect on male fertility was observed in one rat study.
Ability to affect reaction speed when driving or operating machinery
Dizziness or weakness may occur in patients taking Vanatex AH; therefore, patients should take this into account when driving or operating potentially hazardous machinery.
Amlodipine may have a slight or moderate effect on the ability to drive or operate machinery. If patients experience dizziness, headache, fatigue, or nausea while taking amlodipine, their reaction time may be impaired.
Method of administration
Vanatex AH can be taken regardless of food intake. Tablets should be swallowed whole with water at the same time each day, preferably in the morning.
Dosage
The recommended dose of Vanatex AH is 1 tablet daily, preferably taken in the morning.
Prior to switching to Vanatex AH, the patient's condition should be monitored on stable doses of the concurrently used monotherapy agents. The dose of Vanatex AH should correspond to the doses of the individual components in the combination at the time of the switch.
The maximum recommended dose of Vanatex AH is 10 mg/320 mg/25 mg.
Special patient groups
Renal impairment
Since Vanatex AH contains hydrochlorothiazide, it is contraindicated in patients with anuria and severe renal impairment (eGFR < 30 mL/min/1.73 m²).
Dose adjustment is not required in patients with mild to moderate renal impairment.
Hepatic impairment
Since Vanatex AH contains valsartan, it is contraindicated in patients with severe hepatic impairment. For patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose of valsartan is 80 mg; therefore, Vanatex AH is not indicated for this patient group. Dosing recommendations for amlodipine in patients with mild to moderate hepatic impairment have not been established. When switching hypertensive patients with hepatic impairment to Vanatex AH, the lowest available dose of amlodipine should be used.
Heart failure and coronary artery disease
Experience with Vanatex AH, particularly at maximum doses, in patients with heart failure and coronary artery disease is limited. Vanatex AH should be used with caution, especially at the maximum dose of 10 mg/320 mg/25 mg, in these patients.
Elderly patients (aged 65 years and older)
Vanatex AH should be prescribed with caution, particularly with frequent blood pressure monitoring, in elderly patients, especially at the maximum dose of 10 mg/320 mg/25 mg, as data on use in this patient group are limited. When switching elderly patients to Vanatex AH, the lowest available dose of amlodipine should be used.
Paediatric population
There are no adequate data on the use of Vanatex AH in paediatric patients (children under 18 years) for the indication of arterial hypertension.
Children
Safety and efficacy of the medicinal product in children have not been established; therefore, it is not used in this age group.
Overdose.
Symptoms
There are no data on overdose with Vanatex AH. The main symptom of overdose is likely to be pronounced arterial hypotension with dizziness. Amlodipine overdose may lead to marked peripheral vasodilation and possibly reflex tachycardia. Marked and potentially prolonged systemic hypotension, including shock with fatal outcome, has been reported.
Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose, which may have a delayed onset (24–48 hours after ingestion) and require mechanical ventilation, have been reported. Early resuscitation measures (including fluid overload) to support perfusion and cardiac output may be precipitating factors.
Treatment
Amlodipine/valsartan/hydrochlorothiazide
Clinically significant arterial hypotension due to Vanatex AH overdose requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of lower limbs, monitoring of circulating blood volume and diuresis. Vasoconstrictors may be used to restore vascular tone and blood pressure, provided there are no contraindications. Intravenous calcium gluconate may be effective in reversing calcium channel blockade effects.
Amlodipine
If ingestion occurred recently, induction of emesis or gastric lavage should be considered. Administration of activated charcoal immediately or 2 hours after amlodipine intake significantly reduces amlodipine absorption in healthy volunteers.
Amlodipine is unlikely to be removed by hemodialysis.
Valsartan
Valsartan is unlikely to be removed by hemodialysis.
Hydrochlorothiazide
Hydrochlorothiazide overdose is associated with electrolyte depletion (hypokalemia, hypochloremia) and hypovolemia due to excessive diuresis. The most common symptoms are nausea and somnolence. Hypokalemia may lead to muscle cramps and/or exacerbation of arrhythmias associated with concomitant use of digitalis glycosides or certain antiarrhythmic drugs.
The extent to which hydrochlorothiazide is removed by hemodialysis has not been established.
Adverse reactions
The safety profile of Vanatex AH presented below is based on clinical studies of the drug and the known safety profiles of its individual components: amlodipine, valsartan, and hydrochlorothiazide.
Summary of safety profile
The safety of Vanatex AH was evaluated at the maximum dose of 10 mg/320 mg/25 mg in a controlled short-term (8-week) clinical study involving 2271 patients, of whom 582 received valsartan in combination with amlodipine and hydrochlorothiazide. Adverse reactions were generally mild and transient and rarely required discontinuation of therapy. In this active-controlled clinical study, the most common reasons for discontinuation with Vanatex AH were dizziness and hypotension (0.7%).
In the 8-week controlled clinical study, no significant new or unexpected adverse reactions were observed with triple therapy compared to the known effects of monotherapy or dual therapy with the drug's components.
In the 8-week controlled clinical study, laboratory parameter changes observed with Vanatex AH were minor and consistent with the pharmacological mechanisms of action of the individual monotherapeutic agents. The presence of valsartan in the triple combination attenuates the hypokalemic effect of hydrochlorothiazide.
Adverse reactions listed in Table 2 by organ system classes (MedDRA) and frequency are presented for the medicinal product Vanatex AH (amlodipine/valsartan/hydrochlorothiazide) as well as separately for amlodipine, valsartan, and hydrochlorothiazide:
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).
Table 2
| System organ classes (MedDRA) |
Adverse reactions |
Frequency |
|||
| Vanatex AN |
Amlodipine |
Valsartan |
Hydrochloro- thiazide |
||
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
NMSC (basal cell carcinoma and squamous cell carcinoma) |
-- |
-- |
-- |
Frequency unknown |
| Blood and lymphatic system disorders |
Agranulocytosis, bone marrow depression |
-- |
-- |
-- |
Very rare |
| Decreased hemoglobin and hematocrit levels |
-- |
-- |
Frequency unknown |
-- |
|
| Hemolytic anemia |
-- |
-- |
-- |
Very rare |
|
| Leukopenia |
-- |
Very rare |
-- |
Very rare |
|
| Neutropenia |
-- |
-- |
Frequency unknown |
-- |
|
| Thrombocytopenia, sometimes with purpura |
-- |
Very rare |
Frequency unknown |
Rare |
|
| Aplastic anemia |
-- |
-- |
-- |
Frequency unknown |
|
| Immune system disorders |
Hypersensitivity |
-- |
Very rare |
Frequency unknown |
Very rare |
| Metabolism and nutrition disorders |
Anorexia |
Uncommon |
-- |
-- |
-- |
| Hypercalcemia |
Uncommon |
-- |
-- |
Rare |
|
| Hyperglycemia |
-- |
Very rare |
-- |
Rare |
|
| Hyperlipidemia |
Uncommon |
-- |
-- |
-- |
|
| Hyperuricemia |
Uncommon |
-- |
-- |
Common |
|
| Hyperchloremic alkalosis |
-- |
-- |
-- |
Very rare |
|
| Hypokalemia |
Common |
-- |
-- |
Very common |
|
| Hypomagnesemia |
-- |
-- |
-- |
Common |
|
| Hyponatremia |
Uncommon |
-- |
-- |
Common |
|
| Worsening of metabolic signs of diabetes |
-- |
-- |
-- |
Rare |
|
| Psychiatric disorders |
Depression |
-- |
Uncommon |
-- |
Rare |
| Insomnia/sleep disturbance |
Uncommon |
Uncommon |
-- |
Rare |
|
| Mood changes |
-- |
Uncommon |
-- |
||
| Apathy |
-- |
Rare |
-- |
-- |
|
| Nervous system disorders |
Coordination disorders |
Uncommon |
-- |
-- |
-- |
| Dizziness |
Common |
Common |
-- |
Rare |
|
| Postural dizziness, effort dizziness |
Uncommon |
-- |
-- |
-- |
|
| Dysgeusia |
Uncommon |
Uncommon |
-- |
-- |
|
| Extrapyramidal syndrome |
-- |
Frequency unknown |
-- |
-- |
|
| Headache |
Common |
Common |
-- |
Rare |
|
| Arterial hypertension |
-- |
Very rare |
-- |
-- |
|
| Lethargy |
Uncommon |
-- |
-- |
-- |
|
| Paresthesia |
Uncommon |
Uncommon |
-- |
Rare |
|
| Peripheral neuropathy, neuropathy |
Uncommon |
Very rare |
-- |
-- |
|
| Somnolence |
Uncommon |
Common |
-- |
-- |
|
| Syncope |
Uncommon |
Uncommon |
-- |
-- |
|
| Tremor |
-- |
Uncommon |
-- |
-- |
|
| Hypoesthesia |
-- |
Uncommon |
-- |
-- |
|
| Eye disorders |
Visual disturbance |
Uncommon |
Uncommon |
-- |
Rare |
| Visual disorders |
-- |
Uncommon |
-- |
-- |
|
| Acute angle-closure glaucoma |
-- |
-- |
-- |
Frequency unknown |
|
| Choroidal effusion |
Frequency unknown |
||||
| Ear and labyrinth disorders |
Tinnitus |
-- |
Uncommon |
-- |
-- |
| Vertigo |
Uncommon |
-- |
Uncommon |
-- |
|
| Cardiac disorders |
Palpitations |
-- |
Common |
-- |
-- |
| Tachycardia |
Uncommon |
-- |
-- |
-- |
|
| Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) |
-- |
Very rare |
-- |
Rare |
|
| Myocardial infarction |
-- |
Very rare |
-- |
-- |
|
| Vascular disorders |
Flushing |
-- |
Common |
-- |
-- |
| Arterial hypotension |
Common |
Uncommon |
-- |
-- |
|
| Orthostatic hypotension |
Uncommon |
-- |
-- |
Common |
|
| Phlebitis, thrombophlebitis |
Uncommon |
-- |
-- |
-- |
|
| Vasculitis |
-- |
Very rare |
Frequency unknown |
-- |
|
| Respiratory, thoracic and mediastinal disorders |
Cough |
Uncommon |
Very rare |
Uncommon |
|
| Dyspnea |
Uncommon |
Uncommon |
-- |
-- |
|
| Acute respiratory distress syndrome (ARDS), pulmonary edema, pneumonitis |
-- |
-- |
-- |
Very rare |
|
| Rhinitis |
-- |
Uncommon |
-- |
-- |
|
| Throat irritation |
Uncommon |
-- |
-- |
-- |
|
| Gastrointestinal disorders |
Abdominal discomfort, upper abdominal pain |
Uncommon |
Common |
Uncommon |
Rare |
| Very rare: intestinal angioedema. |
-- |
-- |
Very rare |
-- |
|
| Unpleasant breath odor |
Uncommon |
-- |
-- |
-- |
|
| Change in defecation frequency |
-- |
Uncommon |
-- |
-- |
|
| Constipation |
-- |
-- |
-- |
Rare |
|
| Decreased appetite |
-- |
-- |
-- |
Common |
|
| Diarrhea |
Uncommon |
Uncommon |
-- |
Rare |
|
| Dry mouth |
Uncommon |
Uncommon |
-- |
-- |
|
| Dyspepsia |
Common |
Uncommon |
-- |
-- |
|
| Gastritis |
-- |
Very rare |
-- |
-- |
|
| Gingival hyperplasia |
-- |
Very rare |
-- |
-- |
|
| Nausea |
Uncommon |
Common |
-- |
Common |
|
| Pancreatitis |
-- |
Very rare |
-- |
Very rare |
|
| Vomiting |
Uncommon |
Uncommon |
-- |
Common |
|
| Hepatobiliary disorders |
Elevated liver enzymes, including increased serum bilirubin levels |
-- |
Very rare* |
Frequency unknown |
-- |
| Hepatitis |
-- |
Very rare |
-- |
-- |
|
| Intrahepatic cholestasis, jaundice |
-- |
Very rare |
-- |
Rare |
|
| Skin and subcutaneous tissue disorders |
Alopecia |
-- |
Uncommon |
-- |
-- |
| Angioedema |
-- |
Very rare |
Frequency unknown |
-- |
|
| Bullous dermatitis |
-- |
-- |
Frequency unknown |
-- |
|
| Skin reactions resembling lupus erythematosus, reactivation of cutaneous lupus erythematosus |
-- |
-- |
-- |
Very rare |
|
| Erythema multiforme |
-- |
Very rare |
-- |
Frequency unknown |
|
| Exanthema |
-- |
Uncommon |
-- |
-- |
|
| Hyperhidrosis |
Uncommon |
Uncommon |
-- |
-- |
|
| Photosensitivity reactions |
-- |
Very rare |
-- |
Rare |
|
| Pruritus |
Uncommon |
Uncommon |
Frequency unknown |
-- |
|
| Purpura |
-- |
Uncommon |
-- |
Rare |
|
| Rash |
-- |
Uncommon |
Frequency unknown |
Common |
|
| Skin color changes |
-- |
Uncommon |
-- |
-- |
|
| Urticaria |
-- |
Very rare |
-- |
Common |
|
| Necrotizing vasculitis and toxic epidermal necrolysis |
-- |
Frequency unknown |
-- |
Very rare |
|
| Exfoliative dermatitis |
-- |
Very rare |
-- |
-- |
|
| Stevens-Johnson syndrome |
-- |
Very rare |
-- |
-- |
|
| Quincke's edema |
-- |
Very rare |
-- |
-- |
|
| Musculoskeletal and connective tissue disorders |
Arthralgia |
-- |
Uncommon |
-- |
-- |
| Back pain |
Uncommon |
Uncommon |
-- |
-- |
|
| Joint swelling |
Uncommon |
-- |
-- |
-- |
|
| Muscle cramps |
Uncommon |
Uncommon |
-- |
Frequency unknown |
|
| Muscle weakness |
Uncommon |
-- |
-- |
-- |
|
| Myalgia |
Uncommon |
Uncommon |
Frequency unknown |
-- |
|
| Limb pain |
Uncommon |
-- |
-- |
-- |
|
| Ankle swelling |
-- |
Common |
-- |
-- |
|
| Renal and urinary disorders |
Elevated serum creatinine levels |
Uncommon |
-- |
Frequency unknown |
-- |
| Urinary disorders |
Uncommon |
||||
| Nocturia |
-- |
Uncommon |
-- |
-- |
|
| Polyuria |
Common |
Uncommon |
-- |
-- |
|
| Renal dysfunction |
-- |
-- |
-- |
Frequency unknown |
|
| Acute renal failure |
Uncommon |
-- |
-- |
Frequency unknown |
|
| Renal failure and impaired kidney function |
-- |
-- |
Frequency unknown |
Rare |
|
| Reproductive system and breast disorders |
Impotence |
Uncommon |
Uncommon |
-- |
Common |
| Gynecomastia |
-- |
Uncommon |
-- |
-- |
|
| General disorders and administration site conditions |
Akinesia, gait disturbance |
Uncommon |
-- |
-- |
-- |
| Asthenia |
Uncommon |
Uncommon |
-- |
Frequency unknown |
|
| Discomfort, malaise |
Uncommon |
Uncommon |
-- |
-- |
|
| Weakness |
Common |
Common |
Uncommon |
-- |
|
| Non-cardiac chest pain |
Uncommon |
Uncommon |
-- |
-- |
|
| Edema |
Common |
Common |
-- |
-- |
|
| Chills |
-- |
-- |
-- |
Frequency unknown |
|
| Pain |
-- |
Uncommon |
-- |
-- |
|
| Investigations |
Elevated lipid levels |
-- |
Very common |
||
| Elevated blood urea nitrogen |
Uncommon |
-- |
-- |
-- |
|
| Elevated blood uric acid levels |
Uncommon |
-- |
-- |
-- |
|
| Glucosuria |
Rare |
||||
| Decreased blood potassium levels |
Uncommon |
-- |
-- |
-- |
|
| Elevated blood potassium levels |
-- |
-- |
Frequency unknown |
-- |
|
| Increased body weight |
Uncommon |
Uncommon |
-- |
-- |
|
| Decreased body weight |
-- |
Uncommon |
-- |
-- |
|
*More associated with cholestasis.
Non-melanoma skin cancer: based on available data from epidemiological studies, there is a cumulative dose-response relationship between the use of hydrochlorothiazide and the development of NMSC.
Shelf life. 2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 30 °C.
Keep out of the reach of children.
Packaging.
7 film-coated tablets in a blister; 2 blisters in a cardboard box.
14 film-coated tablets in a blister; 1 or 2 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer. Pharmaceutical Works «POLPHARMA» S.A.
Pharmaceutical Works «POLPHARMA» S.A.
Manufacturer's address and place of business.
19, Pelplinska Str., 83-200 Starogard Gdanski, Poland.