Vanatex combi
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VANATEX COMBI
Composition:
Active substances: valsartan, hydrochlorothiazide;
One film-coated 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.
Excipients:
Core: lactose monohydrate, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating of 80 mg/12.5 mg tablet (Mixture for coating the tablets – Type 2): hypromellose, polyethylene glycol 400, titanium dioxide (E 171), iron oxide red (E 172);
Coating of 160 mg/12.5 mg tablet (Mixture for coating the tablets – Type 3): hypromellose, polyethylene glycol 400, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172), iron oxide black (E 172);
Coating of 160 mg/25 mg tablet (Mixture for coating the tablets – Type 4): hypromellose, polyethylene glycol 400, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172), iron oxide black (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
80 mg/12.5 mg: pink, elongated, biconvex film-coated tablets;
160 mg/12.5 mg: reddish-brown, elongated, biconvex film-coated tablets;
160 mg/25 mg: light brown, elongated, biconvex film-coated tablets.
Pharmacotherapeutic group.
Angiotensin II receptor blockers (AT1-receptor blockers) and diuretics.
ATC code C09D A03.
Pharmacological properties.
Pharmacodynamics.
Valsartan
Valsartan is an orally active and specific antagonist of angiotensin II (Ang II) receptors. It selectively acts on the AT1 receptor subtype, which mediates the known effects of angiotensin II. Increased plasma Ang II levels following AT1 receptor blockade by valsartan may stimulate unblocked AT2 receptors, which are likely to counteract the effects of AT1 receptors. Valsartan does not exhibit partial agonist activity at the AT1 receptor and has significantly greater affinity for the AT1 receptor than for the AT2 receptor. Valsartan does not inhibit angiotensin-converting enzyme (ACE) (also known as kininase II), which converts Ang I to Ang II and degrades bradykinin. In clinical studies comparing valsartan with ACE inhibitors, the incidence of dry cough was significantly lower (P < 0.05) in patients receiving valsartan than in those treated with an ACE inhibitor (2.6% vs. 7.9%). In a clinical study involving patients with a history of dry cough during ACE inhibitor therapy, cough occurred in 19.5% of subjects receiving valsartan and 19% of those receiving a thiazide diuretic, compared to 68.5% of patients treated with an ACE inhibitor (P < 0.05).
Administration of valsartan to patients with essential hypertension results in a reduction in blood pressure without affecting pulse rate. In most patients, antihypertensive activity begins within 2 hours after a single oral dose, with maximal blood pressure reduction achieved within 4–6 hours. The antihypertensive effect persists for 24 hours after dosing. With repeated dosing, maximal blood pressure reduction at any dose is generally achieved within 2–4 weeks and is maintained during long-term treatment. When combined with hydrochlorothiazide, an additional significant reduction in blood pressure is achieved.
In hypertensive patients with type 2 diabetes and microalbuminuria, valsartan has been shown to reduce urinary albumin excretion.
Conclusion: 160–320 mg of valsartan leads to a clinically significant reduction in UAE in patients with hypertension and type 2 diabetes.
Hydrochlorothiazide
The primary site of action of thiazide diuretics is the distal convoluted tubules of the kidney. A high-affinity receptor in the renal cortex has been demonstrated, which serves as the main binding site for thiazide diuretics and mediates inhibition of sodium chloride (NaCl) transport in the distal convoluted tubules. The mechanism of action of thiazides involves inhibition of the Na+/Cl− cotransporter, possibly by competing for the Cl− binding site, thereby directly increasing the excretion of sodium and chloride to a similar extent, and indirectly, through this diuretic effect, reducing plasma volume, which leads to increased plasma renin activity, aldosterone secretion, urinary potassium loss, and decreased plasma potassium levels. The renin-aldosterone axis is mediated by angiotensin II; therefore, when valsartan is co-administered, the reduction in plasma potassium is less pronounced than with hydrochlorothiazide monotherapy.
Pharmacokinetics.
Systemic bioavailability of hydrochlorothiazide is reduced by approximately 30% when administered concomitantly with valsartan. Co-administration of hydrochlorothiazide does not significantly affect the pharmacokinetics of valsartan. This interaction does not impact the efficacy of the combination of valsartan and hydrochlorothiazide, as controlled clinical trials have demonstrated a clear antihypertensive effect of this combination, which exceeds that of either active component alone and that of placebo.
Valsartan
Absorption
Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached within 2–4 hours. The mean absolute bioavailability is 23%. Food decreases exposure by approximately 50%.
Distribution
The apparent volume of distribution of valsartan after intravenous administration is approximately 17 liters, indicating that valsartan is not extensively distributed into tissues. Valsartan is highly bound to plasma proteins (94–97%), primarily to serum albumins.
Metabolism
Valsartan is not extensively metabolized, as only about 20% of the dose is recovered as metabolites.
Elimination
Valsartan exhibits multi-exponential decay kinetics (t½α < 1 hour and t½ß approximately 9 hours). Valsartan is primarily eliminated via feces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug. After intravenous administration, the 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
Following oral administration, hydrochlorothiazide is rapidly absorbed (tmax approximately 2 hours), with similar absorption characteristics for both suspensions and tablets. Absolute bioavailability of hydrochlorothiazide is 60–80% after oral administration.
Distribution
Distribution and elimination kinetics are generally described by a bi-exponential decay function. The expected volume of distribution is 4–8 L/kg.
Distributed hydrochlorothiazide is bound to plasma proteins (40–70%), primarily to serum albumins.
Elimination
With regard to hydrochlorothiazide, >95% of the absorbed dose is excreted unchanged in urine. Renal clearance involves passive filtration and active secretion in the renal tubules. Elimination half-life ranges from 6 to 15 hours.
Special patient populations
Elderly patients
Limited data indicate that total clearance of hydrochlorothiazide is reduced in both healthy volunteers and elderly hypertensive patients compared to younger healthy volunteers.
Renal impairment
Dose adjustment of Vanatex Combi is not required in patients with creatinine clearance of 30–70 mL/min.
There are no data on the use of Vanatex Combi in patients with severe renal impairment (creatinine clearance < 30 mL/min) or in patients undergoing dialysis. Valsartan is highly protein-bound and is not effectively removed by dialysis, whereas hydrochlorothiazide can be removed by dialysis.
Renal clearance of hydrochlorothiazide involves passive filtration and active tubular secretion. As expected for a drug that is almost exclusively eliminated by the kidneys, renal function significantly affects the pharmacokinetics of hydrochlorothiazide.
Hepatic impairment
In a pharmacokinetic study in patients with mild (n=6) and moderate (n=5) hepatic dysfunction, exposure to valsartan was approximately twice higher than in healthy volunteers.
There are no data on the use of valsartan in patients with severe hepatic dysfunction. Liver disease does not significantly affect the pharmacokinetics of hydrochlorothiazide.
Non-melanoma skin cancer
Results from two recent pharmacoepidemiological studies using Danish nationwide data sources showed a cumulative dose-dependent association between HCTZ use and the occurrence of basal cell carcinoma and squamous cell carcinoma. One study [1] included a cohort of 71,533 patients with basal cell carcinoma (BCC) and 8,629 patients with squamous cell carcinoma (SCC), compared with 1,430,833 and 172,462 control subjects, respectively. High use of HCTZ (≥ 50,000 mg cumulative) was associated with an adjusted risk ratio (RR) of 1.29 (95% confidence interval (CI): 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A cumulative dose-effect relationship was observed for both BCC and SCC. For example, a cumulative dose of 50,000 mg corresponds to daily use of 12.5 mg HCTZ for approximately 11 years.
Another study [2] showed a possible association between lip cancer (SCC) and HCTZ use: 633 patients with lip cancer (SCC) were compared with 63,067 control subjects using a nested case-control design. A cumulative dose-effect relationship was demonstrated, with an adjusted RR of 2.1 (95% CI: 1.7–2.6) for overall use, increasing to RR 3.9 (3.0–4.9) for high use (~25,000 mg), and RR 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see section "Special precautions for use").
Clinical characteristics.
Indications.
Arterial hypertension in patients whose blood pressure is not adequately controlled with monotherapy using valsartan or hydrochlorothiazide.
Contraindications.
- Hypersensitivity to valsartan, hydrochlorothiazide, other sulfonamide-derived drugs, or to any of the excipients.
- Severe hepatic impairment, hepatic cirrhosis, and cholestasis.
- Severe renal impairment (creatinine clearance < 30 mL/min), anuria.
- Persistent hypokalemia, hyponatremia, hypercalcemia, and symptomatic hyperuricemia.
- Pregnant women or women planning to become pregnant (see "Use in pregnancy or breastfeeding").
- Concomitant use of angiotensin receptor antagonists or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in patients with diabetes mellitus or renal dysfunction (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²).
Interaction with other medicinal products and other forms of interaction.
Interactions associated with both valsartan and hydrochlorothiazide
Concomitant use not recommended
Lithium
Reversible increases in plasma lithium concentrations and symptoms of lithium toxicity have been reported with concomitant use of ACE inhibitors and thiazide diuretics, including hydrochlorothiazide. Due to lack of experience with the concomitant use of valsartan and lithium, this combination is not recommended. If such a combination is necessary, careful monitoring of plasma lithium levels is recommended.
Concomitant use requiring caution
Other antihypertensive agents
Vanatex Combi may enhance the effect of other antihypertensive agents (e.g., ACE inhibitors, beta-blockers, calcium channel blockers).
Pressor amines (e.g., noradrenaline, adrenaline)
A reduced response to pressor amines may occur, although not sufficient to preclude their use.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid > 3 g/day, and nonselective NSAIDs
NSAIDs may reduce the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when used concomitantly. Additionally, concomitant use of Vanatex Combi and NSAIDs may lead to worsening of renal function and increased plasma potassium levels. Therefore, monitoring of renal function at the start of treatment and adequate patient hydration are recommended.
Interactions associated with valsartan
Dual blockade of the renin-angiotensin system (RAS)
Clinical studies indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of adverse reactions such as hypotension, hyperkalemia, and renal dysfunction (including acute renal failure), compared to use of any single agent (see sections "Contraindications", "Special precautions for use", and "Pharmacodynamics").
Concomitant use not recommended
Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, and other substances that may increase potassium levels
If use of a medicinal product affecting potassium levels is considered necessary in combination with valsartan, monitoring of plasma potassium levels is recommended.
Transporters
In vitro studies indicate that valsartan is a substrate of the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance 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 safety measures should be observed when initiating or discontinuing concomitant use of these medicinal products.
Absence of interaction
In drug interaction studies, no clinically significant interactions were observed between valsartan and any of the following agents: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glipizide. Digoxin and indomethacin may interact with the hydrochlorothiazide component of Vanatex Combi (see "Interactions associated with hydrochlorothiazide").
Interactions associated with hydrochlorothiazide
Concomitant use requiring caution
Medicinal products associated with potassium loss and hypokalemia (e.g., potassium-wasting diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid, and derivatives).
If these medicinal products must be co-administered with the combination of hydrochlorothiazide and valsartan, monitoring of plasma potassium levels is recommended. These agents may potentiate the effect of hydrochlorothiazide on plasma potassium levels.
Medicinal products that may induce torsades de pointes
- Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide)
- Class III antiarrhythmics (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, difemanil, intravenous erythromycin, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vinca alkaloids).
Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution when administered concomitantly with medicinal products that may induce torsades de pointes.
Medicinal products affecting plasma sodium levels
The hyponatremic effect of diuretics may be enhanced when used concomitantly with antidepressants, neuroleptics, antiepileptic drugs, and others. Vanatex Combi should be prescribed cautiously during long-term treatment with these agents.
Cardiac glycosides (digitalis)
Thiazide-induced hypokalemia or hypomagnesemia may predispose to digitalis-induced cardiac arrhythmias.
Calcium salts and vitamin D
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may promote increased plasma calcium levels. Concomitant use of thiazide diuretics with calcium salts may lead to hypercalcemia in patients predisposed to hypercalcemia (e.g., hyperparathyroidism, malignancies, or vitamin D-mediated conditions) due to increased calcium reabsorption.
Antidiabetic agents (oral antidiabetics and insulin)
Thiazide therapy may affect glucose tolerance. Adjustment of antidiabetic agent dosage may be necessary.
Metformin should be used with caution due to the risk of lactic acidosis induced by possible functional renal impairment associated with hydrochlorothiazide.
Beta-blockers and diazoxide
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers increases 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 uricosuric agents may be necessary, as hydrochlorothiazide may increase plasma uric acid levels. Increased doses of probenecid or sulfinpyrazone may be required. Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol.
Anticholinergic agents and other drugs affecting gastrointestinal motility
The bioavailability of thiazide diuretics may be increased by anticholinergic agents (e.g., atropine, biperiden), likely 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.
Cholestyramine and colestipol resins
The absorption of thiazide diuretics, including hydrochlorothiazide, is impaired in the presence of anion-exchange resins. This may lead to subtherapeutic effects of thiazide diuretics. However, the potential interaction between hydrochlorothiazide and resins may be minimized by administering hydrochlorothiazide at least 4 hours before or 4–6 hours after resin administration.
Cytotoxic agents (e.g., cyclophosphamide, methotrexate)
Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine)
Thiazides, including hydrochlorothiazide, potentiate the action of curare derivatives.
Cyclosporine
Concomitant administration with cyclosporine may increase the risk of hyperuricemia and gout-like complications.
Alcohol, anesthetics, and sedatives
Concomitant use of thiazide diuretics with agents that may also lower blood pressure (e.g., via reduced central sympathetic activity or direct vasodilation) may potentiate orthostatic hypotension.
Methyldopa
Isolated reports of hemolytic anemia have been received in patients receiving concomitant treatment with methyldopa and hydrochlorothiazide.
Carbamazepine
Hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Such patients should be informed of the possibility of hyponatremic reactions and monitored appropriately.
Contrast agents containing iodine
In cases of diuretic-induced dehydration, there is an increased risk of acute renal failure, particularly with high doses of iodine-containing contrast agents. Adequate fluid replenishment should be ensured prior to administration.
Special precautions for use.
Electrolyte concentration changes.
Concomitant use of Vanatex Combi with potassium salts, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin) is not recommended. Cases of hypokalemia have been reported during treatment with thiazide diuretics. Periodic monitoring of serum potassium levels is recommended. Thiazide diuretics reduce calcium excretion, which may lead to hypercalcemia. Patients receiving diuretics should have periodic determination of plasma electrolyte levels.
Treatment with thiazide diuretics is often associated with the development of hyponatremia and hypochloremic alkalosis. Thiazides enhance urinary magnesium excretion, which may result in hypomagnesemia.
Patients with sodium and/or circulating blood volume deficiency.
Patients receiving thiazide diuretics, including hydrochlorothiazide, should be monitored for clinical signs of water and electrolyte imbalance. In patients with severe sodium and/or circulating blood volume deficiency (e.g., those receiving high doses of diuretics), symptomatic hypotension may occasionally occur after initiation of Vanatex Combi therapy. Therefore, correction of sodium and/or circulating blood volume levels should be performed prior to starting treatment with this medication.
Patients with severe chronic heart failure or other conditions with increased renin-angiotensin-aldosterone system (RAAS) activity.
In patients whose renal function may depend on RAAS activity (e.g., those with severe congestive heart failure), treatment with angiotensin-converting enzyme (ACE) inhibitors has been associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function. Use of Vanatex Combi in patients with severe chronic heart failure is not justified.
Since inhibition of the RAAS with Vanatex Combi cannot exclude the possibility of impaired renal function, Vanatex Combi should not be used in such patients.
Renal artery stenosis.
The drug should not be administered to patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, as such patients may experience increased blood urea nitrogen and plasma creatinine levels.
Primary hyperaldosteronism.
Vanatex Combi should not be used in patients with primary hyperaldosteronism, as their renin-angiotensin system is not activated.
Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy (HOCM).
As with other vasodilators, special caution is required in patients with aortic or mitral valve stenosis or hypertrophic obstructive cardiomyopathy (HOCM).
Renal function impairment.
Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 mL/min). Periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended when using valsartan/hydrochlorothiazide in patients with renal insufficiency.
Vanatex Combi should be used with caution in patients with severe renal impairment (creatinine clearance < 30 mL/min). Thiazide diuretics may precipitate azotemia in patients with chronic renal dysfunction. They are not effective 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.
Renal transplantation.
There is currently no experience regarding the safety of using the drug in patients who have recently undergone kidney transplantation.
Hepatic function impairment.
Dose adjustment is not required in patients with mild to moderate hepatic impairment without cholestasis. However, Vanatex Combi should be used with caution. Thiazide diuretics should be prescribed cautiously in patients with hepatic dysfunction or progressive liver disease, as even minor fluid and electrolyte imbalances may precipitate hepatic coma.
Systemic lupus erythematosus.
Thiazide diuretics have been reported to exacerbate or activate manifestations of systemic lupus erythematosus.
Other metabolic disturbances.
Thiazide diuretics may alter glucose tolerance and increase serum cholesterol, triglycerides, and uric acid levels. Dose adjustments of insulin or oral hypoglycemic agents may be required in diabetic patients. Thiazides may reduce urinary calcium excretion and cause transient and slight elevation of serum calcium levels in the absence of calcium metabolism disorders. Marked hypercalcemia may indicate underlying hyperparathyroidism. Thiazide use should be discontinued prior to testing parathyroid function.
Photosensitivity.
Cases of photosensitivity reactions have been reported with thiazide diuretics. If a photosensitivity reaction occurs during treatment, therapy should be discontinued. If re-administration of the diuretic is considered necessary, protection of exposed skin from sunlight or artificial ultraviolet radiation is recommended.
Pregnancy.
Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued therapy with angiotensin II receptor antagonists is considered essential, women planning pregnancy should be switched to alternative antihypertensive treatments with an established safety profile during pregnancy. If pregnancy is detected, treatment with angiotensin II receptor antagonists should be immediately discontinued, and alternative therapy initiated if necessary.
General recommendations.
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 or asthma.
Hydrochlorothiazide may reduce plasma protein-bound iodine levels and increase free bilirubin concentration in serum.
Angioedema.
Angioedema (including laryngeal and glottal edema leading to airway obstruction and/or facial, lip, throat, 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. If angioedema occurs, treatment with angiotensin II receptor antagonists should be immediately discontinued. Re-administration of the drug is contraindicated.
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 complete symptom resolution.
Acute angle-closure glaucoma.
Hydrochlorothiazide, a sulfonamide derivative, has been associated with idiosyncratic reactions that may lead to acute transient myopia and acute angle-closure glaucoma. Symptoms include acute vision loss or eye pain. These symptoms usually occur within hours to a week after starting the drug. Untreated glaucoma may lead to irreversible vision loss.
The drug should be immediately discontinued. Medicinal or surgical treatment may be required. Risk factors for acute angle-closure glaucoma include allergy to sulfonamides or penicillin.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and renal impairment (including acute renal failure). Concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren for dual RAAS blockade is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").
When combination therapy (dual blockade) is considered absolutely necessary, treatment should occur only under physician supervision with frequent monitoring of renal function, fluid and electrolyte balance, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Doping control.
It should be noted that this medicinal product may lead to a positive doping test.
Excipients.
Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Non-melanoma skin cancer.
Pharmacoepidemiological studies have shown an increased risk of non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) with high cumulative doses of hydrochlorothiazide (HCTZ).
- Patients taking HCTZ alone or in combination with other medicinal products should be informed about the risk of non-melanoma skin cancer and advised to regularly check their skin for new lesions or changes in existing ones, and to report any suspicious skin lesions.
- Suspicious skin lesions should be histologically evaluated by biopsy.
- Patients should be advised to limit exposure to sunlight and UV radiation and use appropriate protection to minimize the risk of skin cancer.
- The use of HCTZ should also be carefully reconsidered in patients with a history of skin cancer (see section "Adverse reactions").
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma.
Medicinal products containing sulfonamide or sulfonamide derivatives 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 usually occur within hours to weeks after starting the drug.
Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, medicinal or surgical treatment may be necessary. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.
Acute respiratory toxicity.
Very rare, severe cases of acute respiratory toxicity, sometimes progressing to acute respiratory distress syndrome (ARDS), have been reported during hydrochlorothiazide treatment. Pulmonary edema may develop within minutes or hours after hydrochlorothiazide intake. 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 after hydrochlorothiazide use.
Use during pregnancy or breastfeeding.
Pregnancy.
Valsartan
Use of angiotensin II receptor antagonists (AIIRAs) is contraindicated throughout pregnancy.
Epidemiological data on teratogenic risk associated with ACE inhibitors during the first trimester of pregnancy are inconclusive, but a small risk cannot be excluded. As there are no controlled epidemiological data on the risk of angiotensin II receptor antagonists, a teratogenic risk may exist for this class of drugs. Unless continued therapy is considered necessary, women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be immediately discontinued, and another medicinal product approved for use in pregnancy should be prescribed if necessary.
It is known that use of angiotensin II receptor antagonists during the second and third trimesters of pregnancy induces fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia) in humans.
If AIIRAs were used from the second trimester of pregnancy, ultrasound examination is recommended to assess renal function and skull ossification.
Newborns of mothers who used AIIRAs should be carefully monitored for the development of arterial hypotension.
Hydrochlorothiazide
Experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Administration of thiazide diuretics into the uterine cavity has led to thrombocytopenia in the fetus or newborn, as well as other adverse effects. Hydrochlorothiazide crosses the placenta. Due to its pharmacological mechanism of action, use during the second and third trimesters may compromise fetoplacental perfusion and may cause disturbances in the fetus and newborn such as jaundice, electrolyte imbalance, and thrombocytopenia.
Breastfeeding.
Due to lack of information on valsartan use during breastfeeding, Vanatex Combi is not recommended for use during this period.
Hydrochlorothiazide passes into breast milk. Therefore, Vanatex Combi is not recommended during breastfeeding.
If pregnancy is detected during treatment, the drug should be discontinued as soon as possible.
Ability to affect reaction speed when driving or operating machinery.
During initial treatment (duration individually determined by the physician), driving and performing tasks that may lead to accidents are prohibited. The extent of restriction thereafter is determined by the physician.
Method of Administration and Dosage
The recommended dose of Vanatex Combi 80 mg/12.5 mg is 1 tablet once daily.
If there is insufficient reduction in arterial pressure after 3–4 weeks of treatment, consider continuing therapy with a dose of 1 tablet of 160 mg/12.5 mg once daily. Tablets of 160 mg/25 mg are indicated for patients in whom adequate reduction in arterial pressure is not achieved with tablets of 160 mg/12.5 mg. If, during subsequent treatment with tablets of 160 mg/25 mg, arterial pressure remains inadequately controlled, consider continuing therapy with a dose of 320 mg/12.5 mg (to achieve this dosage, valsartan and hydrochlorothiazide should be administered in another pharmaceutical form). The dose of 320 mg/25 mg is indicated for patients in whom adequate reduction in arterial pressure is not achieved with the dose of 320 mg/12.5 mg.
The maximum daily dose is 320 mg/25 mg (2 tablets of 160/12.5 mg).
Maximum antihypertensive effect is achieved within 2–4 weeks. Some patients may require 4–8 weeks of treatment.
Vanatex Combi can be taken regardless of food intake, with water.
Additional Information for Special Patient Groups
Renal Impairment
Dose adjustment is not required in patients with creatinine clearance ≥ 30 mL/min. Concomitant use of valsartan with aliskiren is contraindicated in patients with impaired renal function (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²).
Due to the presence of hydrochlorothiazide, Vanatex Combi is contraindicated in patients with severe renal impairment (GFR < 30 mL/min) and anuria.
Diabetes Mellitus
Concomitant use of Vanatex Combi with aliskiren in patients with diabetes mellitus is contraindicated.
Hepatic Impairment
In patients with mild to moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80 mg. Dose adjustment of hydrochlorothiazide is not required in patients with mild to moderate hepatic impairment. Since Vanatex Combi contains valsartan, it is contraindicated in patients with severe hepatic impairment or those with biliary cirrhosis or hepatitis (see sections "Contraindications" and "Special Warnings and Precautions for Use").
Elderly Patients
Dose adjustment is not required for elderly patients.
Children
Vanatex Combi is not recommended for use in children under 18 years of age due to lack of safety and efficacy data.
Overdose
Symptoms: Overdose with valsartan may lead to marked arterial hypotension, which in turn may result in impaired consciousness, circulatory collapse (vascular failure), and/or shock (coma). Additionally, the following signs and symptoms may occur due to hydrochlorothiazide overdose: nausea, drowsiness, hypovolemia, and electrolyte disturbances associated with cardiac arrhythmias and muscle spasms.
Treatment: Therapeutic measures depend on the time since ingestion and the type and severity of symptoms; stabilization of circulation is critically important.
Therapeutic measures depend on the time elapsed since ingestion and the type and severity of symptoms; the primary measure is normalization of hemodynamics.
If the drug was recently ingested, induce vomiting. If a significant time has passed since ingestion, administer an adequate amount of activated charcoal.
In case of arterial hypotension, place the patient in a supine position and immediately restore fluid and electrolyte balance by intravenous administration of isotonic saline solution.
Valsartan cannot be removed by hemodialysis due to its high plasma protein binding; however, hemodialysis is effective for removal of hydrochlorothiazide from the body.
Adverse Reactions.
Adverse reactions of valsartan/hydrochlorothiazide
Metabolism and nutrition disorders: uncommon – dehydration.
Nervous system disorders: very rare – dizziness; uncommon – paraesthesia, hypaesthesia; frequency not known – loss of consciousness.
Eye disorders: uncommon – blurred vision, visual disturbance; frequency not known – choroidal effusion.
Ear and labyrinth disorders: uncommon – tinnitus.
Cardiac disorders: uncommon – arterial hypotension.
Respiratory system disorders: uncommon – cough; frequency not known – non-cardiogenic pulmonary oedema.
Gastrointestinal disorders: very rare – diarrhoea.
Musculoskeletal and connective tissue disorders: uncommon – myalgia (muscle pain); very rare – arthralgia.
Renal and urinary disorders: frequency not known – renal dysfunction.
General disorders and administration site conditions: uncommon – fatigue.
Investigations: frequency not known – increased serum uric acid, increased serum bilirubin and creatinine, hypokalaemia, hyponatraemia, increased blood urea nitrogen, neutropenia.
Additional information on individual components
Unfavourable adverse reactions previously reported with either individual component may also potentially occur with Vanatex Combi.
Adverse reactions of valsartan
Blood and lymphatic system disorders: frequency not known – decreased haemoglobin, decreased haematocrit, neutropenia, thrombocytopenia.
Immune system disorders: very rare – necrotising vasculitis, hypersensitivity reactions/allergic reactions.
Metabolism and nutrition disorders: common – hyponatraemia, hypomagnesaemia, hyperuricaemia, loss of appetite; frequency not known – increased plasma potassium.
Ear and labyrinth disorders: uncommon – vertigo.
Cardiac disorders: frequency not known – vasculitis, hypotension.
Gastrointestinal disorders: uncommon – abdominal pain; very rare – intestinal angioedema.
Hepatobiliary disorders: frequency not known – increased liver function tests, including increased serum bilirubin.
Skin and subcutaneous tissue disorders: frequency not known – Quincke's oedema (angioedema), rash, pruritus, bullous dermatitis.
Renal and urinary disorders: frequency not known – renal failure and renal dysfunction, increased serum creatinine.
Respiratory, thoracic and mediastinal disorders: very rare – upper respiratory tract infections.
Adverse reactions of hydrochlorothiazide
Hydrochlorothiazide has been widely used for many years, often at higher doses than those used in Vanatex Combi. Reports of adverse reactions in patients receiving monotherapy with thiazide diuretics, including hydrochlorothiazide, are available.
Blood and lymphatic system disorders: rare – thrombocytopenia, sometimes with purpura; very rare – agranulocytosis, leucopenia, haemolytic anaemia, bone marrow suppression; frequency not known – aplastic anaemia.
Immune system disorders: very rare – allergic reactions (hypersensitivity reactions).
Metabolism and nutrition disorders: very common – hypokalaemia, increased plasma lipid levels (mainly with high-dose therapy); common – hyponatraemia, hypomagnesaemia, hyperuricaemia; rare – hypercalcaemia, hyperglycaemia, glucosuria and worsening of diabetic metabolic states; very rare – hypochloraemic alkalosis.
Psychiatric disorders: rare – depression, sleep disturbances.
Nervous system disorders: rare – headache, dizziness, paraesthesia.
Eye disorders: uncommon – blurred vision; frequency not known – acute angle-closure glaucoma.
Cardiac disorders: rare – cardiac arrhythmia; common – orthostatic hypotension, which may be potentiated by alcohol, anaesthetics and sedatives.
Respiratory, thoracic and mediastinal disorders: very rare – respiratory failure, including pneumonia and pulmonary oedema, acute respiratory distress syndrome (ARDS).
Gastrointestinal disorders: common – loss of appetite, mild nausea and vomiting; rare – constipation, diarrhoea, gastrointestinal discomfort; very rare – pancreatitis.
Hepatobiliary disorders: rare – cholestasis or jaundice.
Renal and urinary disorders: frequency not known – renal dysfunction, acute renal failure.
Skin and subcutaneous tissue disorders: common – urticaria and other types of rash; rare – photosensitivity; very rare – necrotising vasculitis and toxic epidermal necrolysis, systemic lupus erythematosus, erythema-like reactions, exacerbation of cutaneous lupus erythematosus; frequency not known – erythema multiforme.
Reproductive system and breast disorders: common – impotence.
General disorders and administration site conditions: frequency not known – pyrexia, asthenia.
Musculoskeletal and connective tissue disorders: frequency not known – muscle spasms.
Neoplasms benign, malignant and unspecified (including cysts and polyps): frequency not known – non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).
Description of selected adverse reactions
Non-melanoma skin cancer: epidemiological data indicate a cumulative dose-dependent association between HCTZ and the occurrence of basal cell carcinoma and squamous cell carcinoma (see sections "Pharmacokinetics" and "Special warnings and precautions for use").
Shelf life. 3 years.
Storage conditions.
Store in a dry, light-protected place at a temperature not exceeding 30 °C.
Keep out of the reach of children.
Packaging.
14 film-coated tablets per blister; 2 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
Pharmaceutical Works «Polpharma» S. A.
Address of the manufacturer and location of its business activity.
Pelplinska Street 19, 83-200 Starogard Gdanski, Poland.