Valsartan 160/hydrochlorothiazide 12.5 krka
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT
Valsartan 80/hydrochlorothiazide 12.5 KRKA
Valsartan 160/hydrochlorothiazide 12.5 KRKA
Valsartan 160/hydrochlorothiazide 25 KRKA
Valsartan 320/hydrochlorothiazide 12.5 KRKA
Valsartan 320/hydrochlorothiazide 25 KRKA
(Valsartan 80/hydrochlorothiazide 12.5 KRKA)
(Valsartan 160/hydrochlorothiazide 12.5 KRKA)
(Valsartan 160/hydrochlorothiazide 25 KRKA)
(Valsartan 320/hydrochlorothiazide 12.5 KRKA)
(Valsartan 320/hydrochlorothiazide 25 KRKA)
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, or
320 mg of valsartan and 12.5 mg of hydrochlorothiazide, or
320 mg of valsartan and 25 mg of hydrochlorothiazide;
Excipients: microcrystalline cellulose, lactose monohydrate, magnesium stearate, sodium croscarmellose, povidone, colloidal anhydrous silicon dioxide;
Film coating: hypromellose, titanium dioxide (E 171), polyethylene glycol 4000, iron oxide red (E 172) – only for tablets Valsartan 80/hydrochlorothiazide 12.5 KRKA, Valsartan 160/hydrochlorothiazide 12.5 KRKA, Valsartan 160/hydrochlorothiazide 25 KRKA and Valsartan 320/hydrochlorothiazide 12.5 KRKA; iron oxide yellow (E 172) – only for tablets Valsartan 80/hydrochlorothiazide 12.5 KRKA, Valsartan 160/hydrochlorothiazide 25 KRKA and Valsartan 320/hydrochlorothiazide 25 KRKA.
Medicinal form. Film-coated tablets.
Main physicochemical properties:
Tablets 80 mg/12.5 mg: oval, biconvex, film-coated tablets, pink in color;
Tablets 160 mg/12.5 mg: oval, biconvex, film-coated tablets, red-brown in color;
Tablets 160 mg/25 mg: oval, biconvex, film-coated tablets, light brown in color;
Tablets 320 mg/12.5 mg: oval, biconvex, film-coated tablets, pink in color;
Tablets 320 mg/25 mg: oval, biconvex, film-coated tablets, light yellow in color, with a score on one side.
Pharmacotherapeutic group.
Angiotensin II antagonists and diuretics. Valsartan and diuretics. ATC code C09DA03.
Pharmacological properties.
Pharmacodynamics.
Valsartan
Valsartan is an orally active and specific antagonist of the angiotensin II (Ang II) receptor. It acts selectively on the AT1 receptor subtype, which mediates the known effects of angiotensin II. Elevated plasma levels of Ang II following AT1 receptor blockade by valsartan may stimulate the unblocked AT2 receptor, thereby counterbalancing the effects mediated via the AT1 receptor. Valsartan exhibits no partial agonist activity at the AT1 receptor and has a much greater (approximately 20,000-fold higher) affinity for the AT1 receptor than for the AT2 receptor. It is unknown whether valsartan binds to or blocks other hormonal receptors or ion channels important in cardiovascular regulation.
Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts Ang I to Ang II and degrades bradykinin. Because there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to cause cough. In clinical studies comparing valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (P < 0.05) in patients treated with valsartan than in those receiving an ACE inhibitor (2.6% vs. 7.9%, respectively). In patients who previously experienced dry cough while on an ACE inhibitor, this adverse effect occurred in 19.5% of cases when treated with valsartan and in 19% of cases when treated with a thiazide diuretic, whereas cough was observed in 68.5% of patients receiving an ACE inhibitor (P < 0.05).
Administration of valsartan reduces arterial blood pressure in hypertensive patients without affecting pulse rate. In most patients, the antihypertensive effect begins within 2 hours after a single oral dose, with peak reduction in blood pressure achieved within 4–6 hours. The antihypertensive effect persists for 24 hours after dosing. With repeated administration, maximal blood pressure reduction is typically achieved within 2–4 weeks and is maintained during long-term treatment. When combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.
Abrupt discontinuation of valsartan does not lead to rebound hypertension or other adverse effects.
Hydrochlorothiazide
The site of action of thiazide diuretics is the cortical segment of the distal convoluted renal tubules, where receptors highly sensitive to thiazide diuretics are located, and where inhibition of Na+ and Cl- ion transport occurs in the distal convoluted tubules. The mechanism of action of thiazides involves inhibition of the Na+Cl- symporter, likely through competition at the Cl- binding site, thereby affecting electrolyte reabsorption mechanisms: direct increase in urinary excretion of sodium and chloride in approximately equal proportions, and indirect effects including reduction in plasma volume, followed by increased plasma renin activity, aldosterone secretion, and decreased urinary and serum potassium levels. The renin-aldosterone relationship is mediated by angiotensin II; therefore, when valsartan is co-administered, the decrease in serum potassium is less pronounced than with hydrochlorothiazide monotherapy.
Non-melanoma skin cancer (NMSC)
Based on available epidemiological data, a cumulative dose-dependent association between hydrochlorothiazide and NMSC has been observed. One study included a population of 71,533 cases of basal cell carcinoma (BCC) and 8,629 cases of squamous cell carcinoma (SCC), compared with 1,430,833 and 172,426 individuals in the respective control populations. High cumulative doses of hydrochlorothiazide (≥ 50,000 mg) were associated with an adjusted OR of 1.29 (95% CI: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to hydrochlorothiazide: 633 cases of lip cancer were compared with 63,067 individuals in the control population using a random 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 doses (~25,000 mg) and OR 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see section "Special precautions for use").
Pharmacokinetics.
Valsartan/hydrochlorothiazide
Systemic availability of hydrochlorothiazide is reduced by approximately 30% when co-administered with valsartan. The pharmacokinetics of valsartan are not significantly altered by co-administration with hydrochlorothiazide. This interaction does not affect the combined use of valsartan and hydrochlorothiazide, as the clear antihypertensive effect of the combination exceeds that achieved with monotherapy using either active substance or placebo.
Valsartan
Absorption
After oral administration, peak plasma concentration (Cmax) of valsartan is reached within 2–4 hours. The mean absolute bioavailability is 23% (range 23 ± 7). Food intake reduces the exposure (as measured by AUC) of valsartan by approximately 40% and Cmax by approximately 50%, although plasma concentrations of valsartan are similar about 8 hours after dosing whether taken with or without food. This reduction in AUC, however, is not associated with clinically significant reduction in therapeutic effect; therefore, valsartan can be administered independently of food intake.
Distribution
The steady-state 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 albumin.
Biotransformation
Valsartan undergoes minimal biotransformation, as only about 20% of the dose is recovered as metabolites. A hydroxylated metabolite has been detected in plasma at low concentrations (less than 10% of the AUC for valsartan). This metabolite is pharmacologically inactive.
Elimination
Valsartan exhibits multi-exponential decay kinetics (t½α <1 hour and t½ß approximately 9 hours). Valsartan is primarily eliminated via feces (approximately 83% of the dose) and urine (approximately 13% of the dose), mostly unchanged. 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 (tmax approximately 2 hours). The increase in mean AUC is linear and dose-proportional within the therapeutic range.
The effect of food intake on hydrochlorothiazide absorption is not clinically significant. Absolute bioavailability of hydrochlorothiazide after oral administration is 70%.
Distribution
Apparent volume of distribution is 4–8 L/kg.
Circulating hydrochlorothiazide is bound to plasma proteins (40–70%), primarily to serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at concentrations approximately three times higher than in plasma.
Elimination
Hydrochlorothiazide is primarily excreted unchanged. The terminal elimination half-life from plasma averages between 6 and 15 hours. No changes in hydrochlorothiazide kinetics occur with repeated dosing, and accumulation is minimal with once-daily administration. More than 95% of the absorbed dose is excreted unchanged in urine. Renal clearance involves both passive filtration and active tubular secretion.
Pharmacokinetics in specific patient populations
Elderly patients. In some elderly patients, systemic exposure to valsartan was slightly higher than in younger patients, although this was not clinically significant.
Limited data suggest that systemic clearance of hydrochlorothiazide is lower in elderly patients, both healthy and those with hypertension, compared to healthy young volunteers.
Patients with renal impairment. Dose adjustment is not required in patients with creatinine clearance of 30–70 mL/min.
There are no data on the use of the drug in patients with severe renal impairment (creatinine clearance <30 mL/min) or in patients on hemodialysis. Valsartan is highly bound to plasma proteins and is not removed by hemodialysis. In contrast, hydrochlorothiazide is eliminated during hemodialysis.
In renal insufficiency, mean peak plasma levels and AUC values of hydrochlorothiazide increase, while urinary excretion decreases. In patients with mild to moderate renal impairment, AUC of hydrochlorothiazide increases by 3-fold. In patients with severe renal impairment, AUC increases by 8-fold. Hydrochlorothiazide is contraindicated in patients with severe renal impairment (see section "Contraindications").
Hepatic impairment. Systemic exposure to valsartan was approximately twice as high in patients with mild (n = 6) and moderate (n = 5) hepatic impairment compared to healthy volunteers. There are no data on the use of valsartan in patients with severe hepatic impairment.
Liver disease does not significantly affect the pharmacokinetics of hydrochlorothiazide.
Clinical characteristics.
Indications.
Arterial hypertension in patients whose blood pressure is not adequately controlled by monotherapy.
Contraindications.
Hypersensitivity to any component of the medicinal product; hypersensitivity to other sulfonamide derivatives; severe hepatic dysfunction, hepatic cirrhosis and cholestasis; anuria, severe renal impairment (creatinine clearance <30 mL/min); refractory hypokalemia, hyponatremia, hypercalcemia or symptomatic hyperuricemia; pregnancy or planned pregnancy, breastfeeding (see section "Use in pregnancy or breastfeeding").
Concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").
Hereditary angioedema or angioedema during previous treatment with ACE inhibitors or ARBs.
Interaction with other medicinal products and other forms of interaction.
Interactions with the combination of valsartan and hydrochlorothiazide
Concomitant use not recommended
Lithium
Transient increases in serum lithium concentrations and lithium toxicity have been reported during concomitant use of lithium with ACE inhibitors and/or thiazides. There is no clinical experience with concomitant use of valsartan and lithium; therefore, serum lithium concentrations should be monitored.
Concomitant use requiring special caution
Other antihypertensive agents
The medicinal product may enhance the hypotensive effect of other antihypertensive agents (such as guanethidine, methyldopa, vasodilators, ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, direct renin inhibitors, and dopamine reuptake inhibitors).
Pressor amines (e.g., noradrenaline, adrenaline)
Likely reduced response to pressor amines such as noradrenaline. The clinical significance of this effect is not well established and insufficient to preclude their use.
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and non-selective NSAIDs
NSAIDs may attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when used concomitantly. In addition, concomitant use of valsartan/hydrochlorothiazide and NSAIDs may lead to worsening of renal function and increased serum potassium levels. Therefore, monitoring of renal function at the beginning of treatment is recommended, along with adequate fluid replenishment.
In elderly patients, in those with reduced volume (including those receiving diuretic therapy), or with renal dysfunction, concomitant use of NSAIDs (or COX-2 inhibitors) with ARBs increases the risk of worsening renal function, including acute renal failure. Combined use of these agents requires caution and monitoring of renal function.
Interactions related to valsartan
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ARBs, ACE inhibitors, or aliskiren
Caution should be exercised when using ARBs, including valsartan, concomitantly with other drugs that block the RAAS, such as ACE inhibitors or aliskiren (see section "Special precautions for use").
This is associated with an increased incidence of hypotension, loss of consciousness, hyperkalemia, and renal dysfunction (including acute renal failure) compared to monotherapy. Therefore, dual RAAS blockade by combining ACE inhibitors, angiotensin receptor blockers, or aliskiren is not recommended. If dual RAAS blockade is considered absolutely necessary, treatment should be administered only under specialist supervision and accompanied by monitoring of renal function, electrolyte levels, and blood pressure.
Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus, diabetic nephropathy, or renal impairment (eGFR < 60 mL/min/1.73 m²) is contraindicated (see section "Contraindications").
Concomitant use not recommended
Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, and other substances that may increase potassium levels.
Caution is advised when co-administering valsartan with agents affecting potassium levels. Plasma potassium levels should be frequently monitored.
Concomitant use of ARBs with other medicinal products capable of increasing serum potassium levels (e.g., potassium-sparing diuretics, potassium-containing medicinal products, heparin) increases the risk of hyperkalemia. In such cases, the medicinal product containing valsartan should be used with caution and potassium levels should be monitored.
Transporters
In vitro studies have shown that valsartan is a substrate for the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of these data is unknown. Concomitant use of inhibitors of uptake transporters (e.g., rifampicin, cyclosporine) or efflux transporters (e.g., ritonavir) may increase systemic exposure to valsartan. Appropriate precautions should be taken at the initiation or discontinuation of concomitant therapy with these medicinal products.
Absence of interactions
During studies with valsartan, no clinically significant interactions were observed when valsartan was administered with any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, or glyburide. Digoxin and indomethacin may interact with hydrochlorothiazide.
Interactions related to hydrochlorothiazide
Concomitant use requiring special caution
MEDICINAL PRODUCTS AFFECTING SERUM POTASSIUM LEVELS
The hypokalemic effect of hydrochlorothiazide may be enhanced when used concomitantly with potassium-wasting diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid and its derivatives, antiarrhythmic agents.
If the above-mentioned medicinal products are prescribed in combination with valsartan/hydrochlorothiazide, monitoring of serum potassium levels is recommended (see section "Special precautions for use").
MEDICINAL PRODUCTS THAT MAY INDUCE TORSADES DE POINTES ARRHYTHMIA
Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution concomitantly with medicinal products that may induce torsades de pointes arrhythmia, such as class Ia and III antiarrhythmics and certain neuroleptics.
MEDICINAL PRODUCTS AFFECTING BLOOD SODIUM LEVELS
The hyponatremic effect of diuretics may be enhanced when used concomitantly with medicinal products such as antidepressants, antipsychotics, and antiepileptic drugs. Long-term use of these agents should be prescribed cautiously.
Cardiac glycosides
Hypokalemia or hypomagnesemia may occur during treatment with thiazides in patients with digoxin-induced cardiac arrhythmia (see section "Special precautions for use").
Calcium salts and vitamin D
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may increase serum calcium levels. Concomitant use of thiazide diuretics with calcium salts may cause hypercalcemia in patients predisposed to hypercalcemia (e.g., patients with hyperparathyroidism, malignancies, or conditions associated with vitamin D deficiency) due to increased tubular reabsorption of calcium.
Antidiabetic medicinal products (oral agents and insulin)
Thiazides may alter glucose tolerance. Adjustment of antidiabetic drug dosage may be necessary.
Metformin should be used with caution due to the risk of lactic acidosis caused by potential functional renal impairment associated with hydrochlorothiazide use.
Beta-blockers and diazoxide
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.
MEDICINAL PRODUCTS USED IN THE TREATMENT OF GOUT (probenecid, sulfinpyrazone, and allopurinol)
Dosage adjustment of gout medications may be necessary because hydrochlorothiazide may increase serum uric acid levels. The dose of probenecid or sulfinpyrazone may need to be increased if required. Concomitant use of thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol.
Anticholinergic agents (e.g., atropine, biperiden)
The bioavailability of thiazide diuretics may increase when administered with anticholinergic agents (e.g., atropine, biperiden), particularly due to reduced gastrointestinal motility and delayed gastric emptying. Conversely, prokinetic agents such as cisapride may reduce the bioavailability of thiazide diuretics.
Amantadine
Thiazide diuretics increase the risk of adverse effects caused by amantadine.
Ion-exchange resins
Absorption of thiazide diuretics, including hydrochlorothiazide, is impaired when co-administered with cholestyramine or colestipol. This may result in subtherapeutic effects of thiazide diuretics. To minimize interaction, hydrochlorothiazide should be administered at least 4 hours before or 4–6 hours after the resin.
Cytotoxic agents (e.g., cyclophosphamide, methotrexate)
Thiazides may reduce renal excretion of cytotoxic agents and potentiate their myelosuppressive effects.
Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine)
Thiazides potentiate the action of curare derivatives.
Cyclosporine
Concomitant use with cyclosporine may increase the risk of hyperuricemia and symptoms resembling gout flare-ups.
Alcohol, barbiturates, or narcotics
Concomitant use of thiazide diuretics with substances that also lower blood pressure (e.g., by reducing sympathetic nervous system activity or direct vasodilatory effects) may potentiate orthostatic hypotension.
Methyldopa
Cases of hemolytic anemia have been reported during concomitant use of hydrochlorothiazide and methyldopa.
Iodinated contrast media
Dehydration due to diuretic use increases the risk of acute renal failure, especially with high doses of iodine-containing contrast agents. Patients should be rehydrated prior to administration.
Special precautions.
Changes in serum electrolyte balance
Potassium
Thiazide diuretics may cause hypokalemia or exacerbate existing hypokalemia. Correction of hypokalemia is recommended before initiating thiazide therapy. Concomitant hypomagnesemia may cause hypokalemia that is more difficult to correct. Since the medicinal product contains an ARB II, caution should be exercised when used concomitantly with potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products that may increase serum potassium concentration (e.g., heparin). Hypokalemia has been reported during treatment with thiazide diuretics, including hydrochlorothiazide. Regular monitoring of serum potassium levels is recommended in patients with conditions involving increased potassium loss.
Regular monitoring of potassium and magnesium levels is required. All patients receiving thiazide diuretics should be monitored for electrolyte imbalances.
Patients with sodium and/or circulating blood volume (CBV) deficiency
Patients receiving thiazide diuretics should be monitored for clinical signs of fluid or electrolyte imbalance. Treatment with thiazide diuretics is frequently associated with the development or worsening of existing hyponatremia and hypochloremic alkalosis. This may be accompanied by neurological symptoms (e.g., vomiting, confusion, apathy). Thiazide diuretics should only be used after correction of hyponatremia. Serum sodium concentration should be monitored regularly. Thiazides increase urinary magnesium excretion, which may lead to hypomagnesemia.
In patients with marked sodium and/or CBV deficiency (e.g., those receiving high-dose diuretics), symptomatic arterial hypotension may occur after initiation of treatment with the medicinal product. Sodium and/or CBV should be corrected before starting therapy.
Calcium
Thiazide diuretics reduce calcium excretion in urine and may cause elevated serum calcium levels. Thiazide diuretics should only be used after correction of hypercalcemia or treatment of conditions causing hypercalcemia. Serum calcium concentration should be monitored regularly.
Patients with severe chronic heart failure with congestion or other conditions with RAAS activation
In patients whose renal function primarily depends on RAAS activity (e.g., patients with severe congestive heart failure), administration of medicinal products acting on the RAAS may lead to oliguria and/or progressive azotemia, rarely including acute renal failure and/or fatal outcomes. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function. The safety of using the medicinal product in patients with severe congestive heart failure has not been established. Therefore, the possibility of developing renal failure due to RAAS suppression with the combination of valsartan/hydrochlorothiazide cannot be excluded. Such patients should not take the medicinal product.
Renal artery stenosis
Since serum urea and creatinine levels may increase, the medicinal product is not recommended for patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a solitary kidney.
Primary hyperaldosteronism
The medicinal product is not recommended for patients with primary hyperaldosteronism, as their RAAS is not activated.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
Extreme caution is required in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.
Renal impairment
Dose adjustment is not required in patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min). The medicinal product should be used with caution in patients with severe renal impairment (creatin游戏副本
Method of Administration and Dosage
For patients whose blood pressure is not adequately controlled with monotherapy, a decision may be made to switch to a combination of valsartan/hydrochlorothiazide. In such cases, the dose should be adjusted according to the doses previously used during monotherapy.
The dosage of active substances should be individually tailored. In each case, dose selection for each active ingredient should be performed carefully to avoid the risk of arterial hypotension and other adverse effects.
The recommended dose of the valsartan/hydrochlorothiazide combination is 1 tablet of 80 mg/12.5 mg once daily. If blood pressure is not sufficiently reduced after 3–4 weeks of treatment, consideration should be given to continuing treatment with a dose of 1 tablet of 160 mg/12.5 mg per day. Tablets of 160 mg/25 mg are prescribed to patients in whom adequate blood pressure reduction is not achieved with tablets of 160 mg/12.5 mg. If blood pressure remains insufficiently controlled with 160 mg/25 mg tablets, consideration should be given to continuing treatment with a dose of 320 mg/12.5 mg. Tablets of 320 mg/25 mg are prescribed to patients in whom adequate blood pressure reduction is not achieved with 320 mg/12.5 mg tablets. The maximum daily dose is 320 mg/25 mg.
Valsartan 320 mg/Hydrochlorothiazide 25 mg KRKA tablets may be divided into equal parts.
The antihypertensive effect is primarily observed within the first 2 weeks.
In most patients, the maximum effect is achieved within 4 weeks, although some patients may require 4–8 weeks of treatment. This should be taken into account when adjusting the dose.
If there is no response to treatment after 8 weeks, the use of an additional or alternative medicinal product should be considered.
Method of Administration
Film-coated tablets of Valsartan/Hydrochlorothiazide KRKA should be taken with water and may be administered independently of food intake.
Special Patient Groups
Renal Impairment
Dosage reduction may be required in patients with renal impairment. Due to the presence of hydrochlorothiazide, the product is contraindicated in patients with severe renal impairment (GFR <30 mL/min) and anuria. There is no experience with the use of valsartan in patients with end-stage renal failure (creatinine clearance <10 mL/min) or in patients undergoing dialysis.
Hepatic Impairment
In patients with mild to moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80 mg (see section "Special Warnings and Precautions for Use"). Dose reduction may be necessary in patients with hepatic impairment. Due to the presence of valsartan, the product is contraindicated in patients with severe hepatic impairment or with biliary cirrhosis and cholestasis.
Elderly Patients Aged 65 Years and Older
Dose adjustment is not required; the product can be used in patients of any age.
Children
The safety and efficacy of the product in children have not been established; therefore, its use is not recommended in this patient group.
Overdose.
Symptoms
Overdose with valsartan may lead to marked arterial hypotension, which in turn may result in depressed consciousness, circulatory failure, and/or shock. Overdose with hydrochlorothiazide may cause symptoms such as nausea, drowsiness, hypovolemia, electrolyte imbalance, and consequently arrhythmias and muscle spasms. The most characteristic signs and symptoms of overdose also include tachycardia, arterial hypotension, shock, weakness, confusion, dizziness, paresthesia, exhaustion, disturbances of consciousness, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, and elevated blood urea nitrogen levels (primarily due to renal failure).
Treatment
In all cases of overdose, general supportive measures should be implemented, including monitoring of the patient's condition and measures to stabilize cardiovascular function.
Therapeutic interventions depend on the time elapsed since ingestion of the excessive dose and the severity of symptoms. The most important measure is stabilization of hemodynamics.
If the drug has been recently ingested, vomiting should be induced. If a significant amount of time has passed since drug intake, the patient should be given an adequate amount of activated charcoal.
In the event of arterial hypotension, the patient should be placed in a supine position and isotonic saline solution should be administered intravenously without delay to restore fluid and electrolyte balance.
Valsartan is not removed by hemodialysis due to its strong binding to plasma proteins, whereas hydrochlorothiazide is dialyzable.
Adverse reactions.
The adverse reactions listed below are classified by organ system. Adverse reactions observed with each individual component may also occur during treatment with the combination of valsartan/hydrochlorothiazide.
Adverse reactions occurring with the valsartan/hydrochlorothiazide combination
| Metabolism and nutrition disorders |
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| Dehydration |
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| Nervous system disorders |
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| Dizziness |
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| Paraesthesia |
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| Syncope |
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| Eye disorders |
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| Blurred vision |
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| Ear and labyrinth disorders |
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| Tinnitus |
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| Vascular disorders |
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| Arterial hypotension |
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| Respiratory, thoracic and mediastinal disorders |
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| Cough |
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| Non-cardiogenic pulmonary oedema |
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| Gastrointestinal disorders |
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| Diarrhoea |
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| Musculoskeletal and connective tissue disorders |
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| Myalgia |
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| Arthralgia |
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| Renal and urinary disorders |
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| Renal dysfunction |
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| General disorders |
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| Fatigue |
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| Investigations |
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| Elevated serum uric acid Elevated serum bilirubin and creatinine Hypokalaemia Hyponatraemia Increased blood urea nitrogen Neutropenia |
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Additional information regarding individual components
Adverse reactions that have occurred with the use of valsartan and hydrochlorothiazide individually may also represent potential adverse effects with the combination, even if they were not observed in clinical trials or during the post-marketing period.
Side effects occurring with valsartan administration
| From blood and lymphatic system |
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| Decreased hemoglobin, decreased hematocrit, thrombocytopenia. |
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| From immune system |
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| Other hypersensitivity reactions/allergic reactions, including serum sickness |
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| From metabolism and nutrition |
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| Increased serum potassium level, hyponatremia |
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| From ear and labyrinth |
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| Vertigo |
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| From vascular system |
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| Vasculitis |
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| From gastrointestinal tract |
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| Frequency "very rare" |
Abdominal pain Intestinal angioneurotic edema |
| From liver and biliary system |
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| Elevated liver function tests |
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| From skin and subcutaneous tissues |
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| Angioneurotic edema, bullous dermatitis, rash, pruritus |
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| From renal and urinary system |
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| Renal failure |
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Adverse reactions occurring with hydrochlorothiazide administration
Hydrochlorothiazide has been widely used for many years, often at higher doses than those contained in the medicinal product Valsartan/hydrochlorothiazide Krka. Adverse reactions observed in patients receiving monotherapy with thiazide diuretics, including hydrochlorothiazide, include:
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
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| Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) |
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Immune system |
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| Hypersensitivity reactions |
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| Metabolism and nutrition disorders |
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| Hypokalemia, increased blood lipids (mostly at high doses). |
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| Hyponatremia, hypomagnesemia, hyperuricemia. |
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| Hypercalcemia, hyperglycemia, glucosuria, and worsening of diabetic metabolic control. |
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| Hypochloremic alkalosis |
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| Psychiatric disorders |
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| Depression, sleep disturbances |
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| Nervous system disorders |
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| Headache, dizziness, paresthesia |
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| Eye disorders |
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| Visual disturbances |
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| Acute angle-closure glaucoma, choroidal effusion |
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| Cardiac disorders |
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| Cardiac arrhythmia |
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| Vascular disorders |
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| Postural hypotension |
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| Respiratory, thoracic and mediastinal disorders |
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| Respiratory distress, including pneumonia and pulmonary edema, acute respiratory distress syndrome (ARDS) |
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| Gastrointestinal disorders |
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| Loss of appetite, mild nausea and vomiting. |
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| Constipation, gastrointestinal discomfort, diarrhea. |
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| Pancreatitis |
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| Hepatobiliary disorders |
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| Intrahepatic cholestasis or jaundice |
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| Renal and urinary disorders |
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| Acute renal failure, renal disorders |
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| Skin and subcutaneous tissue disorders |
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| Urticaria and other forms of rash. |
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| Photosensitivity. |
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| Necrotizing vasculitis and toxic epidermal necrolysis, lupus-like skin reactions, recurrence of cutaneous lupus erythematosus. |
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| Polymorphic erythema |
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| General disorders |
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| Pyrexia, asthenia |
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| Musculoskeletal and connective tissue disorders |
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| Muscle spasms |
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| Reproductive system and breast disorders |
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| Impotence |
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Description of selected adverse effects
NMSC: Epidemiological studies have shown a cumulative dose-dependent association between hydrochlorothiazide use and NMSC (see sections "Pharmacodynamics" and "Special precautions").
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are obliged to report any suspected adverse reactions via the national reporting system.
Shelf life.
5 years.
Storage conditions.
Store at temperatures not exceeding 30°C. Keep in the original packaging to protect from light and moisture.
Keep out of reach of children.
Packaging.
14 tablets in a blister pack, 2 or 6 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
KRKA, d.d., Novo mesto, Slovenia.
Manufacturer's address and location of operations.
Smarjeska cesta 6, 8501 Novo mesto, Slovenia.