Valsacor® h 80

INSTRUCTION for medical use of the medicinal product Valsacor® H 80 Valsacor® H 160 Valsacor® HD 160 (Valsacor® H 80) (Valsacor® H 160) (Valsacor® HD 160)

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: tablet core – microcrystalline cellulose, lactose monohydrate, magnesium stearate, sodium croscarmellose, povidone, colloidal anhydrous silicon dioxide.

Film coating: hypromellose, titanium dioxide (E 171), macrogol 4000, iron oxide red (E 172), iron oxide yellow (E 172) – only in Valsacor® H 80 and Valsacor® HD 160.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Valsacor® H 80: oval, biconvex, film-coated tablets, pink in colour;

Valsacor® H 160: oval, biconvex, film-coated tablets, red-brown in colour;

Valsacor® HD 160: oval, biconvex, film-coated tablets, light brown in colour.

Pharmacotherapeutic group. Angiotensin II antagonists and diuretics. Valsartan and diuretics. ATC C09D A03.

Pharmacological properties.

Pharmacodynamics.

Valsartan

Valsartan is a specific antagonist of angiotensin II (Ang II) receptors. It acts selectively on the AT1 receptor subtype, which mediates the known effects of angiotensin II (Ang II). Elevated plasma levels of Ang II following blockade of the AT1 receptor due to valsartan administration may stimulate the unblocked AT2 receptor, thereby maintaining balance between AT1 and AT2 receptor effects. Valsartan exhibits no partial agonist activity at AT1 receptors and has significantly greater (approximately 20,000-fold higher) affinity for the AT1 receptor than for the AT2 receptor. It is unknown whether valsartan binds to other hormonal receptors or ion channels important in cardiovascular regulation or whether it blocks them.

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. The incidence of dry cough is significantly lower in patients receiving valsartan compared to those receiving ACE inhibitors.

Administration of valsartan in patients with arterial hypertension leads to a reduction in blood pressure without affecting pulse rate. In most patients, after a single oral dose, the onset of antihypertensive effect occurs within 2 hours, 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 at any dose is usually achieved within 2–4 weeks and maintained during long-term therapy. When combined with hydrochlorothiazide, an additional significant reduction in blood pressure is achieved.

Abrupt discontinuation of valsartan does not cause rebound hypertension or other adverse effects.

Hydrochlorothiazide

The primary site of action of thiazide diuretics is the distal convoluted renal tubule. In the renal cortex, a high-affinity binding site serves as the main site for thiazide diuretic action, inhibiting NaCl transport in the distal convoluted tubule. The mechanism of action of thiazides involves inhibition of the Na⁺Cl⁻ cotransporter, likely through competition at the chloride site, thereby affecting electrolyte reabsorption: direct increase in urinary excretion of sodium and chloride in approximately equal amounts. The indirect effect of this diuretic leads to reduced plasma volume, followed by increased plasma renin activity, aldosterone secretion, and increased potassium excretion in urine, resulting in decreased serum potassium levels. The renin-aldosterone relationship is mediated by Ang II; therefore, when hydrochlorothiazide is co-administered with valsartan, the reduction in serum potassium is less pronounced than with hydrochlorothiazide monotherapy.

Non-melanoma skin cancer

Available epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of non-melanoma skin cancer (NMSC). One study included a population of 71,533 cases of basal cell carcinoma (BCC) and 8,629 cases of squamous cell carcinoma (SCC), corresponding to 1,430,833 and 172,462 control groups, respectively. High cumulative use of hydrochlorothiazide (≥ 50,000 mg) was associated with an adjusted odds ratio (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 cumulative dose-response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and hydrochlorothiazide exposure: 633 cases of lip cancer corresponded to 63,067 population control groups using a 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 use (~25,000 mg) and OR 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see "Special precautions").

Pharmacokinetics.

Valsartan/hydrochlorothiazide

Systemic availability of hydrochlorothiazide is reduced by approximately 30% when co-administered with valsartan. The pharmacokinetics of valsartan are not significantly affected by co-administration with hydrochlorothiazide. This apparent interaction does not impact the combined use of valsartan and hydrochlorothiazide, as the clear antihypertensive effect of the combination exceeds that achieved with monotherapy using either active substance.

Valsartan

Absorption

After oral administration of valsartan, peak plasma concentrations (C_max) are reached within 2–4 hours. The mean absolute bioavailability is 23%. Food intake reduces exposure (measured as AUC) to valsartan by approximately 40% and C_max by approximately 50%, although from about 8 hours post-dose, plasma concentrations of valsartan are similar in patients who took food and those who took the drug fasting. However, this reduction in AUC is not associated with a 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 has limited tissue distribution. Valsartan is highly bound to serum proteins (94–97%), primarily to albumin.

Metabolism

Valsartan undergoes minimal biotransformation, as only about 20% of the dose is recovered as metabolites. A hydroxylated metabolite has been detected in plasma at low concentrations (less than 10% of the AUC for valsartan). This metabolite is pharmacologically inactive.

Elimination

Valsartan exhibits multi-exponential elimination kinetics (t_½α <1 hour and t_½ß approximately 9 hours). Valsartan is primarily eliminated via feces (approximately 83% of the dose) and urine (approximately 13% of the dose), mostly in unchanged form. After intravenous administration, plasma clearance of valsartan is about 2 L/h, and renal clearance is 0.62 L/h (approximately 30% of total clearance). The elimination half-life of valsartan is 6 hours.

Hydrochlorothiazide

Absorption

Absorption of hydrochlorothiazide after oral administration is rapid (t_max approximately 2 hours). The increase in mean AUC is linear and proportional to dose 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

The 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 plasma levels.

Elimination

Hydrochlorothiazide is excreted primarily in unchanged form. Hydrochlorothiazide is eliminated from plasma with a terminal half-life averaging between 6 and 15 hours. There are no changes in hydrochlorothiazide kinetics 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 secretion into the renal tubules.

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 sulfonamide derivatives; severe impairment of liver function, liver cirrhosis and cholestasis; anuria, severe renal impairment (creatinine clearance < 30 mL/min); refractory hypokalemia, hyponatremia, hypercalcemia or symptomatic hyperuricemia; concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 mL/min/1.73 m²); pregnancy or women planning to become pregnant (see section "Use during pregnancy or breastfeeding").

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 administration of lithium with ACE inhibitors and/or thiazides, including hydrochlorothiazide. Due to insufficient experience with concomitant use of valsartan and lithium, this combination is not recommended. If combination therapy is necessary, monitoring of serum lithium levels is recommended.

Concomitant use requiring special caution

Other antihypertensive medicinal products

The medicinal product may enhance the hypotensive effect of other antihypertensive agents (e.g., ACE inhibitors, beta-blockers, calcium channel blockers).

Pressor amines (e.g., noradrenaline, adrenaline)

Likely reduction in response to pressor amines. The clinical significance of this effect is not established and insufficient to warrant discontinuation of 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. Additionally, concomitant use of valsartan/hydrochlorothiazide and NSAIDs may lead to deterioration in renal function and increased serum potassium levels. Therefore, monitoring of renal function at the beginning of treatment is recommended, and adequate fluid replenishment should be ensured for the patient.

Interactions related to valsartan

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with drugs from the ARB class, ACE inhibitors, or aliskiren

Caution should be exercised when administering ARB class medicinal products, including valsartan, concomitantly with other drugs that block the RAAS, such as ACE inhibitors or aliskiren (see section "Special precautions for use").

Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren in patients with diabetes mellitus or impaired renal function (GFR < 60 mL/min/1.73 m²) is contraindicated (see section "Contraindications").

Concomitant use not recommended

Potassium-sparing diuretics, potassium-containing supplements, potassium-containing salt substitutes, and other substances that may increase potassium levels

Caution is advised when co-administering medicinal products that affect potassium levels. Serum potassium levels should be frequently monitored.

Transporters

In vitro studies have shown that valsartan is a substrate of the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical significance 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 use of these medicinal products.

Absence of interactions

In 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, and glyburide. Digoxin and indomethacin may interact with hydrochlorothiazide in the composition of Valsakor® H 80, Valsakor® H 160, and Valsakor® HD 160 (see interactions 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 hormones (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid and its derivatives.

If the above-mentioned medicinal products are prescribed in combination with hydrochlorothiazide/valsartan, monitoring of serum potassium levels is recommended (see section "Special precautions for use").

MEDICINAL PRODUCTS THAT MAY CAUSE TORSADES DE POINTES ARRHYTHMIA

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide).
• Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide).
• Some neuroleptics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).
• Others (e.g., bepridil, cisapride, diphemanil, intravenous erythromycin, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vincamine).

Due to the risk of hypokalemia, hydrochlorothiazide should be used cautiously concomitantly with medicinal products that may induce torsades de pointes arrhythmia.

MEDICINAL PRODUCTS AFFECTING SERUM SODIUM LEVELS

The hyponatremic effect of diuretics may be enhanced when used concomitantly with antidepressants, antipsychotics, and antiepileptic agents. Long-term use of such medicinal products should be carried out with particular caution.

Cardiac glycosides

In cases of cardiac arrhythmias induced by digoxin during thiazide therapy, hypokalemia or hypomagnesemia may occur (see section "Special precautions for use").

Calcium salts and vitamin D

Administration of thiazide diuretics, including hydrochlorothiazide, in combination with vitamin D or calcium salts may lead to increased serum calcium levels. Concomitant use of thiazide diuretics with calcium salts may cause hypercalcemia in patients predisposed to hypercalcemia (e.g., patients with hyperparathyroidism, malignancies, or conditions associated with vitamin D deficiency) due to increased tubular reabsorption of calcium.

Antidiabetic medicinal products (oral antidiabetics and insulin)

Thiazides may alter glucose tolerance. Dose adjustment of antidiabetic agents may be required.

Metformin should be used with caution due to the risk of lactic acidosis, possibly caused by functional renal impairment associated with hydrochlorothiazide use.

Beta-blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.

MEDICINAL PRODUCTS USED IN THE TREATMENT OF GOUT (probenecid, sulfinpyrazone, and allopurinol)

Dosage adjustment of gout medications may be necessary, as hydrochlorothiazide may increase serum uric acid levels. If necessary, the dose of probenecid or sulfinpyrazone should be increased. 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. Prokinetic agents such as cisapride are also expected to 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 administered concomitantly with cholestyramine or colestipol.

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, including hydrochlorothiazide, 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 through vasodilatory effects) may potentiate orthostatic hypotension.

Methyldopa

Cases of hemolytic anemia have been reported during concomitant use of hydrochlorothiazide and methyldopa.

Carbamazepine

Hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Such patients should be informed about the possibility of hyponatremic reactions and monitored appropriately.

Iodinated contrast media

In cases of dehydration due to diuretic use, there is an increased risk of acute renal failure, particularly with high doses of iodine-containing agents. Patients should be rehydrated prior to administration.

Special precautions for use.

Renal impairment and kidney transplantation

Valsartan/hydrochlorothiazide should not be administered to patients who have undergone kidney transplantation due to lack of experience with safe use of the drug. Dose adjustment is not required in patients with mild or moderate renal impairment (creatinine clearance ≥30 mL/min). Periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended.

Thiazide diuretics may precipitate azotemia in patients with chronic renal impairment.

Renal artery stenosis

Since serum urea and creatinine levels may increase, the use of the drug is not recommended in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a solitary kidney.

Primary hyperaldosteronism

The drug is not recommended for use in patients with primary hyperaldosteronism, as their renin-angiotensin-aldosterone system (RAAS) is not activated.

Patients with severe chronic heart failure with congestion or other conditions with RAAS activation

In patients whose renal function largely depends on RAAS activity (e.g., patients with severe congestive heart failure), treatment with drugs acting on the RAAS may lead to oliguria and/or progressive azotemia, and rarely, acute renal failure. The safety of using the drug in patients with severe congestive heart failure has not been established. Therefore, it cannot be excluded that renal failure may develop due to RAAS suppression during treatment with Valsakor® H 80, Valsakor® H 160, or Valsakor® HD 160. These patients should not take the drug.

Serum electrolyte imbalances

Caution is advised when concomitantly using potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other drugs that may increase serum potassium concentration (e.g., heparin).

Hypokalemia has been reported during treatment with thiazide diuretics. Frequent monitoring of serum potassium levels is recommended.

Hydrochlorothiazide

Hypokalemia has been observed during treatment with thiazide diuretics, including hydrochlorothiazide. Regular monitoring of serum potassium levels is recommended.

Treatment with thiazide diuretics, including hydrochlorothiazide, may cause hyponatremia and hypochloremic alkalosis. Thiazides, including hydrochlorothiazide, increase urinary magnesium excretion, which may lead to hypomagnesemia. Calcium excretion is reduced during treatment with thiazide diuretics, which may lead to hypercalcemia.

Patients receiving diuretic therapy should undergo periodic evaluation of serum electrolytes at appropriate intervals.

Patients with sodium deficiency and/or reduced circulating blood volume (CBV)

Patients receiving thiazide diuretics should be monitored for clinical signs of fluid or electrolyte imbalance. Warning signs include dry mouth, thirst, asthenia (exhaustion, weakness), drowsiness, mental confusion, restlessness (dysphoria), muscle cramps or pain, rapid muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances (nausea and vomiting).

In patients with marked sodium deficiency and/or reduced CBV, such as those receiving high-dose diuretics, symptomatic hypotension may occur after initiation of therapy with the drug. Sodium and/or CBV levels should be corrected prior to starting treatment.

In case of hypotension, the patient should be placed in a supine position and, if necessary, given an intravenous infusion of isotonic saline solution. Treatment may be resumed once blood pressure has stabilized.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

Extreme caution is required in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Hepatic impairment

The drug should be used with caution in patients with mild or moderate hepatic impairment without cholestasis (see sections "Pharmacological properties" and "Dosage and administration"). Thiazides should be used cautiously in patients with hepatic impairment or progressive liver disease, as even minor fluid or electrolyte imbalances may precipitate hepatic coma.

Systemic lupus erythematosus

Thiazide diuretics, including hydrochlorothiazide, may exacerbate or activate systemic lupus erythematosus.

Other metabolic disturbances

Thiazide diuretics may affect glucose tolerance and increase serum cholesterol, triglycerides, and uric acid levels. Diabetic patients may require adjustment of insulin or oral hypoglycemic agent doses.

Thiazides may reduce urinary calcium excretion and cause transient, mild increases in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate hyperparathyroidism. Thiazide use should be discontinued prior to parathyroid function testing.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section "Adverse reactions"). If a photosensitivity reaction occurs during treatment, drug therapy should be discontinued. If re-administration is necessary, protection of exposed skin from sunlight or artificial UV radiation is recommended.

Choroidal effusion, acute myopia, and secondary acute angle-closure glaucoma

Sulfonamides and sulfonamide derivatives may cause idiosyncratic reactions leading to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma. Symptoms include sudden onset of decreased visual acuity or eye pain, typically occurring within hours to weeks after starting the drug. Untreated acute angle-closure glaucoma may result in permanent vision loss.

Drug treatment should be discontinued as soon as possible. Emergency medical or surgical intervention may be required if intraocular pressure remains uncontrolled. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

General disorders

Caution is advised when using the drug in patients with hypersensitivity to other angiotensin II receptor antagonists. Patients with a history of allergy or asthma are at higher risk of allergic reactions.

Non-melanoma skin cancer (NMSC)

An increased risk of non-melanoma skin cancer (NMSC) (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)) with increasing cumulative exposure to hydrochlorothiazide (HCTZ) was observed in two epidemiological studies based on the Danish National Cancer Registry. The photosensitizing effects of hydrochlorothiazide may represent a potential mechanism for NMSC.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and advised to regularly examine their skin for new lesions and promptly report any suspicious skin changes. Patients should be advised to take preventive measures such as limiting exposure to sunlight and ultraviolet radiation and using adequate protection when exposure is unavoidable to minimize skin cancer risk. Suspicious skin lesions should be investigated promptly, potentially including histological examination of biopsies. Consideration may also need to be given to discontinuing hydrochlorothiazide in patients who have previously had NMSC (see "Adverse reactions").

Acute respiratory toxicity

Very rare cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema usually develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening pulmonary function, and hypotension. If ARDS is suspected, valsartan/hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be administered to patients who have previously experienced ARDS after taking hydrochlorothiazide.

Angioedema

Cases of angioedema (including laryngeal and glottal edema leading to airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue) have been reported 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 discontinued immediately. 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"). Symptoms observed in these patients include abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolve after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, valsartan should be discontinued and appropriate monitoring initiated until symptoms completely resolve.

Dual blockade of the RAAS

Hypotension, syncope, stroke, hyperkalemia, and renal function changes, including acute renal failure, have been observed in susceptible patients, particularly when combining drugs affecting this system. Due to dual blockade of the RAAS, concomitant use of aliskiren with angiotensin II receptor antagonists or ACE inhibitors is not recommended.

Hydrochlorothiazide may reduce plasma protein-bound iodine levels.

Hydrochlorothiazide may increase serum free bilirubin concentration.

Elderly patients – dose adjustment is not required.

Important information about certain excipients

Valsakor® H 80, Valsakor® H 160, and Valsakor® HD 160 contain lactose. This medicinal product is contraindicated in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Pregnancy

Like other drugs that directly affect the RAAS, Valsakor® H 80, Valsakor® H 160, and Valsakor® HD 160 are contraindicated in pregnancy or in women who may become pregnant. If pregnancy is detected during treatment, the drug should be discontinued immediately and, if necessary, replaced with another drug approved for use during pregnancy.

Angiotensin II antagonists may cause fetal harm similar to that caused by ACE inhibitors.

It is known that ACE inhibitors administered during the second and third trimesters of pregnancy may cause fetal injury and death. Hydrochlorothiazide crosses the placenta. In utero exposure to thiazide diuretics may lead to thrombocytopenia in the fetus or newborn and may be associated with other adverse reactions observed in adults.

Breastfeeding

If use of the drug is essential, breastfeeding should be discontinued. During breastfeeding, alternative therapies with better-established safety profiles are preferred, especially when nursing a newborn or preterm infant. There is no information on the use of valsartan during breastfeeding. Hydrochlorothiazide passes into human milk in small amounts. Thiazides in high doses cause diuresis, which may suppress milk production.

Ability to influence reaction rate while driving or operating machinery

Driving and operating machinery are prohibited at the beginning of treatment (the duration is determined by the physician). Later, the extent of restriction is determined by the physician.

Dosage and Administration

The recommended dose is 1 tablet of Valsakor® H 80 (80 mg/12.5 mg) once daily. If blood pressure is not adequately controlled after 3–4 weeks of treatment, consider increasing the dose to 1 tablet of Valsakor® H 160 (160 mg/12.5 mg) once daily. Valsakor® HD 160 (160 mg/25 mg) should be prescribed to patients in whom adequate blood pressure control is not achieved with Valsakor® H 160.

If blood pressure remains insufficiently controlled with Valsakor® HD 160, initiate treatment with valsartan/hydrochlorothiazide 320 mg/12.5 mg tablets (Valsakor® H 320). Valsartan/hydrochlorothiazide 320 mg/25 mg tablets (Valsakor® HD 320) should be used in patients who do not achieve adequate blood pressure control with valsartan/hydrochlorothiazide 320 mg/12.5 mg.

The maximum daily dose is 320 mg/25 mg.

Antihypertensive effect is primarily observed within the first 2 weeks. Maximum effect is achieved within 4 weeks in most patients. However, some patients may require 4–8 weeks of treatment. This should be taken into account during dose titration.

Valsakor® H 80, Valsakor® H 160, and Valsakor® HD 160 may be taken independently of food intake, with water.

Additional Information on Special Patient Populations

Geriatric Patients

No dose adjustment is required for elderly patients.

Renal Impairment

No dose adjustment is required in patients with mild or moderate renal impairment (eGFR ≥30 mL/min). Due to the presence of hydrochlorothiazide, the drug is contraindicated in patients with severe renal impairment (eGFR <30 mL/min) and anuria (see sections "Pharmacokinetics", "Contraindications", and "Interaction with Other Medicinal Products and Other Forms of Interaction"). Concomitant use with aliskiren is contraindicated in patients with renal impairment (eGFR <60 mL/min/1.73 m²) (see section "Contraindications").

Diabetes Mellitus

Concomitant use of valsartan and aliskiren is contraindicated in patients with diabetes mellitus (see section "Contraindications").

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"). No dose adjustment of hydrochlorothiazide is required in patients with mild or moderate hepatic impairment. Due to the presence of valsartan, the drug is contraindicated in patients with severe hepatic impairment or biliary cirrhosis and cholestasis (see sections "Pharmacokinetics", "Contraindications", and "Special Warnings and Precautions for Use").

Children

Safety and efficacy of the drug in children have not been established; therefore, its use is not recommended in this patient population.

Overdose

Symptoms

Overdose with valsartan may lead to pronounced arterial hypotension, which in turn may result in impaired consciousness, circulatory failure, and/or shock. Overdose with hydrochlorothiazide may cause the following signs and symptoms: nausea, drowsiness, hypovolemia, electrolyte imbalance, and consequently arrhythmias and muscle cramps. The most characteristic signs and symptoms of overdose also include tachycardia, arterial hypotension, shock, weakness, confusion, dizziness, muscle cramps, paresthesia, exhaustion, disturbances of consciousness, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, and elevated blood urea nitrogen levels (primarily due to renal impairment).

Treatment

Therapeutic measures depend on the time elapsed since ingestion of the excessive dose and the severity of symptoms, with stabilization of hemodynamics being the primary goal.

If the drug was recently ingested, induce vomiting. If a significant amount of time has passed since ingestion, administer an adequate amount of activated charcoal.

In case of arterial hypotension, the patient should be placed in a supine position and immediately given intravenous isotonic saline solution to restore fluid and electrolyte balance.

Valsartan is not removed by hemodialysis due to its strong plasma protein binding; however, hydrochlorothiazide can be cleared by dialysis.

Adverse Reactions

Adverse reactions occurring with the administration of valsartan/hydrochlorothiazide combination

Metabolism and nutrition disorders: dehydration.

Nervous system disorders: dizziness, paraesthesia, syncope, confusion, disorientation, nervousness, mood changes, xanthopsia.

Eye disorders: blurred vision.

Ear and labyrinth disorders: tinnitus.

Vascular disorders: hypotension.

Respiratory, thoracic and mediastinal disorders: cough, non-cardiogenic pulmonary oedema, respiratory distress, pneumonitis.

Gastrointestinal disorders: diarrhoea, thirst, salivary gland inflammation, cholecystitis.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

Skin and subcutaneous tissue disorders: purpura, toxic epidermal necrolysis, eczema.

Cardiac disorders: heart failure.

Renal and urinary disorders: renal dysfunction, interstitial nephritis.

Hepatobiliary disorders: hypochloraemic alkalosis, which may induce hepatic encephalopathy or hepatic coma.

General disorders and administration site conditions: fatigue, anaphylactic reaction, shock.

Investigations: increased serum uric acid levels, increased serum bilirubin and creatinine levels, hypokalaemia, hyponatraemia, increased blood urea nitrogen, neutropenia, hyperuricaemia (which may provoke gout attacks in patients with asymptomatic disease), reduced glucose tolerance (which may lead to manifestation of latent diabetes mellitus).

In patients with arterial hypertension, the following reactions have been observed: abdominal pain, anxiety, arthritis, back pain, bronchitis, chest pain, dizziness, dyspepsia, dyspnoea, dry mouth, epistaxis, impotence, gastroenteritis, headache, increased sweating, hypaesthesia, influenza, insomnia, ligament sprain, muscle cramps, muscle strain, nausea, nasal congestion, nasal sinus congestion, neck pain, oedema, peripheral oedema, otitis media, limb pain, palpitations, pharyngolaryngeal pain, polyuria, pyrexia, nasopharyngitis, sinusitis, somnolence, tachycardia, upper respiratory tract infections, urinary tract infections, vertigo, viral infections, visual disturbances. It is unknown whether these effects are causally related to therapy.

Additional information on individual components

Adverse reactions associated with either of the individual components may also be potential adverse effects of valsartan/hydrochlorothiazide.

Adverse reactions occurring with the administration of valsartan

Blood and lymphatic system disorders: decreased haemoglobin, decreased haematocrit, thrombocytopenia.

Immune system disorders: other hypersensitivity/allergic reactions, including serum sickness.

Metabolism and nutrition disorders: increased serum potassium, hyponatraemia.

Ear and labyrinth disorders: vertigo.

Vascular disorders: vasculitis.

Gastrointestinal disorders: abdominal pain; frequency "very rare" – intestinal angioedema.

Hepatobiliary disorders: increased liver function tests.

Skin and subcutaneous tissue disorders: angioedema, rash, pruritus.

Renal and urinary disorders: renal failure.

In patients with arterial hypertension, the following reactions have been observed: arthralgia, asthenia, back pain, diarrhoea, dizziness, headache, insomnia, decreased libido, nausea, oedema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.

Adverse reactions occurring with the administration of hydrochlorothiazide

Hydrochlorothiazide has been widely used for many years, often at higher doses than those contained in Valsakor® H 80, Valsakor® H 160 and Valsakor® HD 160. In patients receiving monotherapy with thiazide diuretics, including hydrochlorothiazide, the following adverse reactions have been reported:

Blood and lymphatic system disorders: thrombocytopenia (sometimes associated with purpura), agranulocytosis, leucopenia, haemolytic anaemia, bone marrow failure, aplastic anaemia.

Immune system disorders: hypersensitivity reactions.

Metabolism and nutrition disorders: hypokalaemia, increased blood lipids (mostly at high doses), hyponatraemia, hypomagnesaemia, hyperuricaemia, hypercalcaemia, hyperglycaemia, glucosuria, worsening of diabetic metabolic control, hypochloraemic alkalosis.

Psychiatric disorders: depression, sleep disturbances.

Nervous system disorders: headache, dizziness, paraesthesia.

Eye disorders: visual impairment, acute angle-closure glaucoma, choroidal effusion.

Cardiac disorders: cardiac arrhythmia.

Vascular disorders: postural hypotension, which may be potentiated by alcohol, anaesthetics, and sedatives.

Respiratory, thoracic and mediastinal disorders: respiratory distress, including pneumonia and pulmonary oedema, acute respiratory distress syndrome (ARDS) (see section "Special precautions").

Gastrointestinal disorders: loss of appetite, mild nausea and vomiting, constipation, gastrointestinal discomfort, diarrhoea, pancreatitis.

Hepatobiliary disorders: intrahepatic cholestasis or jaundice.

Renal and urinary disorders: acute renal failure, renal disorders.

Skin and subcutaneous tissue disorders: urticaria and other forms of rash, photosensitivity, necrotising vasculitis and toxic epidermal necrolysis, lupus erythematosus-like skin reactions, recurrence of cutaneous lupus erythematosus, polymorphic erythema.

General disorders and administration site conditions: pyrexia, asthenia, increased body temperature, increased fatigue.

Musculoskeletal and connective tissue disorders: muscle cramps.

Reproductive system and breast disorders: impotence.

Benign, malignant and unspecified neoplasms (including cysts and polyps): non-melanoma skin cancer (NMSC) (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC))¹.

¹ Non-melanoma skin cancer: Epidemiological studies have shown a cumulative dose-dependent association between hydrochlorothiazide and NMSC (see "Special precautions" and "Pharmacological properties").

Shelf life. 5 years.

Storage conditions.

Store at temperatures not exceeding 30 °C, in the original packaging to protect from light and moisture.

Keep out of reach and sight of children.

Packaging.

14 tablets in a blister, with 2, 4 or 6 blisters per carton.

15 tablets in a blister, with 2 or 4 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

KRKA, d. d., Novo mesto / KRKA, d. d., Novo mesto.

Manufacturer's address and place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.