Instructions for Valsakor film-coated tablets 320 mg No. 28
Composition
active ingredients: 1 film-coated tablet contains 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, croscarmellose sodium, povidone, colloidal anhydrous silica; hypromellose, titanium dioxide (E 171), macrogol 4000, red iron oxide (E 172) – only in Valsakor® H 320, yellow iron oxide (E 172) – only in Valsakor® HD 320.
Dosage form
Film-coated tablets.
Main physicochemical properties:
Valsakor® H 320: oval biconvex tablets, film-coated, pink in color;
Valsakor® HD 320: oval, biconvex, film-coated tablets, light yellow in color, with a score on one side.
Pharmacotherapeutic group
Angiotensin II antagonists and diuretics. ATC code C09D A03.
Pharmacological properties
Pharmacodynamics.
Valsartan/hydrochlorothiazide
The positive effect of valsartan in combination with hydrochlorothiazide on cardiovascular mortality and morbidity is still unknown.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
Valsartan
Valsartan is an active, potent and specific angiotensin II receptor (AR) antagonist for oral administration. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. When the concentration of angiotensin II in the blood plasma increases after blockade of AT1 receptors, stimulation of unblocked AT2 receptors occurs, which regulate the action of AT1 receptors. Valsartan does not exhibit any agonist activity towards AT1 receptors and has a much higher affinity (approximately 20,000 times) for AT1 receptors than for AT2 receptors. It is not known whether valsartan binds to or blocks other hormone receptors or ion channels that are important in cardiovascular regulation.
Valsartan does not inhibit the activity of angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and catalyzes the breakdown of bradykinin. Since there is no effect on ACE and no increase in bradykinin or substance P levels, it is unlikely that angiotensin II antagonists would be associated with cough.
Administration of valsartan to patients with hypertension results in a reduction in blood pressure without a change in heart rate. In most patients, the onset of antihypertensive action occurs within 2 hours after a single oral dose, and the maximum reduction in blood pressure is achieved within 4-6 hours. The antihypertensive effect lasts for more than 24 hours after dosing. With repeated dosing, the maximum effect is achieved within 2-4 weeks and is maintained during long-term therapy. In combination with hydrochlorothiazide, an additional reduction in blood pressure is achieved.
Abrupt discontinuation of valsartan did not result in the appearance of arterial hypertension or other adverse clinical events.
Hydrochlorothiazide
The point of action of thiazide diuretics is the cortical part of the distal convoluted renal tubules, where receptors are located that are highly sensitive to the action of thiazide diuretics, and where the transport of Na and Cl ions into the distal convoluted tubules is inhibited. The mechanism of action of thiazides is associated with the inhibition of the Na+Cl- pump, which, apparently, occurs due to competition for Cl- transport sites. As a result, the mechanisms of electrolyte reabsorption change: the excretion of sodium and chloride increases to approximately the same extent; as a result of the diuretic effect, a decrease in the volume of circulating plasma is observed with a subsequent increase in renin activity, aldosterone secretion and urinary potassium excretion and, consequently, a decrease in the concentration of potassium in the blood serum. The relationship between renin and aldosterone is mediated by angiotensin II, therefore, concomitant treatment with valsartan, possibly through blockade of the renin-angiotensin-aldosterone system (RAAS), reduces hydrochlorothiazide-induced potassium excretion compared with hydrochlorothiazide monotherapy.
Non-melanoma skin cancer
Available epidemiological data suggest a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of NMSC. One study included a population consisting of 71,533 BCC cases and 8,629 CVD cases, corresponding to 1,430,833 and 172,462 controls, respectively. High levels of hydrochlorothiazide use (cumulative ≥ 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 CVD. A clear cumulative dose-response relationship was observed for both BCC and RCC. Another study showed a possible association between lip cancer (LC) and hydrochlorothiazide exposure: 633 cases of lip cancer were matched to 63,067 controls using a population-based sampling strategy. A cumulative dose-adjusted OR of 2.1 (95% CI: 1.7-2.6) was demonstrated, increasing to an OR of 3.9 (3.0-4.9) for high use (25,000 mg) and an OR of 7.7 (5.7-10.5) for the highest cumulative dose (100,000 mg) (see Precautions).
Pharmacokinetics.
The systemic bioavailability of hydrochlorothiazide is reduced by approximately 30% when co-administered with valsartan. The kinetics of valsartan are not significantly affected by co-administration of hydrochlorothiazide. This apparent interaction does not affect the combined use of valsartan and hydrochlorothiazide, since controlled clinical trials have shown a clear antihypertensive effect greater than that obtained with either active substance alone or placebo.
Valsartan
Absorption
After oral administration of valsartan alone, peak plasma concentrations (Cmax) are reached within 2-4 hours. The mean absolute bioavailability is 23%. Food intake reduces valsartan exposure, as measured by the mean area under the concentration-time curve (AUC) by approximately 40% and Cmax by approximately 50%, although plasma valsartan concentrations in the fasted and fed states are similar approximately 8 hours after dosing. However, this reduction in mean AUC is not associated with a clinically significant reduction in therapeutic effect, and valsartan can be administered either with or without food.
Distribution
The volume of distribution of valsartan at steady state after intravenous administration is approximately 17 L. This indicates that valsartan is not extensively distributed into tissues. Valsartan is highly bound to serum proteins (94-97%), mainly to serum albumin.
Biotransformation
Valsartan is not extensively biotransformed, with only about 20% of the dose recovered as metabolites. The hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of the mean AUC of valsartan). This metabolite is pharmacologically inactive.
Breeding
Valsartan shows multiexponential decay kinetics (t1/2a <1 hour and t1/2β approximately 9 hours). Valsartan is excreted primarily via the biliary tract in the feces (approximately 83% of the dose) and renally in the urine (approximately 13% of the dose), mainly unchanged. After intravenous administration, the plasma clearance of valsartan is approximately 2 l/hour, and its renal clearance is 0.62 l/hour (approximately 30% of the 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), with similar absorption profiles for the suspension and tablet formulations. The absolute bioavailability of hydrochlorothiazide is 60-80% after oral administration. Concomitant administration with food has been reported to result in both an increase and a decrease in the systemic bioavailability of hydrochlorothiazide compared with the fasting state. The frequency of these effects is small and of minimal clinical significance. The increase in mean AUC is linear and dose-proportional over the therapeutic dose range. There is no change in the kinetics of hydrochlorothiazide with repeated dosing, and accumulation is minimal with once-daily dosing.
Distribution
The kinetics of distribution and elimination are generally described by a biexponential decline curve. The apparent volume of distribution is 4-8 l/kg. Hydrochlorothiazide in the general circulation binds to serum proteins (40-70%), mainly serum albumin.
Hydrochlorothiazide also accumulates in erythrocytes, approximately 1.8 times higher than plasma levels.
Breeding
More than 95% of the absorbed dose of hydrochlorothiazide is excreted unchanged in the urine. Renal excretion consists of passive filtration and active secretion in the renal tubules. The terminal half-life is 6-15 hours.
Special patient groups
Elderly people
Slightly higher systemic exposure to valsartan was observed in some elderly subjects than in young subjects; however, this has not been shown to have any clinical significance.
Limited data indicate that the systemic clearance of hydrochlorothiazide is reduced in both healthy elderly subjects and elderly subjects with hypertension compared to healthy young volunteers.
Kidney dysfunction
At the recommended dose of valsartan/hydrochlorothiazide, no dose adjustment is required for patients with creatinine clearance 30-70 ml/min.
There are no data for valsartan/hydrochlorothiazide in patients with severe renal impairment (creatinine clearance < 30 ml/min) and patients undergoing dialysis. Valsartan is highly bound to plasma proteins and is not dialysable, whereas hydrochlorothiazide is cleared by dialysis.
Renal clearance of hydrochlorothiazide consists of passive filtration and active tubular secretion. As expected for a substance that is almost entirely excreted by the kidneys, renal function has a marked effect on the kinetics of hydrochlorothiazide.
Liver dysfunction
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.
Indication
Arterial hypertension in patients whose blood pressure is not adequately controlled by monotherapy.
Contraindication
Hypersensitivity to the active substances or to any of the components of the drug; hypersensitivity to any sulfonamide drug; severe liver dysfunction, cirrhosis and cholestasis; anuria, severe renal dysfunction (creatinine clearance < 30 ml/min); hypokalemia, hyponatremia, hypercalcemia or symptomatic hyperuricemia, resistant to therapy; concomitant use of angiotensin receptor antagonists - including valsartan or angiotensin-converting enzyme inhibitors (ACEIs) with aliskiren in patients with diabetes mellitus or renal insufficiency (glomerular filtration rate (GFR) < 60 ml/min/1.73 m2); pregnant women or women planning to become pregnant (see "Use during pregnancy and lactation").
Interaction with other medicinal products and other types of interactions
Concomitant use is not recommended.
Lithium
Transient increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors and thiazides, including hydrochlorothiazide. Due to insufficient experience with the concomitant use of valsartan and lithium, this combination is not recommended. If the combination proves necessary, monitoring of serum lithium levels is recommended.
Concomitant use requiring caution
Other antihypertensive drugs
Valsakor® H 320 and Valsakor® HD 320 may enhance the effects of other drugs with antihypertensive properties (e.g. ACE inhibitors, beta-blockers, calcium channel blockers).
Pressor amines (e.g. adrenaline)
A reduced response to pressor amines is possible, but this is not sufficient to stop taking them.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid > 3 g/day, and nonselective NSAIDs
Concomitant use of angiotensin II receptor blockers (ARBs) with NSAIDs may result in a weakening of the antihypertensive effect. Concomitant use of Valsacor® H 320 and Valsacor® HD 320 and NSAIDs may increase the risk of worsening renal function and lead to an increase in serum potassium.
Therefore, monitoring of renal function at the beginning of treatment is recommended, as well as adequate fluid intake.
Interactions related to valsartan
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ARA, ACE inhibitors or aliskiren
When ARBs, including valsartan, are used concomitantly with other RAAS-blocking agents such as ACE inhibitors or aliskiren, the incidence of hypotension, syncope, hyperkalemia, and renal dysfunction (including acute renal failure) is increased compared with monotherapy. Dual blockade of the RAAS with ACE inhibitors, ARBs, or aliskiren is not recommended. If dual RAAS blockade is considered absolutely necessary, it should be used only under specialist supervision and with close monitoring of renal function, electrolytes, and blood pressure.
The concomitant use of ARBs, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with severe renal impairment (GFR < 60 ml/min/1.73 m2), patients with type 1 and 2 diabetes mellitus, and patients with diabetic nephropathy.
Concomitant use is not recommended.
Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that can increase potassium levels
If there is a need to take a medicinal product that affects potassium levels in combination with valsartan, monitoring of potassium levels in the blood plasma is recommended.
Conveyors
In vitro studies have shown that valsartan is a substrate for the hepatic uptake transporter OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical significance of these findings is unknown. Concomitant use of inhibitors of the uptake transporter (e.g. rifampicin, cyclosporine) or efflux transporter (e.g. ritonavir) may increase systemic exposure to valsartan. Appropriate precautions should be taken when initiating or discontinuing concomitant use of these medicinal products.
Lack of interaction
Studies have not revealed any clinically significant interaction of valsartan with any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Digoxin and indomethacin may interact with the hydrochlorothiazide component of Valsacor® H 320 and Valsacor® HD 320 (see "Interactions related to hydrochlorothiazide").
Interactions related to hydrochlorothiazide
Concomitant use requiring caution
Drugs associated with increased potassium loss and hypokalemia (e.g., kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormones, amphotericin, carenoxolone, penicillin G, salicylic acid and derivatives).
If these drugs must be prescribed together with the combination of valsartan/hydrochlorothiazide, monitoring of plasma potassium levels is recommended. These drugs may potentiate the effect of hydrochlorothiazide on serum potassium levels.
Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution with medicinal products that may induce torsades de pointes, in particular class Ia and III antiarrhythmics and some antipsychotics.
Drugs that affect serum sodium levels
The hyponatremic effect of diuretics may be enhanced by concomitant administration of such drugs as antidepressants, antipsychotics, antiepileptic drugs, etc. Caution is recommended in the long-term use of these drugs.
Drugs that can cause ventricular tachycardia "torsades de pointes":
Class Ia antiarrhythmic drugs (e.g. quinidine, hydroquinidine, disopyramide);
class III antiarrhythmic drugs (e.g. amiodarone, sotalol, dofetilide, ibutilide);
some neuroleptics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
others (e.g. bepridil, cisapride, diphemanil, erythromycin intravenously, halofantrine, mizolastine, pentamidine, terfenadine, vincamine intravenously).
Due to the risk of hypokalemia, hydrochlorothiazide should be administered with caution with drugs that can induce ventricular tachycardia "torsades de pointes".
Cardiac glycosides
In the presence of digitalis-induced cardiac arrhythmias, hypokalemia or hypomagnesemia may occur when taking thiazides.
Calcium salts and vitamin D
The 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, malignancy, or vitamin D-mediated conditions) by increasing tubular calcium reabsorption.
Antidiabetic drugs (oral agents and insulin)
Thiazide therapy may affect glucose tolerance. Dose adjustment of the antidiabetic drug may be necessary. Metformin should be used with caution due to the risk of lactic acidosis caused by possible functional renal failure associated with hydrochlorothiazide.
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.
Medicines used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol)
Dose adjustment of uricosuric agents may be necessary, as hydrochlorothiazide may increase serum uric acid levels. Dose increase of probenecid or sulfinpyrazone may be necessary. Concomitant use of thiazides may increase the incidence of hypersensitivity reactions to allopurinol.
Anticholinergic drugs (e.g. atropine, biperiden)
These drugs may increase the bioavailability of thiazide-type diuretics, possibly by reducing gastrointestinal and intestinal peristalsis and gastric emptying rate. Conversely, prokinetic drugs such as cisapride may be expected to reduce the bioavailability of thiazide-type diuretics.
Amantadine
Thiazides, including hydrochlorothiazide, may increase the risk of side effects caused by amantadine.
Ion exchange resins
The absorption of thiazide diuretics, including hydrochlorothiazide, is reduced by cholestyramine or colestipol. This may result in subtherapeutic effects of thiazide diuretics. However, staggering the timing of hydrochlorothiazide and resin administration so that hydrochlorothiazide is taken at least 4 hours before or 4 to 6 hours after the resin administration may minimize the risk of interaction.
Cytotoxic drugs (e.g. cyclophosphamide, methotrexate)
Thiazides, including hydrochlorothiazide, may reduce the renal excretion of cytotoxic drugs and enhance their myelosuppressive effects.
Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine)
Thiazides, including hydrochlorothiazide, enhance the effect of curare derivatives.
Cyclosporine
Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-like complications.
Alcohol, barbiturates, narcotics, or antidepressants
In the case of simultaneous use of thiazide diuretics with drugs that can also lower blood pressure (for example, by reducing the activity of the sympathetic central nervous system or direct vasodilator action), potentiation of orthostatic hypotension is possible.
Methyldopa
There have been reports of cases of hemolytic anemia occurring with concomitant use of hydrochlorothiazide and methyldopa.
Carbamazepine
Symptomatic hyponatremia may develop in patients taking hydrochlorothiazide concomitantly with carbamazepine. Therefore, such patients should be informed of the possibility of hyponatremic reactions and monitored appropriately.
In case of dehydration caused by diuretics, there is an increased risk of acute renal failure, especially with high doses of iodine preparation. Before its administration, patients should be rehydrated.
Application features
Serum electrolyte imbalance
Valsartan
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels (e.g. heparin) is not recommended. Potassium levels should be monitored if necessary.
Hydrochlorothiazide
Hypokalemia has been reported during treatment with thiazide diuretics, including hydrochlorothiazide. Frequent monitoring of serum potassium is recommended.
Treatment with thiazide diuretics, including hydrochlorothiazide, has been associated with hyponatremia and hypochloraemic alkalosis. Thiazides, including hydrochlorothiazide, increase urinary magnesium excretion, which may lead to hypomagnesemia. Thiazide diuretics decrease calcium excretion. This may lead to hypercalcemia.
Periodic serum electrolyte analysis should be performed at appropriate intervals for every patient receiving diuretic therapy.
Patients with sodium and/or volume imbalance
Patients taking thiazide diuretics should be monitored for clinical signs of fluid or electrolyte imbalance.
In patients with severe sodium and/or volume imbalance (e.g. those taking high doses of diuretics), symptomatic hypotension may occur in rare cases after starting therapy with Valsacor® H 320 and Valsacor® HD 320. The sodium and/or volume imbalance should be corrected before starting treatment with Valsacor® H 320 and Valsacor® HD 320.
In case of hypotension, the patient should be placed in the supine position and, if necessary, an intravenous infusion of saline should be given. Treatment may be continued as soon as blood pressure has stabilized.
Patients with severe congestive heart failure or other conditions with stimulation of the renin-angiotensin-aldosterone system
In patients whose renal function depends mainly on the activity of the RAAS (e.g. patients with severe congestive heart failure), treatment with agents that act on the RAAS may cause oliguria and/or progressive azotemia, in rare cases with acute renal failure. The safety of Valsakor® H 320 and Valsakor® HD 320 in patients with severe congestive heart failure has not been established.
Therefore, it should not be excluded that renal failure may develop due to inhibition of the RAAS when using Valsakor® H 320 and Valsakor® HD 320.
Valsakor® H 320 and Valsakor® HD 320 should not be used in such patients.
Renal artery stenosis
Valsakor® H 320 and Valsakor® HD 320 should not be used to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, as blood urea and serum creatinine levels may increase in such patients.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not use Valsakor® H 320 and Valsakor® HD 320, as their RAAS is not activated.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, special caution should be exercised in patients suffering from aortic or mitral valve stenosis or hypertrophic obstructive cardiomyopathy.
Kidney dysfunction
No dose adjustment is required for patients with mild to moderate renal impairment and creatinine clearance ≥ 30 ml/min. Valsakor® H 320 and Valsakor® HD 320 should be used with caution in severe renal impairment (creatinine clearance <30 ml/min). Thiazide diuretics may provoke azotemia in patients with chronic renal impairment. They are ineffective as monotherapy in severe renal impairment (creatinine clearance <30 ml/min), but they can be used with caution in combination with loop diuretics even in patients with creatinine clearance <30 ml/min.
Kidney transplantation
There is no experience with the safe use of Valsacor® H 320 and Valsacor® HD 320 in patients with a recent kidney transplant.
Liver dysfunction
In patients with mild to moderate hepatic impairment without cholestasis, no dose adjustment is required. However, Valsacor® H 320 and Valsacor® HD 320 should be used with caution. Liver disease does not significantly alter the pharmacokinetic parameters of hydrochlorothiazide.
Angioedema
Angioedema (including laryngeal and glottis swelling resulting in airway obstruction and/or swelling of the face, lips, pharynx and/or tongue) has been reported in patients treated with valsartan, some of whom had a history of angioedema with other drugs, including other ARBs. If angioedema develops, ARB treatment should be discontinued immediately. Re-administration is contraindicated.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics, including hydrochlorothiazide.
Other metabolic disorders
Thiazide diuretics, including hydrochlorothiazide, may impair glucose tolerance and increase serum cholesterol, triglycerides, and uric acid. Dosage adjustment of antidiabetic agents, including insulin, may be required in diabetic patients.
Thiazides may reduce urinary calcium excretion and cause a concomitant and minor increase in serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be a manifestation of latent hyperaldosteronism. Thiazides should be discontinued before testing parathyroid function.
Photosensitivity
Photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reactions occur during treatment, it is recommended to discontinue treatment. If re-administration of the diuretic is necessary, it is recommended to protect areas that may be exposed to the sun or artificial ultraviolet light.
Pregnancy
Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment should be stopped immediately, and, if appropriate, alternative therapy should be started.
General
Caution should be exercised in patients with hypersensitivity to other ARBs. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies and asthma.
Choroidal effusion, acute myopia, and secondary acute angle-closure glaucoma
Sulfonamides and sulfonamide derivatives may cause idiosyncratic reactions resulting in choroidal effusion with visual field defect, acute transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain, usually occurring within hours to weeks of starting the drug. Untreated acute angle-closure glaucoma may result in permanent vision loss.
Treatment with the drug should be discontinued as soon as possible. Urgent medical or surgical attention may be required if intraocular pressure remains uncontrolled. Risk factors for the development of acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillins.
Non-melanoma skin cancer
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 act as a possible mechanism for NMSC.
Patients taking hydrochlorothiazide should be informed of the risk of developing NMSC and advised to regularly examine their skin for new lesions and to report suspicious skin lesions immediately. Patients should be advised of possible preventive measures, such as limited exposure to sunlight and ultraviolet light and, if exposed, appropriate protection, to minimise the risk of skin cancer. Suspicious skin lesions should be investigated promptly, potentially including histological examination of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients with a history of NMSC (see Adverse Reactions).
Acute respiratory toxicity
Very rare cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported following the administration of hydrochlorothiazide. Pulmonary oedema usually develops within minutes to hours of taking hydrochlorothiazide. Initial symptoms include dyspnoea, fever, worsening pulmonary function and hypotension. If ARDS is suspected, valsartan/hydrochlorothiazide should be discontinued and appropriate treatment should be initiated. Hydrochlorothiazide should not be given to patients who have previously experienced ARDS after taking hydrochlorothiazide.
Dual blockade of RAAS
Hypotension, syncope, stroke, hyperkalemia and changes in renal function, including acute renal failure, have been observed in susceptible individuals, especially with the combination of drugs that affect this system. Due to dual blockade of the RAAS, the concomitant use of aliskiren and ARA II or ACE inhibitors is not recommended.
Special information about some of the excipients
Valsakor® H 320 and Valsakor® HD 320 contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
No dose adjustment is required for elderly patients.
Hydrochlorothiazide may reduce the level of protein-bound iodine in the blood plasma. Hydrochlorothiazide may increase the concentration of free bilirubin in the blood serum.
Use during pregnancy or breastfeeding
Like other drugs that directly act on the RAAS, Valsakor® H 320 and Valsakor® HD 320 are contraindicated for use in pregnant women or women planning to become pregnant. If pregnancy is detected during therapy, Valsakor® H 320 or Valsakor® HD 320 should be discontinued immediately and, if necessary, replaced with another drug approved for use in pregnant women.
ARA II can cause fetal harm similar to that caused by ACE inhibitors.
It is known that the use of ACE inhibitors during the second and third trimesters of pregnancy can cause damage and death to the fetus.
Hydrochlorothiazide crosses the placenta. Intrauterine exposure to thiazide diuretics may result in thrombocytopenia in the fetus or newborn and may be associated with other adverse reactions occurring in adults.
Breastfeeding period
If use of the drug is clearly necessary, breast-feeding should be discontinued. Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. There is no information regarding the use of valsartan during breast-feeding. Hydrochlorothiazide is excreted in human milk in small quantities. Thiazides in high doses cause diuresis, which may suppress milk production.
Ability to influence reaction speed when driving vehicles or other mechanisms
At the beginning of the use of the drug (the period is determined individually by the doctor), it is forbidden to drive a car and perform work that may lead to an accident. Later, the degree of prohibition is determined by the doctor.
Method of administration and doses
Dosage
The recommended dose of Valsakor® H 320 and Valsakor® HD 320 is 1 tablet per day. Titration of the individual components is recommended. In each case, the increase to the next dose by titration of the individual components should be monitored to reduce the risk of arterial hypotension and other adverse events.
When clinically appropriate, direct transfer from monotherapy to the fixed combination may be considered for patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy, respectively, provided that the recommended dose titration sequence for the individual components is followed.
The clinical response to Valsacor® H 320 should be assessed after initiation of therapy. If adequate blood pressure reduction is not achieved, patients should be switched to Valsacor® HD 320.
The maximum daily dose is 320 mg/25 mg.
The antihypertensive effect is mainly observed in the first 2 weeks of treatment.
In most patients, the maximum effect is observed within 4 weeks. However, some patients may require 4-8 weeks of treatment. This should be taken into account when titrating the dose.
If no relevant additional effect is observed after 8 weeks of taking Valsacor® HD 320, a decision should be made to treat with an additional or alternative antihypertensive drug.
Application method
Valsakor® H 320 and Valsakor® HD 320 can be taken regardless of meals, washing down the tablets with water.
Kidney dysfunction
For patients with renal insufficiency, it is unknown
