Valmisar H tablets 80/12.5 mg No. 30

Instructions for Valmisar H tablets 80/12.5 mg No. 30

Composition

active ingredients: valsartan and hydrochlorothiazide;

1 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 of valsartan and 12.5 mg of hydrochlorothiazide, or 320 of valsartan and 25 mg of hydrochlorothiazide;

excipients:

dosage 80/12.5 mg microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

Opadry Pink 03F84641 coating: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, red iron oxide dye (E 172), yellow iron oxide (E 172);

dosage 160/12.5 mg: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

Opadry Brown 03F565001 coating: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide red dye (E 172);

dosage 160/25 mg: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

Opadry Brown 03F57311 coating: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, red iron oxide dye (E 172), yellow iron oxide dye (E 172), black iron oxide dye (E 172);

dosage 320/12.5 mg microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

Opadry Pink 03F540000 coating: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, red iron oxide dye (E 172), black iron oxide dye (E 172);

dosage 320/25 mg: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

Opadry Yellow 03F82329 coating: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide yellow dye (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties:

Valmisar H 80 mg/12.5 mg: biconvex, oval-shaped tablets, film-coated, light orange, embossed with “L16” on one side and plain on the other side;

Valmisar H 160 mg/12.5 mg: biconvex, oval-shaped tablets, film-coated, dark red, embossed with “L17” on one side and plain on the other side;

Valmisar H 160 mg/25 mg: biconvex, oval-shaped tablets, coated with a brown film coating, embossed with “L18” on one side and plain on the other side;

Valmisar H 320 mg/12.5 mg: biconvex, oval-shaped tablets, film-coated, pink, embossed with “L19” on one side and plain on the other side;

Valmisar H 320 mg/25 mg: biconvex, oval-shaped tablets, film-coated, yellow, embossed with “L20” on one side and plain on the other side.

Pharmacotherapeutic group

Angiotensin II antagonists and diuretics. Valsartan and diuretics. ATC code C09D A03.

Pharmacological properties

Pharmacodynamics.

Valsartan

Valsartan is a potent and specific angiotensin II receptor antagonist for oral administration. It acts selectively on the AT1 receptor subtype, which is responsible for the effects of angiotensin II. Increased levels of angiotensin II due to blockade of AT1 receptors by valsartan may stimulate free AT2 receptors, which counteracts the effect of AT1 receptors. Valsartan has no partial agonist activity at AT1 receptors and has a much higher (approximately 20,000-fold) affinity for AT1 receptors than for AT2 receptors.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. No bradykinin-related side effects have been observed. In clinical trials comparing valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (P < 0.05) in patients treated with valsartan than in patients treated with an ACE inhibitor (2.6% versus 7.9%, respectively). Patients previously treated with an ACE inhibitor developed dry cough, with 19.5% of patients treated with valsartan and 19% of patients treated with a thiazide diuretic developing dry cough, while in the ACE inhibitor group, cough was observed in 68.5% of patients (P < 0.05).

In controlled clinical trials, the incidence of cough in patients treated with the combination of valsartan and hydrochlorothiazide was 2.9%.

Valsartan does not interact with or block receptors for other hormones or ion channels that play an important role in regulating the functions of the cardiovascular system.

Administration of the drug to patients with hypertension leads to a decrease in blood pressure without affecting the pulse rate.

In most patients, after oral administration of a single dose of the drug, the onset of antihypertensive activity is noted within 2 hours, and the maximum reduction in blood pressure is achieved within 4–6 hours. The antihypertensive effect persists for more than 24 hours after taking a single dose. With regular use of the drug, the maximum therapeutic effect is usually achieved within 2–4 weeks and is maintained at the achieved level during long-term therapy. The combination with hydrochlorothiazide reduces blood pressure more effectively.

Valsartan does not affect the levels of total cholesterol, triglycerides, serum glucose, or uric acid in patients with hypertension.

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 diuretics, and where the transport of Na and Cl ions 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 excretion of sodium and chlorine ions increases to approximately the same extent. As a result of the diuretic action, a decrease in the volume of circulating plasma is observed, as a result of which renin activity, aldosterone secretion, urinary potassium excretion and, consequently, a decrease in the concentration of potassium in the blood serum increase. The relationship between renin and aldosterone is mediated by angiotensin II, therefore, the appointment of an angiotensin II receptor antagonist will reduce the potassium loss associated with the use of a thiazide diuretic.

Pharmacokinetics.

Valsartan/hydrochlorothiazide

The systemic availability of hydrochlorothiazide is reduced by approximately 30% when co-administered with valsartan. The kinetics of valsartan are not significantly altered when co-administered with hydrochlorothiazide. This interaction does not affect the combined use of valsartan and hydrochlorothiazide, since the clear hypotensive effect of the combination exceeds that achieved with monotherapy with either active substance or placebo.

Valsartan

Absorption. After oral administration, peak plasma concentrations of valsartan are reached within 2-4 hours. The mean absolute bioavailability is 23%. Food intake reduces the exposure (as determined by AUC) of valsartan by approximately 40% and the peak plasma concentration (Cmax) by approximately 50%, although approximately 8 hours after administration, plasma concentrations of valsartan are similar in the fed and fasting state. This decrease in AUC, however, is not accompanied by a clinically significant reduction in therapeutic effect, and valsartan can be taken without regard to food intake.

Distribution: The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 liters, indicating that valsartan is not actively distributed into tissues. Valsartan is extensively bound to serum proteins (94-97%), particularly serum albumin.

Biotransformation: Valsartan is biotransformed to a negligible extent, as only 20% of the dose is recovered as metabolites. The hydroxyl 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 multiexponential decay kinetics (t½α <1 hour and t½ß approximately 9 hours). Valsartan is excreted primarily in the feces (about 83% of the dose) and urine (about 13% of the dose), mainly unchanged.

After intravenous administration, the plasma clearance of valsartan is about 2 l/h, and the renal clearance is 0.62 l/h (about 30% of the total clearance). The half-life of valsartan is 6 hours.

Hydrochlorothiazide

Absorption. Hydrochlorothiazide is rapidly absorbed after oral administration (tmax approximately 2 hours). The increase in mean AUC is linear and dose-proportional within the therapeutic range. The effect of food on the absorption of hydrochlorothiazide is clinically insignificant. The absolute bioavailability of hydrochlorothiazide is 70% after oral administration.

Distribution: The apparent volume of distribution is 4-8 l/kg. Circulating hydrochlorothiazide is bound to plasma proteins (40-70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes in amounts approximately three times higher than in plasma.

Elimination. Hydrochlorothiazide is excreted mainly unchanged. The plasma half-life averages 6 to 15 hours at the terminal elimination stage. There is no change in the kinetics of hydrochlorothiazide upon repeated dosing, and accumulation is minimal with once-daily dosing. More than 95% of the absorbed dose is excreted unchanged in the urine. Renal clearance consists of passive filtration and active tubular secretion.

Pharmacokinetics in specific patient groups

Elderly patients. In some elderly patients, the systemic exposure to valsartan was somewhat greater than in younger patients, but this was not clinically significant. Limited data suggest that in elderly patients, both healthy and hypertensive, the systemic clearance of hydrochlorothiazide is lower than in healthy young volunteers.

There are no data on the use of Valsartan H in patients with severe renal impairment (creatinine clearance < 30 ml/min) and patients on hemodialysis. Valsartan is highly bound to plasma proteins and is not removed by hemodialysis; hydrochlorothiazide, on the contrary, is removed from the body by hemodialysis. In renal failure, the mean peak plasma level and AUC values of hydrochlorothiazide increase, and the rate of urinary excretion decreases. In patients with mild and moderate renal failure, an increase in the AUC value of hydrochlorothiazide is observed by 3 times. In patients with severe renal failure, an increase in the AUC value is observed by 8 times. Hydrochlorothiazide is contraindicated in patients with severe renal failure (see section "Contraindications").

Hepatic impairment. The systemic exposure of valsartan in patients with mild (n = 6) and moderate (n = 5) hepatic impairment was 2-fold higher than in 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, and therefore no dose reduction is required.

Non-melanoma skin cancer (NMSC)

Available epidemiological data suggest a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of NSCLC. One study included 71,533 cases of basal cell carcinoma (including 1,430,833 controls) and 8,629 cases of squamous cell carcinoma (including 172,462 controls). High doses of hydrochlorothiazide (≥ 50,000 mg cumulative) were associated with an adjusted hazard ratio (OR) of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A cumulative dose-response relationship was observed for both basal cell carcinoma and squamous cell carcinoma. Another study showed a possible association between lip cancer and hydrochlorothiazide use: 633 lip cancer cases were matched to 63,067 population controls using a risk selection 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 the high dose (25,000 mg) and OR 7.7 (5.7–10.5) for the highest dose (100,000 mg). For example, a cumulative dose of 100,000 mg corresponds to daily use of a defined daily dose of 25 mg over a period of more than 10 years.

Indication

Arterial hypertension in patients whose blood pressure is not adequately controlled by monotherapy.

Contraindication

Hypersensitivity to any of the components of the drug or to other sulfonamide derivatives.

Severe liver dysfunction, cirrhosis and cholestasis.

Anury.

Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.

Concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in patients with diabetes mellitus (type I and II) or renal impairment (GFR < 60 ml/min/1.73 m2).

Pregnancy, planning a pregnancy (see "Use during pregnancy or breastfeeding").

Hereditary angioedema or angioedema during previous use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists (ARBs).

Interaction with other medicinal products and other types of interactions

Interactions with the combination of valsartan and hydrochlorothiazide

Concomitant use is not recommended.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant use of ACE inhibitors and thiazides, including hydrochlorothiazide. Due to the lack of experience with the concomitant use of valsartan and lithium, this combination is not recommended. If the use of this combination proves necessary, careful monitoring of lithium plasma levels is recommended.

Concomitant use requiring special precautions

Other antihypertensive drugs

The drug may enhance the hypotensive effect of other antihypertensive drugs (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)

Possible decreased response to pressor amines. The clinical significance of this effect is not known for certain and is not sufficient to preclude their use.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and nonselective NSAIDs

In elderly patients, patients with reduced circulating blood volume (including those receiving diuretic therapy) or with renal dysfunction, the simultaneous use of NSAIDs (or COX-2 inhibitors) with ARA II increases the risk of worsening renal function, including acute renal failure. The combined use of these drugs requires caution and monitoring of renal function.

Interactions related to valsartan

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ARA, ACE inhibitors or aliskiren

Caution is required when ARBs, including valsartan, are co-administered with other agents that block the RAAS, such as ACE inhibitors or aliskiren.

This is associated with an increased incidence of hypotension, loss of consciousness, hyperkalemia and renal dysfunction (including acute renal failure) compared with monotherapy. Therefore, dual blockade of the RAAS by the combined use of ACE inhibitors, angiotensin receptor blockers or aliskiren is not recommended. If dual blockade of the RAAS is considered absolutely necessary, treatment should only be carried out under specialist supervision and with close monitoring of renal function, electrolytes and blood pressure.

The concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren is contraindicated in patients with diabetes mellitus (type I and II), diabetic nephropathy or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.3 and 4.8).

Concomitant use is not recommended.

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

If it is necessary to use a medicinal product that affects potassium levels in combination with valsartan, monitoring of potassium levels in the blood plasma is recommended.

The risk of hyperkalemia increases when angiotensin II receptor antagonists are used concomitantly with other medicinal products that may increase serum potassium (e.g. potassium-sparing diuretics, potassium supplements, heparin). In such cases, Valsartan should be used with caution and potassium levels should be monitored.

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 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 glibenclamide. Digoxin and indomethacin may interact with hydrochlorothiazide (see interactions related to hydrochlorothiazide).

Interactions related to hydrochlorothiazide

Concomitant use requiring special precautions

Drugs associated with potassium loss and hypokalemia

The hypokalemic effect of hydrochlorothiazide may be enhanced by concomitant use of kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormones (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid and its derivatives, and antiarrhythmics.

If the above-mentioned medicinal products are prescribed in combination with valsartan/hydrochlorothiazide, monitoring of serum potassium levels is recommended (see section 4.4).

Drugs that can induce torsades de pointes

Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution concomitantly with drugs 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 when used concomitantly with medications such as antidepressants, antipsychotics, antiepileptic drugs, etc. Long-term use of these drugs should be prescribed with caution.

Drugs that can cause torsades de pointes

Class Ia antiarrhythmics (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)

Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution simultaneously with drugs that can cause torsades de pointes.

Digitalis glycosides

Thiazide-induced hypokalemia or hypomagnesemia may occur as an undesirable effect, contributing to the development of digitalis-induced cardiac arrhythmias (see section "Special warnings and precautions for use").

Calcium salts and vitamin D

Thiazide diuretics, including hydrochlorothiazide, in combination with vitamin D or calcium salts may cause an increase in 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 conditions associated with vitamin D deficiency) due to increased tubular calcium reabsorption.

Antidiabetic medications (oral agents and insulin)

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

Metformin should be used with caution due to the risk of lactic acidosis caused by probable 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.

Medications used in the treatment of gout (probenecid, sulfinpyrazone, and allopurinol)

There is a need for dose adjustment of antigout drugs, as hydrochlorothiazide may increase serum uric acid levels. If necessary, the dose of probenecid or sulfinpyrazone should be increased. Concomitant administration of thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol.

Anticholinergic drugs and other drugs that affect gastric motility

The bioavailability of thiazide diuretics may be increased by anticholinergic drugs (e.g. atropine, biperiden), in particular due to a decrease in gastric motility and gastric emptying rate. In turn, prokinetic drugs, e.g. cisapride, are expected to reduce the bioavailability of thiazide diuretics.

Amantadine

Thiazides, including hydrochlorothiazide, increase the risk of side effects caused by amantadine.

Ion exchange resins

The absorption of thiazide diuretics, including hydrochlorothiazide, is impaired by concomitant administration of cholestyramine or colestipol.

This may lead to subtherapeutic effects of thiazide diuretics. To minimize the interaction, hydrochlorothiazide should be administered at least 4 hours before or 4-6 hours after taking the resins.

Cytotoxic drugs (e.g. cyclophosphamide, methotrexate)

Thiazides may reduce the renal excretion of cytotoxic drugs and potentiate their myelosuppressive effect.

Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine)

Thiazides, including hydrochlorothiazide, enhance the effects of skeletal muscle relaxants such as curare derivatives.

Cyclosporine

Concomitant use with cyclosporine may increase the risk of hyperuricemia and the appearance of symptoms resembling an exacerbation of gout.

Alcohol, anesthetics and sedatives

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

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

Contrast agents containing iodine

In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine-containing preparations. The patient should be adequately rehydrated before use.

Application features

Changes in serum electrolyte balance

Potassium

Thiazide diuretics may cause hypokalemia or complicate pre-existing hypokalemia.

Since Valmisar H contains an angiotensin II receptor antagonist, caution should be exercised when Valmisar H is used concomitantly with potassium salts, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (e.g. heparin). Cases of hypokalaemia have been reported during treatment with thiazide diuretics. It is recommended that serum potassium and magnesium levels be monitored regularly in patients with conditions associated with increased potassium loss. Electrolyte balance should be monitored in all patients receiving thiazide diuretics.

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

Treatment with thiazide diuretics is often associated with the development of hyponatremia or with exacerbation of pre-existing hyponatremia and hypochloraemic alkalosis. This may be accompanied by neurological symptoms (vomiting, confusion, apathy). Thiazide diuretics should only be used after correction of hyponatremia. Serum sodium concentration should be monitored regularly.

Thiazides increase the urinary excretion of magnesium, which can ultimately lead to hypomagnesemia.

In patients with severe sodium and/or volume depletion (e.g. those receiving high doses of diuretics), symptomatic hypotension may occur in isolated cases after initiation of therapy with the drug. Correction of sodium and/or volume depletion should be performed before initiation of therapy.

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 resumed as soon as blood pressure has stabilized.

Calcium

Thiazide diuretics reduce urinary calcium excretion and may cause an increase in serum calcium. Thiazide diuretics should be used only after correction of hypercalcemia or treatment of the underlying condition. Serum calcium should be monitored regularly.

Patients with severe chronic heart failure with congestive heart failure or other conditions with stimulation of the renin-angiotensin-aldosterone system (RAAS)

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, rarely with acute renal failure. The use of Valmisar H in patients with severe chronic heart failure is not justified.

Since it cannot be excluded that due to inhibition of the renin-angiotensin-aldosterone system, the use of Valmisar H may also be associated with impaired renal function, the drug should not be used in such patients.

Renal artery stenosis

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

Primary hyperaldosteronism

The drug is not recommended for use in patients with primary hyperaldosteronism, as their RAAS is not activated.

Aortic stenosis of the mitral valve, hypertrophic obstructive cardiomyopathy

As with other vasodilators, special caution should be exercised in patients with aortic or mitral valve stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).

Kidney dysfunction

No dose adjustment is required for patients with mild to moderate renal impairment (creatinine clearance ≥ 30 ml/min).

Valmisar H should be used with caution in severe renal insufficiency (creatinine clearance < 30 ml/min). Thiazide diuretics can provoke azotemia in patients with chronic renal impairment. They are ineffective as monotherapy in severe renal insufficiency (creatinine clearance < 30 ml/min), but they can be used with due caution in combination with loop diuretics even in patients with creatinine clearance < 30 ml/min.

In patients with impaired renal function (creatinine clearance < 60 ml/min), concomitant use of angiotensin receptor blockers, including Valsartan H or angiotensin-converting enzyme inhibitors, with aliskiren is contraindicated.

There is no experience with the use of valsartan in patients with end-stage renal disease (creatinine clearance < 10 ml/min) or in patients undergoing dialysis.

Kidney transplantation

There are currently no data on the safety of the drug in patients who have recently undergone a kidney transplant.

Liver dysfunction

Caution is required when treating patients with impaired hepatic function. No dose adjustment is required in patients with mild to moderate hepatic impairment without cholestasis. Liver disease does not significantly alter the pharmacokinetics of hydrochlorothiazide.

Thiazides may cause electrolyte imbalance, hepatic encephalopathy and hepatorenal syndrome. Therefore, Valmisar N should be prescribed to such patients only after a risk-benefit assessment and monitoring of clinical and laboratory parameters. Valmisar N is contraindicated in patients with biliary cirrhosis or cholestasis.

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

Other metabolic disorders

Thiazide diuretics may affect glucose tolerance and increase serum cholesterol, triglycerides and uric acid levels, which may exacerbate hyperuricemia and lead to gout. Therefore, Valmisar H is not recommended for use in patients with hyperuricemia and/or gout. Diabetics may require adjustment of the dose of insulin or oral hypoglycemic agents.

Thiazides may reduce urinary calcium excretion and cause intermittent and minor increases in serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may indicate the presence of hyperparathyroidism. Thiazides should be discontinued before parathyroid function tests are performed.

Photosensitivity

Photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If a photosensitivity reaction occurs during treatment with the drug, it is recommended to discontinue treatment. If the diuretic needs to be restarted, it is recommended to protect the affected areas from the sun or artificial UV radiation.

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonist 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 with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

General disorders

Caution should be exercised when using the drug in patients with a history of hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies and asthma.

Angioedema

Angioedema (including swelling of the larynx and glottis leading to 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 angiotensin II receptor antagonists, including ACE inhibitors. If angioedema develops, treatment with angiotensin II receptor antagonists should be discontinued immediately. Re-administration is contraindicated.

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

The use of hydrochlorothiazide, a sulfonamide, has been associated with an idiosyncratic reaction that may result in choroidal effusion with visual field defect, acute transient myopia, and acute angle-closure glaucoma. Symptoms include acute decrease in visual acuity or eye pain, usually occurring within a few hours to a week after drug administration. Untreated acute angle-closure glaucoma may result in permanent vision loss.

Hydrochlorothiazide treatment should be discontinued as soon as possible. Urgent medical or surgical attention may be required. Risk factors for the development of acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillins.

Patients with heart failure, previous myocardial infarction

In patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe heart failure), treatment with ACE inhibitors or angiotensin receptor antagonists may be associated with oliguria and/or progressive azotemia and, in rare cases, with acute renal failure and fatal outcome. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function.

Non-melanoma skin cancer (NMSC)

An increased risk of NSCLC (basal cell carcinoma and squamous cell carcinoma) with increasing cumulative dose of hydrochlorothiazide was observed in two epidemiological studies based on the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be a potential mechanism for the development of NSCLC.

Patient