Lizopress 10

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LIZOPRES 10, LIZOPRES 20 (LISOPRES 10, LISOPRES 20)

Composition:

Active substances: lisinopril (as lisinopril dihydrate) and hydrochlorothiazide;

One tablet contains 10 mg or 20 mg of lisinopril (as lisinopril dihydrate) and 12.5 mg of hydrochlorothiazide;

Excipients: mannitol (E 421), calcium hydrogen phosphate dihydrate, maize starch, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: flat cylindrical white or almost white tablets with a bevel.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors and diuretics. ATC code C09BA03.

Pharmacological Properties

Lizopres is a fixed-dose combination preparation containing lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, and hydrochlorothiazide—a thiazide diuretic. Both components exhibit mutually complementary and additive antihypertensive effects.

Pharmacodynamics

Lisinopril. Mechanism of action.

Lisinopril is an inhibitor of the enzyme peptidyl-dipeptidase. Lisinoprial inhibits angiotensin-converting enzyme (ACE), which catalyzes the conversion of angiotensin I into the vasoconstrictor peptide angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. As a result of ACE inhibition, angiotensin II concentrations decrease, leading to reduced vasoconstrictive activity and suppression of aldosterone secretion. This effect leads to an increase in serum potassium concentration.

Lisinopril is believed to reduce blood pressure primarily through inhibition of the renin-angiotensin-aldosterone system (RAAS). However, lisinopril exerts antihypertensive effects even in patients with low-renin hypertension. ACE is identical to kininase II, an enzyme involved in bradykinin degradation. It is not known whether increased levels of bradykinin (a potent vasodilator peptide) influence the therapeutic effect of lisinopril.

Clinical efficacy and safety

Agents affecting the renin-angiotensin system (RAS)

It is known that two large-scale randomized controlled trials (ONTARGET [ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial] and VA NEPHRON-D [The Veterans Affairs Nephropathy in Diabetes]) evaluated the use of combining an ACE inhibitor with an angiotensin II receptor blocker.

The ONTARGET trial included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ ischemic damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.

In these trials, no significant beneficial effect on renal and/or cardiovascular outcomes or mortality was demonstrated; instead, there was an increased risk of hyperkalemia, acute kidney injury, and/or hypotension compared to monotherapy. These results are also considered applicable to other ACE inhibitors and angiotensin II receptor blockers due to their similar pharmacodynamic properties. Therefore, ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

It is known that the ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was conducted to evaluate the potential benefit of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or both. The trial was terminated prematurely due to an increased risk of adverse events. The rate of fatal outcomes due to cardiovascular events and stroke was higher in the aliskiren group compared to the placebo group, and adverse reactions, including serious ones (hyperkalemia, hypotension, and renal failure), occurred more frequently in the aliskiren group than in the placebo group.

Hydrochlorothiazide. Mechanism of action.

Hydrochlorothiazide is a diuretic and antihypertensive agent. It affects electrolyte reabsorption in the distal renal tubules and increases excretion of sodium and chloride ions to a similar extent. Natriuresis may be accompanied by some loss of potassium and bicarbonates. The mechanism of antihypertensive action of thiazide diuretics has not been fully established.

Thiazides generally do not affect normal blood pressure.

Non-melanoma skin cancer (NMSC)

Epidemiological study data indicate an association between cumulative dose of hydrochlorothiazide and the development of NMSC. A clear dose-response relationship was observed for both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). There is evidence suggesting a possible link between lip cancer (SCC) and hydrochlorothiazide use (see section "Special precautions").

Pharmacokinetics

Concomitant administration of lisinopril and hydrochlorothiazide has minimal effect (or no effect at all) on the bioavailability of each component. The fixed-dose combination is bioequivalent to the separate administration of the individual components as distinct dosage forms.

Lisinopril

Absorption. After oral administration of lisinopril, peak plasma concentrations are reached within approximately 7 hours, although there is a tendency toward slight delay in time to peak concentration in patients with acute myocardial infarction. Based on urinary excretion data, the mean absorption of lisinopril across the studied dose range (5–80 mg) is approximately 25%, with inter-subject variability ranging from 6% to 60%. Absolute bioavailability is reduced by approximately 16% in patients with heart failure. Absorption of lisinopril is not affected by food intake.

Distribution. Lisinopril does not bind to other serum proteins except circulating angiotensin-converting enzyme (ACE).

It is known that lisinopril poorly penetrates the blood-brain barrier.

Elimination. Lisinopril is not metabolized, and the entire absorbed amount is excreted unchanged by the kidneys. With repeated dosing, lisinopril has an effective accumulation half-life of 12.6 hours. The clearance of lisinopril in healthy volunteers is approximately 50 mL/min. The decline in serum concentration indicates a prolonged terminal phase, which is not due to drug accumulation. This terminal phase may reflect saturable binding to ACE and is not dose-dependent.

Hepatic impairment.

Compared to healthy volunteers, patients with hepatic impairment due to cirrhosis showed reduced absorption (approximately 30% lower based on urinary excretion data), but increased effect of lisinopril (approximately 50% higher) due to reduced clearance.

Renal impairment.

In renal impairment, elimination of lisinopril, which is primarily excreted by the kidneys, is slowed. However, this delay becomes clinically significant only when the glomerular filtration rate decreases to <30 mL/min.

Table 1

Pharmacokinetic parameters of lisinopril after multiple doses of 5 mg in various patient groups with renal disease

Renal function according to creatinine clearance	Number of doses	Cmax (ng/mL)	Tmax (h)	AUC (0–24 h) (ng·h/mL)	t1/2 (h)
>80 mL/min	6	40.3	6	492±172	6.0±1.1
30–80 mL/min	6	36.6	8	555±364	11.8±1.9
5–30 mL/min	6	106.7	8	2228±938	19.5±5.2

When creatinine clearance is 30–80 mL/min, the mean AUC (area under the concentration-time curve) increases by only 13%; when creatinine clearance is 5–30 mL/min, a 4- to 5-fold increase in the mean AUC is observed.

Lisinopril can be removed from the body by hemodialysis. After a 4-hour hemodialysis session, plasma lisinopril concentration decreased on average by 60% (with a dialysis clearance rate of 40–55 mL/min).

Heart failure. Patients with heart failure are more susceptible to the effects of lisinopril compared to healthy volunteers (mean AUC increased by 125%), but based on data regarding urinary excretion of lisinopril, it has been established that their absorption is reduced by approximately 16% compared to healthy volunteers.

Elderly patients. Elderly patients have higher plasma AUC values (approximately 60% higher) compared to younger volunteers.

Hydrochlorothiazide

When monitoring hydrochlorothiazide plasma concentrations for at least 24 hours, its elimination half-life ranged from 5.6 to 14.8 hours.

At least 61% of the drug is excreted unchanged within 24 hours. After oral administration of hydrochlorothiazide, the diuretic effect begins within 2 hours, reaches its peak at 4 hours, and persists for 6–12 hours.

Hydrochlorothiazide crosses the placental barrier but does not cross the blood-brain barrier.

Clinical characteristics.

Indications.

Treatment of patients with mild to moderate arterial hypertension that has a stable course under therapy with individual drugs at the same dosages.

Contraindications.

• Hypersensitivity to the active substances or to any of the excipients listed in the section "Composition".
• Hypersensitivity to other angiotensin-converting enzyme (ACE) inhibitors.
• Hypersensitivity to any sulfonamide derivatives.
• History of angioedema associated with the use of ACE inhibitors.
• Hereditary or idiopathic angioedema.
• Pregnancy or planned pregnancy (see section "Use during pregnancy or breastfeeding").
• Severe renal impairment (creatinine clearance < 30 mL/min).
• Severe hepatic impairment.
• Anuria.
• Lysopres is contraindicated for concomitant use with medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate <60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").
• Concomitant use with sacubitril/valsartan is contraindicated; initiation of Lysopres therapy should not occur earlier than 36 hours after the last dose of sacubitril/valsartan (see also sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Antihypertensive medicinal products

Concomitant use with other antihypertensive agents may enhance antihypertensive effects. Concomitant use with nitroglycerin, other nitrates, or vasodilators enhances the antihypertensive effect.

Combination of lisinopril with aliskiren-containing products should be avoided (see sections "Contraindications" and "Special precautions for use").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalemia, and decreased renal function (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Contraindications" and "Special precautions for use").

Medicinal products that increase the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use").

Concomitant use of ACE inhibitors with mammalian target of rapamycin inhibitors (mTOR) (e.g., temsirolimus, sirolimus, everolimus), neutral endopeptidase inhibitors (e.g., racecadotril), tissue plasminogen activator, or vildagliptin increases the risk of angioedema.

Lithium-containing products

Cases of reversible increases in serum lithium levels and signs of lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Diuretics and ACE inhibitors reduce renal clearance of lithium, increasing the risk of lithium toxicity. Therefore, the use of lisinopril and hydrochlorothiazide in combination with lithium-containing products is not recommended. If such combination therapy is necessary, serum lithium levels should be closely monitored (see section "Special precautions for use").

Potassium-sparing diuretics, potassium-containing dietary supplements or salt substitutes, and other medicinal products that may increase plasma potassium levels

Although serum potassium levels usually remain within normal limits during lisinopril therapy, hyperkalemia may occur in some patients. Potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or salt substitutes may lead to significant increases in serum potassium levels, particularly in patients with renal impairment or type 2 diabetes mellitus. Caution should be exercised when lisinopril is used concomitantly with other agents that increase serum potassium levels, such as trimethoprim or co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim has effects similar to potassium-sparing diuretics such as amiloride. Therefore, concomitant use of lisinopril with the above-mentioned medicinal products is not recommended. If concomitant use is necessary, these agents should be used with caution and with periodic monitoring of serum potassium levels (see section "Special precautions for use").

Heparin

Concomitant use of ACE inhibitors and heparin may lead to hyperkalemia. Monitoring of serum potassium levels is recommended.

Medicinal products capable of inducing torsades de pointes ventricular tachycardia

Due to the risk of hypokalemia, caution should be exercised when hydrochlorothiazide is used concomitantly with medicinal products capable of inducing torsades de pointes ventricular tachycardia (some antiarrhythmics, antipsychotics, and other agents).

Tricyclic antidepressants / antipsychotic agents / anesthetics

Concomitant use of certain anesthetics, tricyclic antidepressants, or antipsychotics with ACE inhibitors may lead to additional reduction in blood pressure (see section "Special precautions for use").

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid

Prolonged use of NSAIDs (selective cyclooxygenase-2 inhibitors, acetylsalicylic acid at doses > 3 g/day, nonselective NSAIDs) may reduce the antihypertensive and diuretic effects of ACE inhibitors and thiazides. Concomitant use of NSAIDs and ACE inhibitors may lead to increased serum potassium levels and worsening of renal function. These effects are usually reversible. In rare cases, renal failure may develop, particularly in patients with pre-existing renal impairment, such as elderly patients or those with dehydration.

Gold preparations

Nitritoid (vasomotor) reactions have been more frequently observed in patients receiving ACE inhibitors during treatment with injectable gold preparations (e.g., sodium aurothiomalate). Nitritoid reactions are characterized by symptoms of vasodilation (flushing), nausea, dizziness, and hypotension, which may be severe.

Sympathomimetic agents

Sympathomimetic agents may attenuate the antihypertensive effect of ACE inhibitors. Thiazides may reduce vascular responsiveness to norepinephrine, but not sufficiently to preclude the use of pressor agents.

Antidiabetic agents

Thiazide use may impair glucose tolerance. This effect most commonly occurs during the first weeks of combination therapy in patients with impaired renal function. Dose adjustments of hypoglycemic agents, including insulin, may be required in patients with diabetes mellitus.

Thiazide diuretics may potentiate the hyperglycemic effect of diazoxide.

Amphotericin B (parenteral), carbenoxolone, corticosteroids, corticotropin (ACTH), or stimulant laxatives

The hypokalemic effect of hydrochlorothiazide may be enhanced by medicinal products affecting potassium levels and hypokalemia (e.g., other potassium-wasting diuretics, laxatives, amphotericin, carbenoxolone, salicylate derivatives).

Hypokalemia may develop during concomitant use of steroids or ACTH.

Calcium salts

Thiazide diuretics may increase serum calcium levels due to reduced excretion. If concomitant use of calcium supplements or vitamin D is necessary, careful monitoring of serum calcium levels and dose adjustments when needed are recommended.

Cardiac glycosides

Hypokalemia may increase cardiac sensitivity or reactivity to toxic effects induced by digitalis preparations (including increased ventricular excitability).

Cholestyramine and colestipol

Concomitant use with cholestyramine and colestipol reduces the absorption of hydrochlorothiazide. Therefore, sulfonamide diuretics should be taken at least 1 hour before or 4–6 hours after administration of these agents.

Non-depolarizing muscle relaxants (e.g., tubocurarine chloride)

Thiazides may increase sensitivity to non-depolarizing muscle relaxants (e.g., tubocurarine).

Sotalol

Hypokalemia induced by thiazide use increases the risk of arrhythmias during sotalol therapy.

Allopurinol

Concomitant use of ACE inhibitors and allopurinol increases the risk of renal impairment and leukopenia.

Cyclosporine

Concomitant use of ACE inhibitors and cyclosporine increases the risk of renal impairment and hyperkalemia. Monitoring of serum potassium levels is recommended.

Lovastatin

Concomitant use of ACE inhibitors and lovastatin increases the risk of hyperkalemia.

Cytostatic agents, immunosuppressants, procainamide

Thiazides may reduce renal excretion of cytotoxic agents (e.g., cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects (see section "Special precautions for use").

Other concomitant medicinal products

Thiazides increase the risk of adverse reactions caused by amantadine.

Alcohol, barbiturates, and anesthetics may potentiate orthostatic hypotension.

Special precautions for use.

Symptomatic arterial hypotension

In rare cases, symptomatic arterial hypotension may occur in patients with uncomplicated arterial hypertension. Blood pressure reduction is most likely in patients with reduced circulating blood volume, for example, during diuretic therapy, on a low-salt diet, following hemodialysis, diarrhea, or vomiting, or in patients with severe renin-dependent hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

In such patients, serum electrolyte levels should be monitored regularly. Dose selection and treatment of patients at increased risk of clinically significant hypotension should be initiated under close medical supervision.

The medicinal product should be used with particular caution in patients with ischemic heart disease or cerebrovascular disease, since excessive reduction in arterial blood pressure may lead to myocardial infarction or acute cerebrovascular accident.

In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, intravenous infusion of physiological saline solution should be administered. Transient hypotension is not a contraindication for taking the next dose. After restoration of circulating blood volume and normalization of arterial pressure, therapy may be resumed at lower doses or one of the components may be used as monotherapy.

In some patients with heart failure but with normal or reduced arterial pressure during lisinopril therapy, a decrease in systemic arterial pressure may occur. This effect is expected and usually not a reason to discontinue the drug. In case of clinically significant hypotension, dose reduction or discontinuation of lisinopril and hydrochlorothiazide therapy may be required.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy

As with other ACE inhibitors, lisinopril should be used with caution in patients with mitral valve stenosis and left ventricular outflow tract obstruction (e.g., due to aortic sten游戏副本

Method of Administration and Dosage.

Essential arterial hypertension.

Fixed-dose combination therapy is not suitable for initiating treatment. A fixed-dose combination product may replace the combination of 10 mg or 20 mg of lisinopril and 12.5 mg of hydrochlorothiazide in patients whose condition has been stabilized on therapy with the individual active substances at the same doses administered as separate drugs. The standard dose is 1 tablet once daily. As with any other medication taken once daily, Lisopres should be taken approximately at the same time each day.

If the desired therapeutic effect is not achieved within 2–4 weeks of treatment, the dose may be increased to 2 tablets once daily.

Previous diuretic therapy.

Symptomatic arterial hypotension may develop after administration of the first dose of Lisopres. This condition is more likely to occur in patients with disturbances in water and electrolyte balance due to prior diuretic therapy. Diuretics should be discontinued 2–3 days before starting treatment with Lisopres. If this is not possible, treatment should be initiated with monotherapy using lisinopril at a dose of 5 mg.

Renal function impairment.

Thiazide diuretics are not recommended for patients with impaired renal function; thiazides are ineffective when creatinine clearance is 30 mL/min or lower (i.e., in moderate or severe renal insufficiency).

Lisopres must not be used as initial therapy in patients with renal insufficiency. In patients with creatinine clearance >30 and <80 mL/min, the drug may be administered only after individual dose titration of each component. The recommended dose of lisinopril when used as monotherapy in mild renal insufficiency is 5–10 mg.

Elderly patients.

Dose adjustment is not required in elderly patients.

It is known that the efficacy and tolerability profiles of lisinopril and hydrochlorothiazide when used concomitantly are similar in elderly and younger patients with arterial hypertension. The efficacy of lisinopril administered at doses of 20 to 80 mg was comparable in elderly patients (aged 65 years and older) and younger patients; monotherapy with lisinopril also effectively reduced diastolic blood pressure, similar to monotherapy with hydrochlorothiazide or atenolol. According to available clinical trial data, age does not affect the tolerability of lisinopril.

Children.

The safety and efficacy of this medicinal product for use in children have not been established.

Overdose.

Human data on overdose are limited. In cases of ACE inhibitor overdose, the following symptoms may occur: arterial hypotension, circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough.

In case of overdose, infusion of physiological saline solution is indicated.

If arterial hypotension develops, the patient should be placed in a supine position. Infusion of angiotensin II and/or intravenous administration of catecholamines may be necessary. If the drug has been recently ingested, measures aimed at eliminating lisinopril should be performed (e.g., induction of emesis, gastric lavage, administration of adsorbents and sodium sulfate).

Lisinopril may be removed from systemic circulation by hemodialysis (see section "Special precautions for use"). In case of bradycardia unresponsive to therapy, implantation of an artificial pacemaker is indicated. Vital signs, serum electrolyte levels, and serum creatinine concentration should be closely monitored.

Symptoms of hydrochlorothiazide overdose include increased diuresis, suppression of consciousness (up to coma), seizures, paresis, cardiac arrhythmias, and renal failure.

Atropine administration is indicated for correction of bradycardia or pronounced vagal reactions.

Hypokalemia may potentiate arrhythmias in patients receiving digoxin.

Adverse reactions.

Below are listed adverse reactions reported during treatment with lisinopril and (or) hydrochlorothiazide. The frequency of adverse reactions is defined according to the following categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data).

Among adverse reactions, cough, dizziness, arterial hypotension, and headache were most commonly observed (occurring in 1–10% of patients). According to clinical studies, adverse reactions were generally mild, transient in nature, and in most cases did not require discontinuation of therapy.

Lisinopril

	Frequency of adverse reactions
Organ system	Common	Uncommon	Occasional	Rare	Frequency not known
Blood and lymphatic system			decreased hemoglobin levels, decreased hematocrit	bone marrow suppression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis (see section "Special precautions"), hemolytic anemia, lymphadenopathy, autoimmune disorders
Immune system					anaphylactic/ anaphylactoid reaction
Endocrine system			syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition				hypoglycemia
Psychiatric		mood lability, symptoms of depression	confusion		hallucinations
Nervous system	dizziness, headache, syncope	paraesthesia, vertigo, taste disturbances, sleep disorders	disorders of smell
Cardiac		myocardial infarction or stroke, likely due to excessive reduction in blood pressure in high-risk patients (see section "Special precautions"), palpitations, tachycardia
Vascular system	orthostatic effects (including orthostatic hypotension)	Raynaud's syndrome			flushing
Respiratory, thoracic and mediastinal system	cough (see section "Special precautions")	rhinitis		bronchospasm, sinusitis, allergic alveolitis and/or eosinophilic pneumonia
Gastrointestinal system	diarrhea, vomiting	nausea, abdominal pain, dyspepsia	dry mouth	pancreatitis, angioneurotic edema of the intestine
Hepatobiliary system				hepatitis (hepatocellular or cholestatic), jaundice, hepatic failure* (see section "Special precautions")
Skin and subcutaneous tissue		rash, pruritus	hypersensitivity/ angioedema of the face, limbs, lips, tongue, glottis and/or larynx (see section "Special precautions"), urticaria, alopecia, psoriasis	increased sweating, bullous eruption (pemphigus), toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, cutaneous pseudolymphoma**
Renal and urinary system	renal function impairment		uremia, acute renal failure	oliguria, anuria
Reproductive system and breast		impotence	gynecomastia
General disorders		asthenic syndrome, fatigue
Investigations		increased liver enzyme activity and bilirubin, increased urea, increased serum creatinine, hyperkalemia	hyponatremia

* In rare cases, hepatitis has been reported with subsequent progression to liver failure. If jaundice or a marked increase in liver enzyme activity occurs during treatment with the combination of lisinopril and hydrochlorothiazide, the drug should be discontinued; the patient must remain under close medical supervision.

** A syndrome has been reported, characterized by one or more of the following symptoms: fever, vasculitis, myalgia, arthralgia (arthritis), increased levels of antinuclear antibodies (ANA), elevated erythrocyte sedimentation rate (ESR), eosinophilia, leukocytosis, rash, photosensitivity, or other skin reactions.

Hydrochlorothiazide

	Frequency of adverse reactions
Organ system	Rare	Frequency unknown
Infections and parasitic diseases		sialadenitis
Benign, malignant and unspecified neoplasms (including cysts and polyps)		non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)
Blood and lymphatic system disorders		leukopenia, neutropenia (agranulocytosis), thrombocytopenia, aplastic anemia, hemolytic anemia, bone marrow suppression
Metabolism and nutrition disorders		anorexia; hyperglycemia; glucosuria; hyperuricemia, electrolyte imbalance (including hyponatremia and hypokalemia, hypochloremic alkalosis, hypomagnesemia), increased cholesterol and triglyceride levels, gout
Psychiatric disorders		restlessness, depression, sleep disorders
Nervous system disorders		decreased appetite, paresthesia, pre-coma state
Eye disorders		xanthopsia, transient decrease in visual acuity, choroidal effusion, acute myopia, acute angle-closure glaucoma
Ear and labyrinth disorders		dizziness
Cardiac disorders		orthostatic hypotension
Vascular disorders		necrotizing angiitis (vasculitis, cutaneous vasculitis)
Respiratory, thoracic and mediastinal disorders	acute respiratory distress syndrome (ARDS) (see section "Special warnings and precautions for use")	respiratory distress syndrome (including pneumonitis and pulmonary edema)
Gastrointestinal disorders		gastric mucosa irritation, diarrhea, constipation, pancreatitis
Hepatobiliary disorders		jaundice (jaundice due to intrahepatic cholestasis)
Skin and subcutaneous tissue disorders		photosensitivity reactions, rash, systemic lupus erythematosus, lupus-like skin reactions, exacerbation of systemic lupus erythematosus, urticaria, anaphylactic reactions, toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders		muscle spasm, muscle weakness
Renal and urinary disorders		renal dysfunction, interstitial nephritis
General disorders		fever, weakness

Description of some adverse reactions

Non-melanoma skin cancer (NMSC): epidemiological study data indicate an association between the cumulative dose of hydrochlorothiazide and the development of NMSC (see sections "Pharmacological properties" and "Particular precautions for use").

Reporting of suspected adverse reactions.

Reporting of adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

10 tablets in a blister; 3 blisters per carton.

10 tablets in a blister; 5 blisters per carton.

Prescription status. Prescription only.

Manufacturer: JSC "KYIV VITAMIN PLANT".

Manufacturer's address and place of business.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Website: www.vitamin.com.ua.