Statorim®-h

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT STATOREM®-H

Composition:

Active substances: lisinopril, hydrochlorothiazide;

each tablet contains lisinopril dihydrate equivalent to lisinopril 10 mg and hydrochlorothiazide 12.5 mg, or lisinopril dihydrate equivalent to lisinopril 20 mg and hydrochlorothiazide 25 mg;

Excipients: mannite (E 421), calcium hydrogen phosphate, maize starch, pregelatinized starch, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, round, biconvex tablets, smooth on both sides.

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

Pharmacological Properties

Pharmacodynamics

Statoram®-H is a fixed-dose combination medication containing lisinopril—an angiotensin-converting enzyme (ACE) inhibitor—and hydrochlorothiazide (HCTZ)—a thiazide diuretic. Both components have distinct mechanisms of action and produce an additive antihypertensive effect that is mutually complementary.

Lisinopril

Lisinopril is a peptidyl-dipeptidase inhibitor. It inhibits ACE, the enzyme responsible for converting angiotensin I into angiotensin II—a potent vasoconstrictor peptide. Angiotensin II also stimulates aldosterone secretion from the adrenal cortex. Inhibition of ACE leads to reduced angiotensin II levels, thereby decreasing vasoconstrictor activity and aldosterone secretion. Reduced aldosterone secretion may result in increased serum potassium concentration.

Lisinopril lowers blood pressure primarily by inhibiting the renin-angiotensin-aldosterone system (RAAS). Nevertheless, lisinopril exerts antihypertensive effects even in patients with low-renin hypertension. ACE is identical to kininase II, the enzyme responsible for bradykinin degradation. It remains uncertain whether increased levels of bradykinin—a potent vasodilator peptide—contribute to the therapeutic effect of lisinopril.

Hydrochlorothiazide

HCTZ is a diuretic and antihypertensive agent. It affects electrolyte reabsorption in the distal renal tubules and increases the excretion of sodium and chloride in approximately equimolar amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. The mechanism of the antihypertensive effect of thiazides is not fully understood. Thiazides generally do not affect normal blood pressure.

Non-melanoma skin cancer (NMSC)

Results from two pharmacoepidemiological studies based on data from the Danish National Cancer Registry demonstrated a cumulative dose-dependent association between HCTZ and the development of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). One study included a population of 71,533 patients with BCC and 8,629 patients with SCC, compared to 1,430,833 and 172,462 control subjects, respectively. Use of high cumulative doses of HCTZ (≥ 50,000 mg) was associated with an adjusted risk ratio (RR) of 1.29 (95% confidence interval [CI]: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear cumulative dose-dependent relationship was observed for both BCC and SCC. Another study indicated a possible association between lip cancer (SCC) and HCTZ use: 633 cases of lip cancer (SCC) were compared with 63,067 control subjects using a random sampling strategy. A cumulative dose-dependent relationship was demonstrated with an adjusted RR of 2.1 (95% CI: 1.7–2.6), increasing to RR 3.9 (3.0–4.9) for high doses (~25,000 mg) and RR 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see section "Special precautions for use").

Pharmacokinetics

There is no clinically significant pharmacokinetic interaction between lisinopril and hydrochlorothiazide. The combined tablet is bioequivalent to the co-administration of the individual components.

Lisinopril

Absorption

After oral administration of lisinopril, maximum serum concentration (Cmax) is reached within approximately 7 hours, although in patients with acute myocardial infarction, a slight delay in the time to reach Cmax has been observed. The mean absorption of lisinopril is approximately 25%, with individual variability (6–60%) across all tested doses (5–80 mg). Absolute bioavailability decreases by approximately 16% in patients with heart failure.

Food intake does not affect the absorption of lisinopril.

Distribution

Lisinopril does not bind to plasma proteins other than circulating ACE.

Preclinical studies have shown that lisinopril poorly penetrates the blood-brain barrier.

Elimination

Lisinopril is not metabolized and is excreted entirely unchanged in urine. After multiple dosing, the elimination half-life of lisinopril is 12.6 hours. The clearance of lisinopril in healthy volunteers is approximately 50 mL/min. The decline in serum concentration shows a prolonged terminal phase, which does not lead to drug accumulation. This terminal phase may reflect saturated binding to ACE and is not proportionally dose-dependent.

Hepatic impairment

Liver dysfunction in patients with cirrhosis results in reduced (by approximately 30%) absorption of lisinopril and increased (by approximately 50%) drug exposure compared to healthy volunteers (due to reduced clearance).

Renal impairment

Renal impairment reduces the elimination of lisinopril, which is excreted by the kidneys; however, this reduction becomes clinically significant only when glomerular filtration rate (GFR) is below 30 mL/min.

With creatinine clearance of 30–80 mL/min, the mean area under the concentration-time curve (AUC) increases by only 13%, whereas with creatinine clearance of 5–30 mL/min, AUC increases 4–5 fold.

Lisinopril is removed during hemodialysis. During 4 hours of hemodialysis, plasma lisinopril concentration decreases on average by 60%, and dialysis clearance ranges between 40–55 mL/min.

Heart failure

Patients with heart failure exhibit greater exposure to lisinopril compared to healthy volunteers (AUC increases on average by 125%). However, based on urinary excretion data, absorption of the drug in patients with heart failure is approximately 16% lower than in healthy volunteers.

Elderly patients

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

Hydrochlorothiazide

Absorption

When plasma levels of HCTZ were maintained for at least 24 hours, the elimination half-life in plasma ranged from 5.6 to 14.8 hours.

Distribution

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

Elimination

At least 61% of the HCTZ dose is excreted unchanged within 24 hours. After oral administration, urinary excretion of HCTZ begins within 2 hours, reaches its peak at approximately 4 hours, and continues for 6–12 hours.

Clinical characteristics.

Indications.

The medicinal product Statorim®-N is indicated for the treatment of mild to moderate arterial hypertension in patients whose condition has been stabilized following treatment with the individual components in the same proportions.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients of the medicinal product.

Hypersensitivity to any other angiotensin-converting enzyme (ACE) inhibitor.

Hypersensitivity to any sulfonamide-containing medicinal products.

Concomitant use with sacubitril/valsartan.

Treatment with Statorim®-N must be initiated only 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

History of angioedema associated with previous treatment with ACE inhibitors.

Hereditary or idiopathic angioedema.

Second and third trimesters of pregnancy (see sections "Special precautions for use" and "Use during pregnancy or lactation").

Severe renal impairment (creatinine clearance < 30 mL/min).

Anuria.

Severe hepatic impairment.

Concomitant use of Statorim®-N with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Antihypertensive agents

In combination with other antihypertensive agents, Statorim®-N may lead to a reduction in arterial pressure. Concomitant use of nitroglycerin and other nitrates or other vasodilating agents may further reduce arterial pressure.

Combination of lisinopril with aliskiren-containing medicinal 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, and aliskiren is associated with a higher incidence of adverse reactions such as arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure), compared to treatment with a single RAAS-acting agent (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Medicinal products that may increase the risk of angioedema

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

Concomitant use of ACE inhibitors with racecadotril, mammalian target of rapamycin (mTOR) inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (see section "Special precautions for use").

Concomitant treatment with tissue plasminogen activators may increase the risk of angioedema.

Lithium

Elevated and potentially toxic serum lithium concentrations have been reported during concomitant use with ACE inhibitors. Diuretics and ACE inhibitors reduce renal lithium clearance and increase the risk of lithium toxicity. The combination of lisinopril and hydrochlorothiazide with lithium is not recommended. If concomitant use is necessary, careful monitoring of serum lithium levels is required (see section "Special precautions for use").

Potassium-containing dietary supplements, potassium-sparing diuretics, potassium-containing salt substitutes, and other medicinal products that may affect serum potassium levels

The potassium-wasting effect of thiazide diuretics is usually counterbalanced by the potassium-sparing effect of lisinopril.

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving this medicinal product.

Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels. Caution should also be exercised when Statorim®-N is used concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, the combination of Statorim®-N with the above-mentioned medicinal products is not recommended. If concomitant use is necessary, they should be used with caution and with frequent monitoring of serum potassium levels (see section "Special precautions for use").

Medicinal products capable of inducing ventricular arrhythmia (torsades de pointes)

Due to the increased risk of hypokalemia with concomitant use of hydrochlorothiazide (HCTZ) and medicinal products that may induce ventricular arrhythmia (e.g., antiarrhythmic agents, certain antidepressants, and other medicinal products associated with ventricular arrhythmia), they should be used with caution.

Tricyclic antidepressants/antipsychotics/anesthetics

Concomitant use of certain anesthetics, tricyclic antidepressants, and antipsychotic medicinal products with ACE inhibitors may lead to further reduction in arterial pressure (see section "Special precautions for use").

Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid

Prolonged use of NSAIDs (selective cyclooxygenase-2 inhibitors, acetylsalicylic acid (> 3 g/day), and non-selective NSAIDs) may reduce the antihypertensive and diuretic effects of ACE inhibitors and thiazide diuretics. In addition, NSAIDs and ACE inhibitors may have an additive effect on increasing serum potassium levels and may lead to impaired renal function. These effects are usually reversible. Acute renal failure may rarely occur, particularly in patients with pre-existing renal impairment (elderly patients or those with dehydration).

Gold preparations

Nitritoid reactions (symptoms of vasodilation, including flushing, nausea, dizziness, and hypotension, which may be severe) after injection of gold preparations (e.g., sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitor therapy.

Sympathomimetic agents

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

Antidiabetic agents

Treatment with thiazide diuretics may impair glucose tolerance. This phenomenon is more likely during the first 2 weeks of combination therapy and in patients with impaired renal function. Dose adjustments of insulin or oral hypoglycemic agents may be necessary in patients with diabetes mellitus. Thiazide diuretics may potentiate the hyperglycemic effect of diazoxide.

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

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

Hypokalemia may develop during treatment with corticosteroids or adrenocorticotropic hormone (ACTH).

Calcium salts

Thiazide diuretics may increase serum calcium levels by reducing calcium excretion. If calcium or vitamin D supplements are required, serum calcium levels should be monitored and the dosage adjusted accordingly.

Cardiac glycosides

Hypokalemia may increase cardiac sensitivity or response to the toxic effects of digitalis preparations (including increased ventricular excitability).

Cholestyramine and colestipol

Absorption of HCTZ is reduced by colestipol or cholestyramine. Therefore, sulfonamide diuretics should be administered at least 1 hour before or 4–6 hours after these medicinal products.

Non-depolarizing muscle relaxants

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

Trimethoprim

Concomitant use of ACE inhibitors and thiazides together with trimethoprim increases the risk of hyperkalemia.

Sotalol

Thiazide-induced hypokalemia may increase the risk of sotalol-induced arrhythmia.

Allopurinol

Concomitant use of ACE inhibitors with allopurinol increases the risk of renal impairment, which may lead to an increased risk of leukopenia.

Cyclosporine
Concomitant use of ACE inhibitors and cyclosporine increases the risk of renal impairment and hyperkalemia. Monitoring of serum potassium levels is recommended. Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-like complications.

Heparin

Hyperkalemia may occur during concomitant use of ACE inhibitors with heparin. 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").

Amantadine

Thiazides, including HCTZ, may increase the risk of adverse reactions associated with amantadine.

Co-trimoxazole (trimethoprim/sulfamethoxazole)

Patients receiving co-trimoxazole (trimethoprim/sulfamethoxazole) concomitantly may have an increased risk of hyperkalemia (see section "Special precautions for use").

Alcohol, barbiturates, or anesthetics

Postural hypotension may be potentiated by concomitant use of alcohol, barbiturates, or anesthetics.

Special precautions for use.

Non-melanoma skin cancer (NMSC)

In two epidemiological studies conducted using the Danish National Cancer Registry, an increased risk of developing NMSC (BCC and SCC) was observed with increasing cumulative doses of hydrochlorothiazide. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for the development of NMSC.

Patients taking HCTZ should be informed about the risk of developing NMSC, the need for regular skin examinations to detect new lesions, and the necessity to promptly report any suspicious skin changes. To minimize the risk of skin cancer, patients should be advised to follow preventive measures, including limiting exposure to sunlight and UV radiation, and using appropriate protective measures when exposure is unavoidable. Suspicious skin lesions should be evaluated promptly, including histological examination of biopsy material. Furthermore, the possibility of continuing HCTZ therapy should be reconsidered in patients with a history of NMSC (see section "Adverse reactions").

Symptomatic hypotension

Symptomatic arterial hypotension is rarely observed in patients with uncomplicated arterial hypertension, but the risk of blood pressure reduction is higher in patients with reduced circulating blood volume, such as those on diuretic therapy, on a salt-restricted diet, undergoing hemodialysis, or experiencing diarrhea or vomiting, as well as 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 titration and treatment initiation in patients at increased risk of clinically significant hypotension should be conducted under close medical supervision.

Lisinopril should be used with particular caution in patients with ischemic heart disease or cerebrovascular disorders, as excessive reduction in blood pressure may lead to myocardial infarction or acute cerebrovascular events.

In case of hypotension, the patient should be placed in a supine position and, if necessary, receive intravenous infusion of physiological saline. Transient hypotension is not a contraindication to administering the next dose.

After restoration of circulating blood volume and normalization of blood 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 low blood pressure on lisinopril therapy, a reduction in systemic arterial pressure may occur. This effect is expected and usually does not require discontinuation of the drug. However, if clinically significant hypotension develops, dose reduction or discontinuation of lisinopril and hydrochlorothiazide therapy may be necessary.

Aortic and mitral valve stenosis/hypertrophic cardiomyopathy

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

Use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section "Special precautions"). Use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications" and "Special precautions").

The available data on the risk of teratogenic effects associated with exposure to ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a small increase in this risk cannot be excluded.

If continued therapy with ACE inhibitors is considered necessary, patients planning pregnancy should be switched to alternative antihypertensive treatment comprising medications with an established safety profile during pregnancy. If pregnancy occurs, treatment with ACE inhibitors must be discontinued immediately, and alternative therapy should be initiated if necessary.

It is known that the use of ACE inhibitors during the second and third trimesters of pregnancy causes fetotoxic effects in humans (impaired renal function, oligohydramnios, delayed ossification of skull bones) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If ACE inhibitors have been used during the third trimester of pregnancy, ultrasound monitoring of fetal renal function and skull ossification is recommended. Newborns whose mothers have taken ACE inhibitors should be closely monitored for possible development of arterial hypotension (see sections "Contraindications" and "Special precautions").

Hydrochlorothiazide

Clinical experience with the use of HCTZ during pregnancy, especially in the first trimester, is limited. Data from animal studies are insufficient.

HCTZ crosses the placenta. Its pharmacological mechanism of action suggests that the use of this drug during the second and third trimesters of pregnancy may impair fetoplacental perfusion and lead to fetal and neonatal adverse reactions such as jaundice, electrolyte imbalances, and thrombocytopenia.

HCTZ must not be used for the treatment of edema, arterial hypertension, or preeclampsia in pregnant women, as instead of providing beneficial effects on the course of the disease, it increases the risk of plasma volume reduction and worsens uteroplacental blood flow.

HCTZ should not be used for the treatment of essential hypertension in pregnant women except when alternative drugs cannot be used.

Breastfeeding period

ACE inhibitors

As there are no data on the use of lisinopril/hydrochlorothiazide during breastfeeding, lisinopril/hydrochlorothiazide is not recommended. Alternative treatments with a well-established safety profile should be preferred, especially when nursing a newborn or premature infant.

Hydrochlorothiazide

HCTZ is excreted in small amounts into breast milk. High doses of thiazides may enhance diuresis, potentially leading to decreased breast milk production.

The use of lisinopril/HCTZ during breastfeeding is contraindicated. If alternative treatment is not possible during breastfeeding, the lowest possible dose of lisinopril/HCTZ should be prescribed.

Effect on the ability to drive and operate machinery

Like other antihypertensive agents, lisinopril/HCTZ may mildly or moderately affect the ability to drive or operate machinery. The risk is increased at the beginning of treatment or when the dose is changed, as well as when the combined preparation is taken concomitantly with alcohol; however, this effect depends on individual patient sensitivity.

The possibility of dizziness and fatigue should be considered when driving or operating machinery.

Dosage and Administration

Essential hypertension

The usual dose is 1 tablet once daily. STATOREM®-H should be taken at approximately the same time each day. If the expected therapeutic effect cannot be achieved within 2–4 weeks, the dose may be increased to 2 tablets once daily.

Renal impairment

Thiazides should not be used in patients with impaired renal function and are ineffective in moderate to severe renal insufficiency (creatinine clearance ≤ 30 mL/min).

The medicinal product STATOREM®-H is not recommended for initial treatment of patients with renal insufficiency.

In patients with creatinine clearance > 30 and < 80 mL/min, the medicinal product STATOREM®-H may be used after individual component dose adjustment. The recommended initial dose of lisinopril monotherapy in such patients is 5–10 mg.

Previous diuretic therapy

Symptomatic arterial hypotension may occur after administration of the first dose of STATOREM®-H. This primarily affects dehydrated patients (e.g., as a result of diuretic therapy). Diuretic treatment should be discontinued 2–3 days prior to initiating STATOREM®-H. If this is not possible, therapy should be initiated with lisinopril alone at a dose of 5 mg.

Elderly patients

No dose adjustment is required.

When using lisinopril/HCTZ, no differences in efficacy or tolerability related to age have been observed.

Lisinopril at daily doses of 20–80 mg was equally effective in elderly patients (aged 65 years and older) and younger adult patients. Monotherapy with lisinopril showed the same efficacy in reducing diastolic blood pressure as monotherapy with HCTZ or atenolol. Age did not affect lisinopril tolerability.

Children

The safety and efficacy of the lisinopril/HCTZ combination in children have not been established.

Overdose

Symptoms

Human data on overdose are limited.

The most likely symptoms of ACE inhibitors overdose include: arterial hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

Additional symptoms of HCTZ overdose may include: increased diuresis, impaired consciousness (including coma), seizures, paresis, arrhythmia, and renal failure.

In cases of concomitant use of digitalis preparations, hypokalemia may develop, increasing the risk of arrhythmias.

Treatment

For the treatment of overdose, intravenous administration of normal saline is recommended. In case of severe arterial hypotension, the patient should be placed in a supine position. Administration of angiotensin II (if available) or intravenous catecholamines may be considered. If drug intake was recent, measures to remove lisinopril from the body should be initiated (induced vomiting, gastric lavage, use of adsorbents and sodium sulfate). Lisinopril can be removed from systemic circulation by hemodialysis (see section "Pharmacological properties"). For resistant bradycardia, cardiac pacing is indicated. Frequent monitoring of vital signs, serum electrolytes, and creatinine levels should be performed.

Bradycardia or excessive vagal reactions may also be alleviated by administration of atropine.

Adverse Reactions

Below are the adverse reactions reported during treatment with lisinopril and/or HCTZ, categorized by system organ class and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000, including isolated cases), frequency not known (cannot be estimated from available data).

The most commonly observed adverse reactions during treatment with lisinopril and/or HCTZ were: cough, dizziness, arterial hypotension, and headache.

Lisinopril

Blood and lymphatic system disorders: rare – decreased hemoglobin levels, decreased hematocrit; very rare – bone marrow suppression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis (see section "Special precautions for use"), hemolytic anemia, lymphadenopathy, autoimmune disorders.

Immune system disorders: frequency not known – anaphylactic/anaphylactoid reactions.

Endocrine system disorders: rare – syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders: very rare – hypoglycemia.

Nervous system disorders: common – dizziness, headache, syncope; uncommon – paresthesia, vertigo, taste disturbances, sleep disturbances; rare – smell disturbances.

Psychiatric disorders: uncommon – mood changes, depression; rare – confusion; frequency not known – hallucinations.

Cardiac and vascular disorders: common – arterial hypotension (including orthostatic); uncommon – myocardial infarction or stroke due to marked arterial hypotension in high-risk patients (see section "Special precautions for use"), palpitations, tachycardia, Raynaud's syndrome; frequency not known – flushing.

Respiratory, thoracic and mediastinal disorders: common – cough (see section "Special precautions for use"); uncommon – rhinitis; very rare – bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia.

Gastrointestinal disorders: common – diarrhea, vomiting; uncommon – nausea, abdominal pain, dyspepsia; rare – dry mouth; very rare – pancreatitis, intestinal angioedema.

Hepatobiliary disorders: uncommon – increased liver enzyme activity and serum bilirubin; very rare – hepatitis (hepatocellular or cholestatic), jaundice, liver failure (see section "Special precautions for use")*.

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus; rare – hypersensitivity/angioedema (face, extremities, lips, tongue, glottis and/or larynx) (see section "Special precautions for use"), urticaria, alopecia, psoriasis; very rare – increased sweating, bullous eruption, severe skin reactions (pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, cutaneous pseudolymphoma**).

Renal and urinary disorders: common – impaired renal function; rare – uremia, acute renal failure; very rare – oliguria/anuria.

Reproductive system and breast disorders: uncommon – impotence; rare – gynecomastia.

General disorders: uncommon – increased fatigue, asthenia.

Investigations: uncommon – increased blood urea nitrogen, increased serum creatinine concentration, hyperkalemia; rare – hyponatremia.

*Very rare cases of hepatitis leading to liver failure have been reported. Patients who develop jaundice or marked increases in liver enzyme activity during therapy should discontinue the drug and undergo appropriate medical evaluation.

**Cases of a symptom complex that may include one or more of the following have been reported: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear factor (ANF), elevated erythrocyte sedimentation rate (ESR), eosinophilia, leukocytosis, rash, photosensitivity, or other dermatological manifestations.

Hydrochlorothiazide

Infections and infestations: frequency not known – sialadenitis.

Benign, malignant and unspecified neoplasms including cysts and polyps: frequency not known – non-melanoma skin cancer (NMSC) (basal cell carcinoma and squamous cell carcinoma of the skin).

Blood and lymphatic system disorders: frequency not known – leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, bone marrow suppression.

Metabolism and nutrition disorders: frequency not known – anorexia, hyperglycemia, glucosuria, hyperuricemia, electrolyte imbalance (including hyponatremia, hypokalemia, hypochloremic alkalosis, hypomagnesemia), increased cholesterol and triglyceride levels, gout.

Psychiatric disorders: frequency not known – restlessness, depression, sleep disturbances.

Nervous system disorders: frequency not known – loss of appetite, paresthesia, dizziness.

Eye disorders: frequency not known – xanthopsia, transient visual disturbances, acute myopia, acute angle-closure glaucoma, choroidal effusion.

Ear and labyrinth disorders: frequency not known – vertigo.

Cardiac and vascular disorders: frequency not known – orthostatic hypotension, necrotizing angiitis (vasculitis, cutaneous vasculitis).

Respiratory, thoracic and mediastinal disorders: very rare – acute respiratory distress syndrome (ARDS) (see section "Special precautions for use"); frequency not known – respiratory distress syndrome, including pneumonitis and pulmonary edema.

Gastrointestinal disorders: frequency not known – gastric mucosal irritation, diarrhea, constipation, pancreatitis.

Hepatobiliary disorders: frequency not known – jaundice (intrahepatic cholestatic jaundice).

Skin and subcutaneous tissue disorders: frequency not known – photosensitivity reactions, rash, systemic lupus erythematosus, lupus-like skin reactions, reactivation of skin manifestations of systemic lupus erythematosus, urticaria, anaphylactic reactions, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: frequency not known – muscle cramps, muscle weakness.

Renal and urinary disorders: frequency not known – impaired renal function, interstitial nephritis.

General disorders: fever, weakness.

Description of selected adverse reactions

Non-melanoma skin cancer (NMSC): Based on available data from epidemiological studies, an association has been described between cumulative dose of HCTZ and NMSC (see sections "Pharmacological properties" and "Special precautions for use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life.

For dosage 10 mg/12.5 mg: 4 years.

For dosage 20 mg/25 mg: 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

For dosage 10 mg/12.5 mg:

14 tablets in a blister. 2 or 6 blisters in a cardboard package.

10 tablets in a blister. 3 or 6 blisters in a cardboard package.

For dosage 20 mg/25 mg:

10 tablets in a blister. 3 or 6 blisters in a cardboard package.

Prescription category.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's address and location of its business activity.

54 Skryabina Street, Sumy, Sumy region, 40020, Ukraine.