ZOFENOZIDE

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOFENOZID (ZOFENOZID)

Composition:

Active substances: zofenopril calcium, hydrochlorothiazide;

One tablet contains 30 mg of zofenopril calcium and 12.5 mg of hydrochlorothiazide;

Excipients: microcrystalline cellulose, lactose monohydrate, corn starch, pregelatinized, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate; film coating: Opadry II Orange: polyvinyl alcohol, titanium dioxide (E 171), macrogol 4000, talc, yellow FCF aluminum lake (E 110), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Round film-coated tablets of light red color, with a score line on one side.

The score line is intended solely for tablet splitting to facilitate swallowing and not for dividing into equal doses.

Pharmacotherapeutic group. Agents acting on the renin-angiotensin system. Combined preparations of ACE inhibitors. ACE inhibitors and diuretics. Zofenopril and diuretics. ATC code C09B A15.

Pharmacological Properties.

Pharmacodynamics.

Zofenozide is a combination preparation consisting of zofenopril, an angiotensin-converting enzyme (ACE) inhibitor, and hydrochlorothiazide, a thiazide diuretic. The mechanisms of action of both components are complementary, and their antihypertensive effects are mutually enhanced.

Zofenopril is a sulfhydryl-containing ACE inhibitor that suppresses the enzyme catalyzing the conversion of angiotensin I to angiotensin II—a peptide with vasoconstrictive activity. This leads to reduced vasoconstrictor activity and decreased aldosterone secretion. The latter may result in increased serum potassium concentration with simultaneous excretion of sodium and fluid from the body. Disruption of the negative feedback loop between angiotensin II and renin secretion leads to increased plasma renin activity. The mechanism of zofenopril’s blood pressure-lowering effect is primarily based on inhibition of the renin-angiotensin-aldosterone system (RAAS). ACE is identical to kininase II, the enzyme responsible for bradykinin degradation—a potent vasodilatory peptide. This likely plays a role in the therapeutic effect of ACE inhibitors.

Hydrochlorothiazide is a diuretic and antihypertensive agent. It affects electrolyte reabsorption in the distal portion of the renal tubules. Hydrochlorothiazide enhances the excretion of sodium and chloride in approximately equal amounts. Natriuresis may be accompanied by loss of potassium and bicarbonate. Due to blockade of the RAAS, concomitant administration of hydrochlorothiazide with zofenopril likely reduces potassium loss associated with diuretic action. Diuresis begins within 2 hours after hydrochlorothiazide administration, reaches its peak approximately 4 hours later, and lasts for about 6–12 hours.

Additional Information

Concomitant use of ACE inhibitors and angiotensin II receptor blockers (ARBs) has been investigated in two large-scale randomized controlled trials (ONTARGET [ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial], VA NEPHRON-D [The Veterans Affairs Nephropathy in Diabetes]).

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was a study conducted in patients with type 2 diabetes and diabetic nephropathy. These studies did not demonstrate a significant beneficial effect on renal and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similarity in their pharmacodynamic properties, these findings are also applicable to other ACE inhibitors and ARBs. Therefore, patients with diabetic nephropathy should not receive concomitant treatment with ACE inhibitors and ARBs.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to evaluate the benefit of adding aliskiren to standard therapy with an ACE inhibitor or ARB in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular mortality and stroke occurred more frequently in the aliskiren group than in the placebo group, and reports of important adverse events and serious adverse events (hyperkalemia, hypotension, and renal dysfunction) were more common in the aliskiren group than in the placebo group.

Non-melanoma skin cancer (NMSC). Epidemiological data have shown an association between cumulative hydrochlorothiazide dose and the development of NMSC. One study included a population of 71,533 patients with basal cell carcinoma (BCC) and 8,629 patients with squamous cell carcinoma (SCC), compared with 1,430,833 and 172,462 control subjects, respectively. High-dose hydrochlorothiazide use (cumulative ≥ 50,000 mg) was associated with an adjusted odds ratio (OR) 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 dose-response relationship was observed for both BCC and SCC. Another study suggested a possible association between lip cancer (SCC) and hydrochlorothiazide: 633 patients with lip cancer were compared with 63,067 control subjects using a risk-set sampling strategy. A dose-response relationship was demonstrated: adjusted OR was 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) with high doses (~25,000 mg) and OR 7.7 (5.7–10.5) at the highest cumulative dose (~100,000 mg) (see also section "Special Warnings and Precautions for Use").

Pharmacokinetics.

Concomitant administration of zofenopril and hydrochlorothiazide has little or no effect on the bioavailability of the individual active substances. The combination product is bioequivalent to the individual components administered together.

Zofenopril

Zofenopril is a prodrug, as the active inhibitor is the free sulfhydryl compound, zofenoprilat, formed via thioester hydrolysis.

Absorption. Zofenopril is rapidly and completely absorbed after oral administration and is almost entirely converted to zofenoprilat. Maximum plasma concentration (Cmax) is reached within 1.5 hours after oral administration of zofenopril. The kinetics of a single dose are linear within the dose range of 10–80 mg of zofenopril. No accumulation occurs after administration of 15–60 mg of zofenopril over 3 weeks. The presence of food in the gastrointestinal tract reduces the rate, but not the extent, of absorption, and the area under the concentration-time curve (AUC) of zofenoprilat is nearly identical with or without food.

Distribution. Approximately 88% of the circulating radioactivity measured ex vivo after administration of radiolabeled zofenopril is bound to plasma proteins, and the steady-state volume of distribution is 96 liters.

Biotransformation. Eight metabolites, accounting for 76% of total urinary radioactivity, were identified in human urine after administration of radiolabeled zofenopril. The main metabolite is zofenoprilat (22%), which is further metabolized via several pathways, including glucuronide conjugation (17%), cyclization and glucuronide conjugation (13%), conjugation with cysteine (9%), and S-methylation of the thiol group (8%).

Elimination. Radiolabeled zofenoprilat is excreted in urine (76%) and feces (16%) after intravenous administration, and 69% and 26% of total radioactivity are recovered in urine and feces, respectively, after oral administration, indicating two elimination pathways—renal and hepatic. The elimination half-life of zofenoprilat after oral administration of zofenopril is 5.5 hours, and its total systemic clearance is 1300 mL/min.

Pharmacokinetics in Specific Patient Populations

Elderly Patients. Dose adjustment is not required in elderly patients with normal renal function.

Renal Impairment. Based on comparison of key pharmacokinetic parameters of zofenoprilat measured after oral administration of radiolabeled zofenopril, it has been established that in patients with mild renal impairment (creatinine clearance > 45 and < 90 mL/min), zofenopril is eliminated at a rate similar to that in patients with normal renal function (creatinine clearance > 90 mL/min). In patients with moderate to severe renal impairment (7–44 mL/min), elimination is reduced to approximately 50% of normal. In patients with end-stage renal disease undergoing hemodialysis or peritoneal dialysis, elimination is reduced to 25% of normal.

Hepatic Impairment Pharmacokinetics. In patients with mild to moderate hepatic impairment receiving a single dose of radiolabeled zofenopril, Cmax and Tmax values for zofenoprilat were similar to those in patients with normal liver function. However, the area under the concentration-time curve (AUC) in patients with liver cirrhosis was approximately twice as high compared to patients with normal hepatic function. Therefore, patients with mild to moderate hepatic impairment should receive half the initial dose recommended for patients with normal liver function. Pharmacokinetic data for zofenopril and zofenoprilat in patients with severe hepatic impairment are lacking; therefore, zofenopril is contraindicated in these patients.

Hydrochlorothiazide

Absorption. Hydrochlorothiazide is well absorbed (65–75%) after oral administration. Plasma concentration is linearly related to the administered dose. Absorption of hydrochlorothiazide varies depending on intestinal transit time, increasing with longer transit, e.g., when taken with food. Plasma concentration assessment over 24 hours showed that the elimination half-life from plasma ranges from 5.6 to 14.8 hours, and Cmax is reached 1–5 hours after administration.

Distribution. Thiazides are widely distributed in body fluids and are highly bound (92%) to plasma proteins, primarily albumin, with displaced molecules being most actively bound. This results in lower renal clearance and thus a prolonged duration of action. A relationship between plasma hydrochlorothiazide levels and the degree of blood pressure reduction has not been established.

Elimination. Hydrochlorothiazide is primarily excreted by the kidneys. Most of the drug is excreted unchanged in urine, with more than 95% of unchanged hydrochlorothiazide recovered in urine within 3–6 hours after oral administration. In patients with renal disease, plasma hydrochlorothiazide concentration increases and elimination half-life is prolonged. Hydrochlorothiazide crosses the placental barrier but does not cross the blood-brain barrier.

Preclinical Safety Data

Acute toxicity, repeated-dose toxicity, and genotoxicity studies revealed no specific risks for humans.

Reproductive toxicity studies conducted in rats and rabbits did not reveal teratogenic effects of zofenopril or hydrochlorothiazide. However, in pregnant rats and rabbits, the combination significantly increased maternal toxicity compared to zofenopril alone.

Carcinogenicity studies with the combination of zofenopril/hydrochlorothiazide have not been conducted.

Carcinogenicity studies with zofenopril monotherapy in mice and rats showed no carcinogenic effects.

In standard preclinical safety pharmacology, repeated-dose toxicity, genotoxicity, and carcinogenicity studies, no specific risk for humans was identified with hydrochlorothiazide.

Clinical characteristics.

Indications.

Essential hypertension of mild to moderate severity.

This combined medicinal product is indicated for patients with inadequate response to monotherapy with zofenopril.

Contraindications.

• Pregnancy or planning pregnancy (see sections "Special precautions" and "Use in pregnancy or breastfeeding").
• Hypersensitivity to zofenopril or to any other angiotensin-converting enzyme (ACE) inhibitor.
• Hypersensitivity to hydrochlorothiazide or to other sulfonamide derivatives.
• Hypersensitivity to any of the excipients listed in the section "Composition".
• History of angioedema associated with previous therapy with an ACE inhibitor.
• Concomitant use with sacubitril/valsartan or other angiotensin II receptor blockers (ARBs). Treatment with the medicinal product Zofenozid must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan or ARB (see also sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions").
• Hereditary or idiopathic angioedema.
• Severe hepatic dysfunction.
• Severe renal impairment (creatinine clearance < 30 mL/min).
• Bilateral renal artery stenosis or stenosis of the artery of a single kidney.

Concomitant use of this medicinal product with aliskiren-containing drugs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Pharmacological properties" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Zofenopril

Medicinal products increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated, as it increases the risk of angioedema (see sections "Contraindications" and "Special precautions").

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

Concomitant use not recommended

Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that increase serum potassium levels

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients treated with zofenopril. Potassium-sparing diuretics such as spironolactone, triamterene, or amiloride, as well as potassium supplements or potassium-containing salt substitutes, may lead to a significant increase in serum potassium levels. Caution should also be exercised when zofenopril is used concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of zofenopril with the above-mentioned medicinal products is not recommended. If concomitant use is indicated, these products should be used with caution, with regular monitoring of serum potassium levels.

ACE inhibitors, angiotensin II receptor blockers, or aliskiren

Clinical trial data show that dual blockade of the renin-angiotensin-aldosterone system (RAAS) resulting from combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with an increased frequency of adverse reactions such as arterial hypotension, hyperkalemia, and decreased renal function (including acute renal failure), compared to treatment with a single RAAS-acting medicinal product (see sections "Pharmacological properties", "Contraindications", and "Special precautions").

Concomitant use requiring caution

Thiazide or loop diuretics

Prior treatment with high-dose diuretics may lead to dehydration and risk of arterial hypotension during the initial phase of zofenopril therapy (see section "Special precautions").

Hypotensive effects can be minimized by discontinuing the diuretic, increasing fluid or salt intake, or by initiating zofenopril at low starting doses.

Anaesthetic agents

ACE inhibitors may potentiate the hypotensive effect of certain anaesthetic medicinal products.

Narcotics / tricyclic antidepressants / antipsychotics / barbiturates

Orthostatic hypotension may occur.

Other antihypertensive agents (e.g., β-blockers, α-blockers, calcium antagonists)

Additive hypotensive effect or potentiation of effect may occur. Nitroglycerin, other nitrates, or other vasodilators should be used with caution.

Cimetidine

Possible increased risk of hypotensive effect.

Cyclosporine

Hyperkalemia may occur when ACE inhibitors are used concomitantly with cyclosporine.

Serum potassium levels should be monitored.

Heparin

Hyperkalemia may occur when ACE inhibitors are used concomitantly with heparin.

Serum potassium levels should be monitored.

Allopurinol, procainamide, systemic corticosteroids, cytostatic or immunosuppressive agents

Concomitant use with ACE inhibitors increases the risk of hypersensitivity reactions. Information from other ACE inhibitors indicates an increased risk of leukopenia with concomitant use.

Antidiabetic agents

Rarely, ACE inhibitors may enhance the hypoglycemic effects of insulin and oral antidiabetic agents, such as sulfonylureas, in patients with diabetes mellitus. In such cases, dose reduction of the antidiabetic agent may be necessary when used concomitantly with ACE inhibitors.

Hemodialysis using high-flux dialysis membranes

Risk of anaphylactoid reactions is increased when used concomitantly with ACE inhibitors.

Sympathomimetic agents

Possible reduction in the hypotensive effect of ACE inhibitors; careful patient monitoring is required to ensure desired therapeutic effect.

Antacids

May reduce the bioavailability of ACE inhibitors.

Food

May reduce the rate, but not the extent, of absorption of zofenopril.

Gold compounds

There have been reports of increased incidence of nitritoid reactions (symptoms of vasodilation, including flushing, nausea, dizziness, hypotension, which may be severe) after injection of gold compounds, such as sodium aurothiomalate, in patients receiving ACE inhibitor therapy.

Additional information

Cytochrome P450 enzyme system. There are no clinical data on direct interaction between zofenopril and other active substances metabolized by cytochrome P450 enzymes. However, in vitro metabolism studies with zofenopril have shown no potential for interaction with active substances metabolized by CYP enzymes.

Hydrochlorothiazide

Concomitant use requiring caution

Cholestyramine and colestipol resins

Absorption of hydrochlorothiazide is impaired in the presence of anion-exchange resins. After single-dose administration, cholestyramine and colestipol resins bind hydrochlorothiazide and reduce its gastrointestinal absorption by 85% and 43%, respectively.

Sulfonamide-derived diuretics should be taken at least 1 hour before or 4–6 hours after administration of these resins.

Corticosteroids, ACTH, parenteral amphotericin B, carbenoxolone, stimulant laxatives

Concomitant use with hydrochlorothiazide may increase the risk of electrolyte disturbances, particularly hypokalemia.

Calcium salts

Concomitant use with thiazide diuretics may increase serum calcium levels due to reduced excretion.

Cardiac glycosides

Hypokalemia or hypomagnesemia induced by thiazide diuretics predisposes to cardiac arrhythmias caused by cardiac glycosides.

Medicinal products causing torsades de pointes

Caution should be exercised when hydrochlorothiazide is used concomitantly with medicinal products that may cause torsades de pointes, such as certain antiarrhythmics, some neuroleptics, and other agents capable of inducing torsades de pointes, due to the risk of hypokalemia.

Vasopressor amines (e.g., adrenaline)

Response to vasopressor amines may be reduced, but not to an extent that precludes their use with hydrochlorothiazide.

Non-depolarizing neuromuscular blocking agents (e.g., tubocurarine)

The effect of neuromuscular blocking agents may be enhanced when used with hydrochlorothiazide.

Amantadine

Thiazide diuretics may increase the risk of adverse reactions caused by amantadine.

Medicinal products used for the treatment of gout (probenecid, sulfinpyrazone, allopurinol)

Dose adjustment of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid levels. Increased doses of probenecid or sulfinpyrazone may be needed. Concomitant use of thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol.

Additional information

Effect on laboratory test results: due to the effects of thiazide diuretics on calcium metabolism, they may influence tests of parathyroid function.

Zofenopril/hydrochlorothiazide

Concomitant use not recommended

Lithium preparations

Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and further enhance the already elevated risk of lithium toxicity associated with ACE inhibitors. Therefore, the medicinal product is not recommended for use with lithium preparations. If combination therapy is necessary, careful monitoring of serum lithium levels is required.

Biochemical parameters

Thiazide diuretics may reduce serum protein-bound iodine concentration without evidence of thyroid dysfunction.

Concomitant use requiring caution

Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid at doses ≥ 3 g/day

NSAIDs may reduce the antihypertensive effect of ACE inhibitors and diuretics. Additionally, additive effects of NSAIDs and ACE inhibitors on increasing serum potassium levels have been reported, while renal function may decrease. These effects are generally reversible and are more commonly observed in patients with renal impairment. Rarely, acute renal failure may occur, particularly in patients with renal impairment, e.g., due to dehydration, or in elderly patients.

Ethanol

Enhances the antihypertensive effect of ACE inhibitors and hydrochlorothiazide.

Trimethoprim

Concomitant use of ACE inhibitors and thiazide diuretics with trimethoprim increases the risk of hyperkalemia.

Special precautions for use.

Zofenopril

Arterial hypotension

Like other ACE inhibitors and diuretics, the medicinal product Zofenozyd may cause a significant decrease in arterial pressure, especially after the first dose, although symptomatic arterial hypotension is rarely observed in patients with uncomplicated arterial hypertension.

It is more likely to occur in patients with disturbances in water-electrolyte balance due to diuretic therapy, a salt-restricted diet, dialysis, diarrhea, or vomiting, as well as in patients with severe renin-dependent arterial hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Symptomatic arterial hypotension has been observed in patients with heart failure, with or without concomitant renal impairment. The likelihood of its occurrence is higher in patients with more severe degrees of heart failure, associated with the use of high-dose loop diuretics, hyponatremia, or impaired renal function.

In patients at increased risk of symptomatic arterial hypotension, treatment should be initiated under strict medical supervision, preferably in a hospital setting, starting with low doses that are gradually increased. Diuretic therapy should be temporarily discontinued, if possible, at the beginning of treatment with this medicinal product.

These recommendations also apply to patients with angina pectoris or cerebrovascular disease, in whom excessive reduction in arterial pressure may lead to myocardial infarction or acute cerebrovascular accident.

If arterial hypotension develops, the patient should be placed in a supine position. Intravenous administration of 0.9% sodium chloride solution may be required to restore circulating blood volume. A decrease in arterial pressure after the first dose does not preclude subsequent dose escalation, provided arterial hypotension is effectively managed.

Patients with renovascular hypertension

When using ACE inhibitors in patients with bilateral renal artery stenosis or stenosis of the renal artery of a single functioning kidney, there is an increased risk of developing severe arterial hypotension and renal failure, and diuretic therapy may act as a triggering factor. Renal failure may be accompanied by only minor changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.

Such patients should start therapy with a low dose, gradually increasing it, under careful medical supervision and with monitoring of renal function.

Patients with renal impairment

Appropriate careful monitoring of renal function should be performed during therapy. Cases of renal failure have been reported during ACE inhibitor therapy, primarily in patients with severe heart failure or kidney disease, including renal artery stenosis. In some patients without apparent kidney pathology, increases in blood urea and creatinine concentrations have been observed, especially when diuretics are used concomitantly. In such cases, dose reduction of the active substances may be necessary. Careful monitoring of renal function is recommended during the first few weeks of treatment.

Patients undergoing hemodialysis

If high-flux polycrylonitrile membranes (e.g., AN 69) are used for hemodialysis, anaphylactoid reactions may occur within the first minutes of the session in patients taking ACE inhibitors, with clinical manifestations such as facial swelling, flushing, arterial hypotension, and dyspnea. Therefore, it is recommended to use an alternative membrane or another antihypertensive agent.

The efficacy and safety of zofenopril in patients with myocardial infarction undergoing hemodialysis have not been established; therefore, it should not be used in such patients.

Patients undergoing low-density lipoprotein (LDL) apheresis

Anaphylactoid reactions may occur in patients taking ACE inhibitors who undergo LDL apheresis with dextran sulfate, similar to those observed in patients undergoing hemodialysis with high-flux membranes (see above). Therefore, such patients should be treated with an antihypertensive agent from another class.

Anaphylactic reactions during desensitization therapy or after insect bites

Rarely, anaphylactoid reactions, potentially life-threatening, have occurred in patients taking ACE inhibitors during desensitization therapy (e.g., with venom from Hymenoptera) or after insect bites. These reactions were avoided when ACE inhibitors were temporarily discontinued, but recurred after inadvertent re-administration. Therefore, caution should be exercised when performing such therapy in patients taking ACE inhibitors.

Kidney transplantation

There is no experience with the use of this medicinal product in patients who have recently undergone kidney transplantation; therefore, it is not recommended for such patients.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive agents that suppress the renin-angiotensin system; therefore, zofenopril is not recommended for them.

Hypersensitivity/angioedema

Angioedema of the face, extremities, lips, mucous membranes, tongue, epiglottis, and/or larynx may occur in patients taking ACE inhibitors, more frequently during the first weeks of treatment, although severe angioedema may occasionally occur after prolonged ACE inhibitor therapy. Therapy with ACE inhibitors should be immediately discontinued and replaced with a medicinal product from another class of antihypertensive agents.

Angioedema involving the tongue, epiglottis, and larynx may be fatal. In such cases, immediate medical assistance is required, including (but not limited to) immediate subcutaneous administration of 1:1000 adrenaline solution (0.3–0.5 mL) or slow intravenous administration of 1 mg/mL adrenaline (which should be diluted according to instructions), under strict ECG and blood pressure monitoring. The patient should be hospitalized and kept under observation for at least 12–24 hours until all symptoms have completely resolved.

Even in cases where only tongue swelling occurs without respiratory distress, the patient may require monitoring, as treatment with antihistamines and corticosteroids alone may be insufficient.

ACE inhibitor-induced angioedema occurs more frequently in patients of non-Caucasian race than in others.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may have an increased risk of developing angioedema when taking an ACE inhibitor (see section "Contraindications").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Treatment with sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of the medicinal product. Treatment with the medicinal product Zofenozyd should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin may increase the risk of angioedema (e.g., swelling of the airways or tongue with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction"). Caution should be exercised when initiating racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in a patient already taking any ACE inhibitor.

Cough

A dry, non-productive cough that resolves after discontinuation of therapy may occur with ACE inhibitors, which should be considered in the differential diagnosis of cough.

Hepatic impairment

Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice followed by fulminant hepatic necrosis and (sometimes) fatal outcome. The mechanism of this syndrome is unclear. Patients who develop jaundice or a significant increase in liver enzymes during ACE inhibitor therapy should discontinue the ACE inhibitor and receive appropriate treatment.

Serum potassium levels

ACE inhibitors may cause hyperkalemia because they inhibit aldosterone release. In patients with normal renal function, this effect is usually mild. However, hyperkalemia may occur in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, heparin, trimethoprim, or co-trimoxazole (also known as trimethoprim/sulfamethoxazole), and especially aldosterone antagonists or angiotensin receptor blockers. Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium levels and renal function should be monitored (see section "Interaction with other medicinal products and other forms of interaction").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Available data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS with concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Pharmacological properties" and "Interaction with other medicinal products and other forms of interaction").

If dual RAAS blockade therapy is considered absolutely necessary, it should be performed only under physician supervision and with frequent careful monitoring of renal function, electrolyte levels, and blood pressure.

ACE inhibitors and angiotensin receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Surgery/anesthesia

In patients undergoing major surgery or anesthesia, ACE inhibitors may cause arterial hypotension up to shock, as they may block angiotensin II formation due to compensatory renin release. If discontinuation of ACE inhibitors is not possible, careful monitoring of circulating blood and plasma volume is required.

Aortic stenosis/mitral valve stenosis/hypertrophic cardiomyopathy

ACE inhibitors should be used with caution in patients with mitral valve stenosis and impaired outflow from the left ventricle and should be avoided in cases of cardiogenic shock and stenosis causing significant hemodynamic impact.

Neutropenia/agranulocytosis

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients taking ACE inhibitors. The risk of neutropenia is related to the dose and type of ACE inhibitor and depends on the patient's clinical condition. Neutropenia is rarely observed in patients with uncomplicated clinical presentation but may occur in patients with mild renal impairment, especially when associated with collagen vascular diseases such as systemic lupus erythematosus or scleroderma, immunosuppressive therapy, allopurinol or procainamide treatment, or a combination of these risk factors. Some of these patients developed severe infections that were refractory to intensive antibiotic therapy.

When using zofenopril in such patients, it is recommended to determine leukocyte count and differential count before starting treatment, every 2 weeks during the first 3 months of zofenopril therapy, and thereafter as needed. All patients should be advised to report any signs of infection (e.g., sore throat, fever), and a differential leukocyte count should be performed. Zofenopril and other concomitant medications (see section "Interaction with other medicinal products and other forms of interaction") should be discontinued if neutropenia (neutrophil count less than 1000/mm³) is detected or suspected. After discontinuation of ACE inhibitors, neutrophil count returns to baseline levels.

Psoriasis

ACE inhibitors should be used with caution in patients with psoriasis.

Proteinuria

Proteinuria may occur more frequently in patients with pre-existing renal impairment or those taking relatively high doses of ACE inhibitors. In patients with a history of kidney disease, urine protein levels (in the first morning urine sample using test strips) should be determined before starting treatment and regularly during treatment.

Patients with diabetes mellitus

In patients with diabetes mellitus already taking oral antidiabetic agents or insulin, blood glucose levels should be carefully monitored during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

Lithium preparations

Combination of lithium preparations and the medicinal product Zofenozyd is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Ethnic differences

Like other ACE inhibitors, zofenopril may have a lower antihypertensive effect in patients of non-Caucasian race compared to other patients.

ACE inhibitors more frequently cause angioedema in patients of non-Caucasian race than in patients of other races.

Pregnancy

The medicinal product Zofenozyd is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, it should be immediately discontinued and replaced with another medicinal product permitted for use during pregnancy (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Hydrochlorothiazide

Renal function impairment

In patients with kidney disease, the use of thiazide diuretics may exacerbate azotemia. Cumulative effects of this active substance may manifest in patients with impaired renal function. If progressive renal impairment becomes evident (indicated by increased non-protein nitrogen levels), the prescribed treatment should be carefully reviewed and, if necessary, the diuretic discontinued.

Hepatic function impairment

Thiazide diuretics should be used with caution in patients with impaired liver function or progressive liver disease, as even minor changes in water-electrolyte balance may precipitate hepatic coma.

Metabolic and endocrine effects

Thiazide diuretics may impair glucose tolerance. Adjustment of insulin or oral antidiabetic agent dosage may be necessary (see section "Interaction with other medicinal products and other forms of interaction"). Latent diabetes mellitus may become apparent during thiazide diuretic therapy, and increased cholesterol and triglyceride levels are possible. These agents may provoke exacerbation of hyperuricemia and/or gout in some patients.

Electrolyte imbalance

All patients taking diuretics should undergo periodic determination of serum electrolyte levels at appropriate intervals.

Thiazide diuretics, including hydrochlorothiazide, may cause disturbances in water-electrolyte balance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Early signs of water-electrolyte imbalance include dry mouth, thirst, weakness, drowsiness, lethargy, restlessness, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, and gastrointestinal disorders such as nausea and vomiting.

Although hypokalemia may develop with thiazide diuretic use, concomitant administration with zofenopril may reduce diuretic-induced hypokalemia. The risk of hypokalemia is highest in patients with hepatic cirrhosis, those with sudden increase in diuresis, those receiving inadequate electrolyte intake with food, and those taking corticosteroids or ACTH concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Hyponatremia due to dilution may occur in patients with edema during hot weather. Chloride deficiency is generally mild and usually does not require treatment.

Thiazide diuretics may reduce calcium excretion in urine and cause mild, reversible elevation of serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide diuretics should be discontinued before testing parathyroid gland function.

Thiazide diuretics may increase magnesium excretion in urine, potentially leading to hypomagnesemia.

Systemic lupus erythematosus

Exacerbation or worsening of systemic lupus erythematosus has been reported during thiazide diuretic use.

Non-melanoma skin cancer (NMSC)

In two epidemiological studies based on data from the Danish National Cancer Registry, increasing cumulative doses of hydrochlorothiazide were associated with an increased risk of NMSC (BCC and SCC). The photosensitizing effects of hydrochlorothiazide may be a possible mechanism for NMSC development.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and advised to regularly check their skin for any new lesions and immediately report any suspicious skin changes. To minimize the risk of skin cancer, patients should be advised to limit exposure to sunlight and UV radiation and use appropriate protection when exposed. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsy specimens. Patients with a history of NMSC may also require reassessment of hydrochlorothiazide use (see also section "Undesirable effects").

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

Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction characterized by choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the medicinal product. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. The primary treatment is prompt discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, surgical, medical, or operative treatment methods may be necessary. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Acute respiratory toxicity

Very rare, severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide use. Pulmonary edema usually develops within minutes or hours after hydrochlorothiazide administration. Initial symptoms include dyspnea, fever, worsening lung condition, and arterial hypotension. If ARDS is suspected, the medicinal product should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be used in patients who previously developed ARDS after taking hydrochlorothiazide.

Anti-doping test

Hydrochlorothiazide, contained in this medicinal product, may cause a false-positive result in anti-doping tests.

Other

Hypersensitivity reactions are possible in patients both with and without a history of allergy or bronchial asthma.

Cases of photosensitivity reactions have been reported with thiazide diuretic use (see section "Undesirable effects"). If a photosensitivity reaction occurs during treatment, use of the medicinal product is recommended to be discontinued. If re-prescription of a diuretic is necessary, it is recommended to protect exposed skin areas from sunlight or ultraviolet radiation.

Zofenopril/hydrochlorothiazide

In addition to the warnings related to individual components, the following should be considered:

Pregnancy

The medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with the medicinal product Zofenozyd, it should be immediately discontinued. If necessary, it should be replaced with another medicinal product permitted for use during pregnancy (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Patients with renal impairment

Considering the effects of zofenopril and hydrochlorothiazide in patients with impaired renal function, the medicinal product should not be prescribed to patients with moderate or severe renal impairment (creatinine clearance < 45 mL/min).

Hypokalemia risk

Combination of an ACE inhibitor with a thiazide diuretic does not exclude the possibility of hypokalemia. Regular monitoring of serum potassium levels is required.

Galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption syndrome

This medicinal product contains lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

Zofenopril

Use of ACE inhibitors is contraindicated in pregnant women or women planning to become pregnant (see sections "Contraindications" and "Special precautions for use").

Exceptions are cases where long-term ACE inhibitor therapy is indicated for life-threatening conditions in women planning pregnancy. In all other cases, such patients are recommended to switch to alternative antihypertensive agents with a proven safety profile during pregnancy. If pregnancy is diagnosed, ACE inhibitor therapy should be immediately discontinued and alternative therapy initiated if necessary.

Use of ACE inhibitors during the first trimester of pregnancy is associated with teratogenic risk, and during the second and third trimesters with fetotoxic effects (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia) (see preclinical safety data). Infants whose mothers took ACE inhibitors during pregnancy should be closely monitored for arterial hypotension (see sections "Contraindications" and "Special precautions for use").

Hydrochlorothiazide

Experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Considering the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters may impair fetoplacental perfusion and affect the fetus and newborn, causing jaundice, electrolyte imbalance, and thrombocytopenia.

Hydrochlorothiazide should not be used to treat gestational edema, pregnancy-induced hypertension, or preeclampsia due to the risk of reduced plasma volume and placental hypoperfusion without positive effect on disease course.

Hydrochlorothiazide should not be used to treat essential hypertension in pregnant women except in exceptional cases when no other therapy is possible.

Zofenopril/hydrochlorothiazide

Considering the effects on pregnancy of the individual components of this combination medicinal product, use of the medicinal product is contraindicated in pregnant women and women planning to become pregnant (see sections "Contraindications" and "Special precautions for use").

Lactation

There is no information on the use of the medicinal product during lactation; therefore, it is not recommended for breastfeeding women. It is preferable to use other medicinal products with a proven safety profile during lactation, especially when breastfeeding newborns or preterm infants.

Hydrochlorothiazide

Hydrochlorothiazide passes into human breast milk in small amounts. High doses of thiazides causing intense diuresis may suppress milk production. Use of the medicinal product during lactation is not recommended. If use of the medicinal product during lactation is necessary, the dose should be as low as possible.

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect on the ability to drive or operate machinery have not been conducted. When driving vehicles or operating machinery, it should be remembered that drowsiness, dizziness, or fatigue may occasionally occur.

Dosage and Administration

Dosage

Adults

Prior to initiating therapy with the fixed-dose combination, it is recommended to establish the appropriate doses of the individual components (i.e., zofenopril and hydrochlorothiazide).

Direct substitution of monotherapy agents with the fixed-dose combination product may be considered when appropriate.

For patients without disturbances in water-electrolyte balance, the usual effective dose is 1 tablet once daily.

Zofenozid is not recommended for patients suspected of having water-electroly0te imbalance.

Elderly patients (aged 65 years and older)

Dose adjustment is not required for elderly patients with normal creatinine clearance. Zofenozid is not recommended for elderly patients with reduced creatinine clearance (less than 45 mL/min).

Creatinine clearance can be calculated based on serum creatinine concentration using the Cockcroft-Gault formula:

The above method is used to calculate creatinine clearance in men. For women, the resulting value should be multiplied by 0.85.

Patients with renal impairment or undergoing dialysis

Patients with mild renal impairment and arterial hypertension (creatinine clearance > 45 mL/min) may receive the same dose and dosing regimen of Zofenozid as patients with normal renal function.

Use of Zofenozid is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 45 mL/min) (see section "Special Warnings and Precautions for Use").

Zofenozid is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications").

Use of Zofenozid is not recommended in patients with arterial hypertension undergoing dialysis.

Patients with hepatic impairment

For patients with arterial hypertension and mild to moderate hepatic impairment who have previously received zofenopril 30 mg as monotherapy, the same dosing regimen may be used as in patients with normal hepatic function.

Zofenozid is contraindicated in patients with arterial hypertension and severe hepatic impairment.

Administration

Zofenozid should be administered once daily, independent of food intake.

For easier swallowing, the tablet may be divided into two halves and swallowed separately at the prescribed time.

Children

Use of Zofenozid in children and adolescents under 18 years of age is not recommended due to lack of data on safety and efficacy.

Overdose

Symptoms of overdose include severe arterial hypotension, shock, stupor, bradycardia, electrolyte disturbances, and renal failure.

Treatment

Symptomatic and supportive therapy should be administered. In case of overdose, the patient should be closely monitored, preferably in an intensive care unit. Frequent monitoring of serum electrolytes and creatinine levels is required. Therapeutic measures depend on the nature and severity of symptoms. If ingestion was recent, measures to prevent absorption may be taken, such as gastric lavage, administration of adsorbents, and sodium sulfate. In case of decreased blood pressure, the patient should be placed in a shock position and therapy with agents to increase circulating blood volume and/or administration of angiotensin II should be considered. Bradycardia and excessive vagal reactions should be treated with atropine. If necessary, an artificial pacemaker should be used. ACE inhibitors may be removed from the circulation by hemodialysis. Polycrylonitrile membranes with high permeability should be avoided.

Overdose with hydrochlorothiazide is characterized by electrolyte disturbances (hypokalemia, hypochloremia) and dehydration due to excessive diuresis. The most common signs and symptoms of overdose are nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or exacerbation of cardiac arrhythmias caused by concomitant use of digitalis glycosides or certain antiarrhythmic agents.

Adverse Reactions.

In controlled clinical trials involving 597 patients who were randomly assigned to receive zofenopril and hydrochlorothiazide, no adverse reactions specific to this combination were observed. Only adverse reactions previously established for zofenopril calcium or hydrochlorothiazide were reported. The frequency of adverse reactions was not related to the patient's sex or age.

List of adverse reactions presented in table form

All adverse reactions observed during clinical trials, as well as those with at least a probable or possible relationship to the use of the medicinal product, are listed in the table. These reactions are classified by system organ classes (MedDRA) and frequency of occurrence: 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).

Infections and infestations: uncommon – infectious disease, bronchitis, pharyngitis.

Metabolism and nutrition disorders: uncommon – hypercholesterolemia, hyperglycemia, hyperlipidemia, hypokalemia, hyperkalemia (see sections "Interaction with other medicinal products and other forms of interaction", "Special precautions for use"), hyperuricemia.

Nervous system disorders: common – dizziness, headache; uncommon – somnolence, syncope, arterial hypertension.

Psychiatric disorders: uncommon – insomnia.

Cardiac disorders: uncommon – angina pectoris, atrial fibrillation, myocardial infarction, palpitations.

Vascular disorders: uncommon – flushing, arterial hypotension (see section "Special precautions for use"), arterial hypertension.

Respiratory, thoracic and mediastinal disorders: common – cough; uncommon – dyspnea.

Gastrointestinal disorders: uncommon – nausea, dyspepsia, gastritis, gingivitis, dry mouth, abdominal pain.

Skin and subcutaneous tissue disorders: uncommon – angioedema, psoriasis, acne, dry skin, pruritus, urticaria.

Musculoskeletal and connective tissue disorders: uncommon – back pain.

Renal and urinary disorders: uncommon – polyuria.

General disorders and administration site conditions: uncommon – asthenia, influenza-like symptoms, peripheral edema.

Reproductive system and breast disorders: uncommon – erectile dysfunction.

Investigations: uncommon – increased creatinine levels, abnormal liver function test results.

Additional information regarding individual components

Adverse reactions known to be characteristic of each active substance when used separately may occur during the use of this medicinal product.

Zofenopril

Adverse reactions observed during the use of ACE inhibitors.

Blood and lymphatic system disorders: agranulocytosis and pancytopenia may occur in some patients. Cases of hemolytic anemia have been reported in patients with glucose-6-phosphate dehydrogenase deficiency.

Endocrine disorders: frequency unknown – disorders of antidiuretic hormone secretion.

Metabolism and nutrition disorders: rare – hyperkalemia (see sections "Interaction with other medicinal products and other forms of interaction", "Special precautions for use"); very rare – hypoglycemia.

Psychiatric disorders: rare – depression, mood changes, sleep disorders, confusion.

Nervous system disorders: common – dizziness*, headache*; uncommon – paresthesia, dysgeusia, disturbance of equilibrium.

Eye disorders: rare – blurred vision.

Ear and labyrinth disorders: rare – tinnitus.

Cardiac disorders: rare – palpitations; isolated cases of tachycardia, arrhythmias, angina pectoris, and myocardial infarction have been reported during ACE inhibitor use in the setting of arterial hypotension.

Vascular disorders: rare – loss of consciousness (syncope), arterial hypotension. Arterial hypotension is most commonly observed in certain risk groups (see section "Special precautions for use"). Arterial hypotension may be accompanied by symptoms such as dizziness, feeling of weakness, and visual disturbances.

Rarely, skin hyperemia may occur.

Respiratory, thoracic and mediastinal disorders: common – cough*; rare – dyspnea, sinusitis, rhinitis, glossitis, bronchitis, bronchospasm. In a small subgroup of patients, ACE inhibitor use has been associated with the development of angioedema involving facial and oropharyngeal tissues. In isolated cases, angioedema has caused obstruction of the upper airways, leading to fatal outcomes.

Gastrointestinal disorders: common – nausea*, vomiting*; uncommon – abdominal pain, diarrhea, constipation, dry mouth. Isolated cases of pancreatitis and intestinal obstruction associated with ACE inhibitor use have been reported.

Very rarely, angioedema of the small intestine may occur.

Hepatobiliary disorders: isolated cases of cholestatic jaundice and hepatitis associated with ACE inhibitor use have been reported.

Skin and subcutaneous tissue disorders: uncommon – allergic and hypersensitivity reactions such as rash*, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriasis-like rash, alopecia, which may be accompanied by fever, myalgia, arthralgia, eosinophilia, and/or increased titer of antinuclear antibodies (ANA).

Rare – hyperhidrosis, angioneurotic edema*, pruritus, urticaria.

Musculoskeletal and connective tissue disorders: uncommon – myalgia, muscle cramps*.

Renal and urinary disorders: worsening or development of renal impairment is possible. Cases of acute renal failure have been reported (see section "Special precautions for use").

Rare – urinary disorders have been observed.

Reproductive system and breast disorders: rare – erectile dysfunction.

General disorders and administration site conditions: common – fatigue*; uncommon – asthenia*; very rare – peripheral edema and chest pain.

Investigations

Increased blood urea and creatinine levels may occur, which are reversible upon discontinuation of the drug, particularly in patients with pre-existing renal impairment, severe heart failure, or renovascular hypertension.

In some patients, decreased hemoglobin and hematocrit, reduced platelet and leukocyte counts have been observed. Elevated liver enzymes and bilirubin levels in serum have been reported.

*Adverse reactions typical for ACE inhibitors and observed during clinical trials in patients receiving zofenopril.

Hydrochlorothiazide

Below are the adverse reactions observed during the use of hydrochlorothiazide as monotherapy.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Frequency unknown: non-melanoma skin cancer (NMSC) (basal cell carcinoma and squamous cell carcinoma).

NMSC: based on available epidemiological data, a link has been established between cumulative hydrochlorothiazide dose and NMSC (see also sections "Pharmacological properties" and "Special precautions for use").

Blood and lymphatic system disorders: leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, bone marrow suppression.

Immune system disorders: anaphylactic reactions.

Metabolism and nutrition disorders: anorexia, dehydration, gout, diabetes mellitus, metabolic alkalosis, hyperuricemia, hyperglycemia, hyperamylasemia, electrolyte imbalances (hyponatremia, hypokalemia, hypomagnesemia, hypochloremia, hypercalcemia, including).

Psychiatric disorders: apathy, confusion, depression, increased excitability, restlessness, sleep disturbances.

Nervous system disorders: convulsions, clouding of consciousness, coma, headache, dizziness, paresthesia, paresis.

Eye disorders: frequency unknown: choroidal effusion, acute myopia, acute angle-closure glaucoma.

Xanthopsia, blurred vision, myopia (exacerbation), decreased lacrimation.

Ear and labyrinth disorders: vertigo.

Cardiac disorders: cardiac arrhythmias, palpitations.

Vascular disorders: orthostatic hypotension, thrombosis, embolism, shock.

Respiratory, thoracic and mediastinal disorders: pneumonia, interstitial lung disease, pulmonary edema.

Very rare: acute respiratory distress syndrome (ARDS) (see section "Special precautions for use").

Gastrointestinal disorders: dry mouth, nausea, vomiting, gastric discomfort, diarrhea, constipation, abdominal pain, paralytic intestinal obstruction, flatulence, sialadenitis, pancreatitis.

Hepatobiliary disorders: cholestatic jaundice, cholecystitis.

Skin and subcutaneous tissue disorders: pruritus, purpura, urticaria, photosensitivity reactions, rash, cutaneous form of systemic lupus erythematosus, necrotizing vasculitis, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: muscle cramps, myalgia.

Renal and urinary disorders: renal function impairment, acute renal failure, interstitial nephritis, glucosuria.

Reproductive system and breast disorders: erectile dysfunction.

General disorders and administration site conditions: asthenia, fever, fatigue, thirst.

Investigations: changes in electrocardiogram, increased blood cholesterol and triglyceride levels.

Reporting suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions. Keep out of reach of children. No special storage conditions are required for this medicinal product.

Packaging. 14 tablets in a blister; 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. BluFarma - Indústria Farmacêutica, S.A.

Manufacturer's address and location of business activity.

S. Martinho do Bispo, Coimbra, 3045-016, Portugal.

Marketing Authorization Holder.

LLC "ASINO UKRAINE"

Address of Marketing Authorization Holder.

Ukraine, 03124, Kyiv, Vatslava Havela Boulevard, 8.

In case of adverse reactions or questions regarding the safety and efficacy of the medicinal product, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINE" at: Vatslava Havela Boulevard, 8, Kyiv, 03124, tel/fax: +380442812333.