Ramises® com

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RAMiZESCOM

Composition:

Active substances: ramipril, hydrochlorothiazide;

1 tablet contains ramipril 5 mg and hydrochlorothiazide 25 mg or ramipril 2.5 mg and hydrochlorothiazide 12.5 mg;

Excipients: lactose monohydrate, microcrystalline cellulose 102, crospovidone, hypromellose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets 5 mg/25 mg: white or almost white, round-shaped tablets with a flat surface, bevel edge and a score line;

tablets 2.5 mg/12.5 mg: white or almost white, round-shaped tablets with a convex surface and a score line or white or almost white, round-shaped tablets with a flat surface, bevel edge and a score line.

Pharmacotherapeutic group. Combined angiotensin-converting enzyme (ACE) inhibitors.

ATC code C09BA05.

Pharmacological Properties.

Mechanism of Action.

Ramipril. Ramiprilat, the active metabolite of the prodrug ramipril, is an inhibitor of the enzyme dipeptidyl carboxypeptidase I (also known as angiotensin-converting enzyme, or kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to angiotensin II, an active vasoconstrictor substance, and the breakdown of bradykinin, which is an active vasodilator. Reduction in angiotensin II formation and inhibition of bradykinin degradation lead to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. In patients of non-Caucasian race (of Afro-Caribbean origin) with arterial hypertension (a population generally characterized by low renin activity levels), the response to monotherapy with ACE inhibitors has been, on average, less pronounced than in patients of other racial groups.

Hydrochlorothiazide. Hydrochlorothiazide is a thiazide diuretic. The mechanism of its antihypertensive action has not yet been fully elucidated. Thiazide diuretics inhibit the reabsorption of sodium and chloride ions in the distal tubules. Enhanced renal excretion of these ions is accompanied by increased urine production (due to osmotic binding of water). Excretion of potassium and magnesium is also increased, while excretion of uric acid is reduced. Possible mechanisms of the hypotensive effect of hydrochlorothiazide include changes in sodium balance, reduction in extracellular fluid and plasma volume, changes in renal vascular resistance, or decreased responsiveness to norepinephrine and angiotensin II.

Pharmacodynamics.

Ramipril. Administration of ramipril results in a significant reduction in peripheral arterial resistance. Generally, no significant changes in renal plasma flow or glomerular filtration rate occur. In patients with arterial hypertension, ramipril administration reduces blood pressure in both supine and upright positions, without being accompanied by a compensatory increase in heart rate.

In most patients, the antihypertensive effect begins approximately 1–2 hours after oral administration of a single dose. Maximum effect after a single oral dose usually occurs within 3–6 hours. The antihypensive effect after a single dose typically lasts for 24 hours.

With prolonged treatment using ramipril, the maximum antihypertensive effect develops within 3–4 weeks. It has been demonstrated that the antihypertensive effect persists for up to 2 years during long-term therapy.

Abrupt discontinuation of ramipril does not cause rapid or excessive elevation of blood pressure (rebound phenomenon).

Hydrochlorothiazide. For hydrochlorothiazide, the onset of diuretic effect occurs approximately 2 hours after administration and lasts for 6–12 hours, with maximum effect occurring at 4 hours. The antihypertensive effect begins after 3–4 days of treatment and may persist for up to 1 week after discontinuation of therapy.

The antihypertensive effect is accompanied by a slight increase in glomerular filtration rate, renal vascular resistance, and plasma renin activity.

Concomitant Administration of Ramipril and Hydrochlorothiazide. Administration of this combination leads to a greater reduction in blood pressure than administration of either active ingredient alone. Concomitant use of ramipril and hydrochlorothiazide reduces potassium loss associated with the diuretic effect, likely due to inhibition of the renin-angiotensin-aldosterone system. Combining an ACE inhibitor with a thiazide diuretic provides a synergistic effect and also reduces the risk of diuretic-induced hypokalemia.

Pharmacokinetics.

Ramipril.

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration of ramipril is reached within 1 hour. Absorption is at least 56%, and is not significantly affected by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of the drug at doses of 2.5 mg and 5 mg is 45%.

Maximum plasma concentrations of ramiprilat, the sole active metabolite of ramipril, are reached 2–4 hours after ramipril administration. After administration of usual doses of ramipril once daily, steady-state plasma concentrations of ramiprilat are achieved after approximately 4 days of treatment.

Distribution. Plasma protein binding is approximately 73% for ramipril and 56% for ramiprilat.

Metabolism. Ramipril is almost completely metabolized to ramiprilat, as well as to diketopiperazine ester, diketopiperazine acid, and glucuronides of ramipril and ramiprilat.

Elimination. Metabolite excretion occurs predominantly via the kidneys. The decline in ramiprilat plasma concentration is multiphasic. Due to strong binding to ACE and slow dissociation from the enzyme, ramiprilat exhibits a prolonged terminal elimination phase at very low plasma concentrations. The effective half-life of ramipril after repeated doses of 5–10 mg ramipril once daily is 13–17 hours, and is longer with lower doses (1.25–2.5 mg). This difference is due to the saturable binding capacity of the enzyme for ramiprilat. After a single oral dose of ramipril, neither ramipril nor its metabolites were detected in breast milk. However, the effect of repeated dosing is unknown.

Patients with Impaired Renal Function (see section "Dosage and Administration"). In patients with impaired renal function, renal excretion of ramiprilat is reduced, and renal clearance of ramiprilat is proportional to creatinine clearance. This leads to elevated plasma concentrations of ramiprilat, which decline more slowly than in individuals with normal renal function.

Patients with Impaired Hepatic Function (see section "Dosage and Administration"). In patients with impaired hepatic function, conversion of ramipril to ramiprilat occurs more slowly due to reduced activity of hepatic esterases. In such patients, increased plasma levels of ramipril are observed. However, maximum plasma concentrations of ramiprilat in these patients do not differ from those in individuals with normal hepatic function.

Hydrochlorothiazide.

Absorption. After oral administration, approximately 70% of hydrochlorothiazide is absorbed from the gastrointestinal tract. Maximum plasma concentrations of hydrochlorothiazide are reached within 1.5–5 hours.

Distribution. Plasma protein binding for hydrochlorothiazide is approximately 40%.

Metabolism. Hydrochlorothiazide is metabolized in the liver to a very minor extent.

Elimination. Hydrochlorothiazide is excreted almost entirely (>95%) unchanged by the kidneys; 50–70% of a single dose is excreted within 24 hours. The elimination half-life is 5–6 hours.

Patients with Impaired Renal Function (see section "Dosage and Administration"). In patients with impaired renal function, renal excretion of hydrochlorothiazide is reduced, and renal clearance of hydrochlorothiazide is proportional to creatinine clearance. This leads to elevated plasma concentrations of hydrochlorothiazide, which decline more slowly than in individuals with healthy kidneys.

Patients with Impaired Hepatic Function (see section "Dosage and Administration"). In patients with liver cirrhosis, the pharmacokinetics of hydrochlorothiazide do not undergo significant changes.

No studies have been conducted on the pharmacokinetics of hydrochlorothiazide in patients with heart failure.

Ramipril and Hydrochlorothiazide. Concomitant administration of ramipril and hydrochlorothiazide does not affect their bioavailability. The combination product can be considered bioequivalent to a product containing the individual active ingredients.

Clinical characteristics.

Indications.

Treatment of essential hypertension in patients for whom combination therapy (ramipril and hydrochlorothiazide) is recommended.

Contraindications.

Hypersensitivity to ramipril or other angiotensin-converting enzyme (ACE) inhibitors, hydrochlorothiazide, other thiazide diuretics, sulfonamides, or any of the excipients contained in the medicinal product.

History of angioedema (hereditary, idiopathic, or previously experienced during treatment with ACE inhibitors or angiotensin II receptor antagonists).

Patients with arterial hypotension or hemodynamically unstable conditions.

Concomitant use with sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Concomitant use of ACE inhibitors and extracorporeal treatment methods leading to blood contact with negatively charged surfaces should be avoided, as such use may lead to severe anaphylactoid reactions. These extracorporeal treatment methods include dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate (see section "Interaction with other medicinal products and other forms of interaction").

Bilateral renal artery stenosis or unilateral renal artery stenosis in the presence of a single functioning kidney.

Severe renal impairment (creatinine clearance < 30 mL/min) in patients not undergoing hemodialysis.

Clinically significant electrolyte imbalances, the course of which may worsen during treatment with the medicinal product (see section "Special precautions for use").

Refractory hypokalemia or hypercalcemia.

Refractory hyponatremia.

Symptomatic hyperuricemia (gout).

Anuria.

Severe hepatic impairment, hepatic encephalopathy.

Pregnancy or women planning to become pregnant (see "Use during pregnancy or breastfeeding").

Breastfeeding period (see section "Use during pregnancy or breastfeeding").

Concomitant use with medicinal products containing aliskiren in patients with diabetes or in patients with moderate or severe renal impairment (creatinine clearance < 60 mL/min).

Concomitant use with angiotensin II receptor antagonists in patients with diabetic nephropathy.

Interaction with other medicinal products and other forms of interaction.

Clinical studies have demonstrated that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased incidence of adverse reactions such as arterial hypotension, hyperkalemia, and renal dysfunction (including the development of acute renal failure), compared to treatment with a single RAAS-acting medicinal product (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Contraindicated combinations.

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"). Treatment with ramipril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of Ramizess® Com.

Extracorporeal treatment methods resulting in blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate, are contraindicated due to an increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or another class of antihypertensive agents.

Combinations requiring special caution.

Potassium salts, heparin, potassium-sparing diuretics, and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim, tacrolimus, cyclosporine). Hyperkalemia may occur; therefore, plasma potassium levels should be carefully monitored.

Antihypertensive medicinal products (e.g., diuretics) and other active substances that may reduce blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). Increased risk of arterial hypotension may occur (see section "Dosage and administration" regarding diuretics).

Vasopressor sympathomimetics and other active substances (e.g., epinephrine) that may reduce the antihypertensive effect of ramipril. Regular monitoring of blood pressure is recommended. Additionally, hydrochlorothiazide may reduce the effect of vasopressor sympathomimetics.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatic agents, and other substances that may cause changes in blood parameters. Increased risk of hematological reactions (see section "Special precautions for use").

Lithium salts. Since ACE inhibitors may reduce lithium excretion, this may lead to increased lithium toxicity. Plasma lithium levels should be regularly monitored. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and further elevate the already increased risk associated with ACE inhibitors. Therefore, concomitant use of ramipril/hydrochlorothiazide and lithium is not recommended.

Antidiabetic agents, including insulin. Hypoglycemic reactions may occur. Hydrochlorothiazide may reduce the effect of antidiabetic agents. Therefore, blood glucose levels should be closely monitored at the beginning of concomitant therapy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. A reduced antihypertensive effect of Ramizess® Com is expected. Moreover, concomitant use of ACE inhibitors and NSAIDs may be associated with an increased risk of renal dysfunction and elevated blood potassium levels.

Oral anticoagulants. The anticoagulant effect may be reduced when used concomitantly with hydrochlorothiazide.

Corticosteroids, ACTH, amphotericin B, carbenoxolone, licorice consumption in large amounts, laxatives (with prolonged use), and other potassium-losing agents or active substances that reduce plasma potassium levels. Increased risk of hypokalemia.

Digitalis preparations, active substances capable of prolonging the QT interval, antiarrhythmic agents. Proarrhythmic effects may be enhanced and antiarrhythmic effects may be reduced in the presence of electrolyte imbalances (e.g., hypokalemia, hypomagnesemia).

MEDICINAL PRODUCTS AFFECTING SERUM POTASSIUM LEVELS.

Periodic monitoring of serum potassium levels and ECG examination are recommended if hydrochlorothiazide is used concomitantly with medicinal products whose effects influence changes in serum potassium levels (e.g., digitalis glycosides and antiarrhythmic agents), and with the following medicinal products associated with polymorphic ventricular tachycardia (torsades de pointes) (including certain antiarrhythmic agents), since hypokalemia is a predisposing factor for the development of torsades de pointes:

• Class Ia antiarrhythmic agents (quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic agents (amiodarone, sotalol, dofetilide, ibutilide);
• Certain neuroleptics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Other medicinal products (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vinpocetine).

Methyldopa. Hemolysis is possible.

Cholestyramine or other ion-exchange resins taken orally. Impaired absorption of hydrochlorothiazide. Sulfonamide diuretics should be taken at least 1 hour before or 4–6 hours after administration of these agents.

Curare-like muscle relaxants. Possible potentiation and prolonged duration of action of muscle relaxants.

Calcium salts and medicinal products that increase plasma calcium levels. Increased plasma calcium concentrations may be expected when used concomitantly with hydrochlorothiazide; therefore, plasma calcium levels should be carefully monitored.

Carbamazepine. Risk of hyponatremia due to potentiation of hydrochlorothiazide's effect.

Iodinated contrast agents. In cases of dehydration caused by diuretic use, including hydrochlorothiazide, there is an increased risk of acute renal failure, especially when large doses of iodinated contrast agents are administered.

Penicillin. Excretion of hydrochlorothiazide occurs in the distal tubules of the nephron, thereby reducing penicillin excretion.

Quinine. Hydrochlorothiazide reduces quinine excretion.

mTOR inhibitors (mammalian target of rapamycin) or vildagliptin. Increased incidence of angioedema has been observed in patients concomitantly using ACE inhibitors and mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin. Caution should be exercised at the beginning of such therapy (see section "Special precautions for use").

Heparin. Possible increase in serum potassium concentrations.

Neprilysin inhibitors. Increased risk of angioedema has been reported with concomitant use of ACE inhibitors and neprilysin inhibitors, e.g., racecadotril (see section "Special precautions for use").

Salicylates. When high doses of salicylates are used, hydrochlorothiazide may enhance their toxic effects on the central nervous system.

Cyclosporine. Hyperuricemia may be enhanced and the risk of gout-related complications increased when used concomitantly with cyclosporine.

Alcohol. Ramipril may lead to enhanced vasodilation and thus potentiate the effect of alcohol.

Alcohol, barbiturates, narcotics, or antidepressants. May potentiate orthostatic arterial hypotension.

Salt. Possible reduction of the antihypertensive effect of the medicinal product with increased dietary salt intake.

Beta-blockers and diazoxide. Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycemic effect of diazoxide.

Amantadine. Thiazides, including hydrochlorothiazide, may increase the risk of amantadine side effects.

Pressor amines (e.g., adrenaline). Possible reduction in the effect of pressor amines, although not to the extent that their use is precluded.

Antigout agents (probenecid, sulfinpyrazone, and allopurinol). Dose adjustment of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid levels. Increased dosage of probenecid or sulfinpyrazone may be necessary. Increased frequency of hypersensitivity reactions to allopurinol may occur with concomitant use of thiazides.

Anticholinergic agents (e.g., atropine, biperiden). Due to reduced gastrointestinal motility and delayed gastric emptying, bioavailability of thiazide-type diuretics increases.

Effect of medicinal products on laboratory test results.

Due to effects on calcium metabolism, thiazides may affect the assessment of parathyroid gland function (see section "Special precautions for use").

Specific hyposensitization. Due to ACE inhibition, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom may increase. This effect is also considered possible with other allergens.

The product contains lactose and therefore should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Special precautions for use.

Special patient groups

Pregnancy. Treatment with ACE inhibitors or angiotensin II receptor antagonists should not be initiated during pregnancy. Except in cases where continued treatment with an ACE inhibitor/angiotensin II receptor antagonist is considered absolutely necessary, women planning pregnancy should be switched to another antihypertensive agent known to be safe during pregnancy. As soon as pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be stopped immediately and, if necessary, replaced with another suitable agent (see sections "Contraindications" and "Use in pregnancy or lactation").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalaemia, and deterioration of renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

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

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

Patients at high risk of hypotension.

Patients with increased renin-angiotensin-aldosterone system (RAAS) activity. In patients with increased RAAS activity, there is a risk of sudden, marked reduction in blood pressure and deterioration of renal function due to ACE inhibition. This is particularly relevant when an ACE inhibitor or a concomitant diuretic is initiated or its dose is increased for the first time. Increased RAAS activity requiring medical monitoring, including continuous blood pressure monitoring, may be expected in patients:

• with severe arterial hypertension;
• with decompensated heart failure;
• with haemodynamically significant obstruction of inflow or outflow from the left ventricle (e.g. aortic or mitral valve stenosis);
• with unilateral renal artery stenosis and a functioning contralateral kidney;
• with marked or latent fluid or electrolyte depletion (including patients receiving diuretics);
• with liver cirrhosis and/or ascites;
• undergoing major surgery or receiving anaesthesia with agents that may cause hypotension.

In patients with hepatic impairment, the response to treatment with Ramises® Com may be either enhanced or reduced. Furthermore, in patients with severe cirrhosis associated with oedema and/or ascites, renin-angiotensin system activity may be markedly increased; therefore, particular caution is required when treating these patients.

Prior to initiating therapy, correction of dehydration, hypovolaemia, or electrolyte depletion is generally recommended (however, in patients with heart failure, such corrective measures should be carefully weighed against the risk of volume overload).

Surgery. If possible, treatment with ACE inhibitors such as ramipril should be discontinued one day prior to surgery.

Patients at risk of cardiac or cerebral ischaemia in case of acute hypotension. During the initial phase of treatment, close medical supervision is required.

Primary hyperaldosteronism. The combination ramipril + hydrochlorothiazide is not the treatment of choice for primary hyperaldosteronism. However, if ramipril + hydrochlorothiazide is administered to a patient with primary hyperaldosteronism, plasma potassium levels should be closely monitored.

Elderly patients. See section "Dosage and administration".

Patients with hepatic disorders. In patients with liver disease, electrolyte imbalances caused by diuretics such as hydrochlorothiazide may lead to hepatic encephalopathy. If hepatic encephalopathy occurs, treatment should be discontinued immediately.

Thiazides should be used with caution in patients with hepatic impairment or progressive liver disease, as these agents may induce intrahepatic cholestasis, and even minor disturbances in fluid and electrolyte balance may precipitate hepatic coma. Hydrochlorothiazide is contraindicated in patients with severe hepatic insufficiency (see section "Contraindications").

Monitoring of renal function. Renal function should be monitored before and during treatment, and dosage adjusted accordingly, especially during the first weeks of therapy. Patients with impaired renal function (see section "Dosage and administration") require particularly close monitoring. There is a risk of worsening renal function, particularly in patients with congestive heart failure or after kidney transplantation.

Patients with renal impairment. In patients with kidney disease, thiazides may precipitate sudden onset of uraemia. Cumulative effects of the active substances may occur in patients with impaired renal function. If progression of renal dysfunction becomes evident, as indicated by increasing blood urea nitrogen levels, the decision to continue treatment should be carefully reconsidered. Discontinuation of diuretic therapy should be considered (see section "Contraindications").

Electrolyte imbalance. As with all patients receiving diuretic therapy, plasma electrolyte levels should be measured regularly at appropriate intervals. Thiazides, including hydrochlorothiazide, may cause disturbances in fluid and electrolyte balance (hypokalaemia, hyponatraemia, and hypochloraemic alkalosis).

Although hypokalaemia may occur during treatment with thiazide diuretics, concomitant administration of ramipril may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is highest in patients with liver cirrhosis, those with increased diuresis, those receiving inadequate electrolyte intake, and those receiving concomitant corticosteroids or ACTH (see section "Interaction with other medicinal products and other forms of interaction"). Plasma potassium levels should be determined at the beginning of treatment. If low potassium levels are detected, correction is required.

Dilutional hyponatraemia may occur. Low sodium levels may initially be asymptomatic, making regular monitoring essential. In elderly patients and those with liver cirrhosis, such monitoring should be performed more frequently.

Thiazides have been shown to increase urinary magnesium excretion, potentially leading to hypomagnesaemia.

Hyperkalaemia. Hyperkalaemia has been observed in some patients receiving ACE inhibitors. Patients at risk of hyperkalaemia include those with renal impairment, elderly patients (aged 70 years or older), patients with untreated or poorly controlled diabetes mellitus, those taking potassium supplements, potassium-sparing diuretics, or other agents that increase plasma potassium levels, and those with conditions such as dehydration, acute heart failure, or metabolic acidosis. If concomitant use of these agents is indicated, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Monitoring of electrolytes: hyponatraemia. In isolated patients receiving ramipril, syndrome of inappropriate antidiuretic hormone secretion (SIADH) with subsequent hyponatraemia has been observed. Regular monitoring of serum sodium levels is recommended in elderly patients and in other patients at risk of developing hyponatraemia.

Hepatic encephalopathy. In patients with liver disease, electrolyte imbalances caused by diuretic therapy, including hydrochlorothiazide, may lead to hepatic encephalopathy. In case of hepatic encephalopathy, treatment should be discontinued immediately.

Hypercalcaemia. Hydrochlorothiazide enhances calcium reabsorption in the kidneys, potentially leading to hypercalcaemia. This may interfere with tests assessing parathyroid function.

Angioedema. Angioedema has been reported in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). The risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory distress) may be increased in patients concurrently taking medicinal products capable of inducing angioedema, such as mTOR inhibitors (mammalian target of rapamycin) (e.g. temsirolimus, everolimus, sirolimus), vildagliptin, or neprilysin inhibitors (NEP) (such as racecadotril). Combination therapy with ramipril and sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

If angioedema occurs, treatment with Ramises® Com should be discontinued immediately and emergency therapy initiated. The patient should remain under medical supervision for at least 12–24 hours and may be discharged only after complete resolution of symptoms.

Cases of intestinal angioedema have been reported in patients receiving ACE inhibitors such as Ramises® Com (see section "Adverse reactions"). These patients presented with abdominal pain (with or without nausea/vomiting).

Anaphylactic reactions during desensitisation. The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased during treatment with ACE inhibitors. Prior to desensitisation, temporary discontinuation of Ramises® Com is recommended.

Neutropenia/agranulocytosis. Neutropenia/agranulocytosis has been reported rarely. Bone marrow suppression has also been reported. To detect possible leucopenia, monitoring of white blood cell counts is recommended. More frequent monitoring is advisable at the beginning of treatment and in patients with renal impairment, concomitant collagen disorders (e.g. systemic lupus erythematosus or scleroderma), or those receiving other medicinal products that may affect blood counts (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Ethnic differences. ACE inhibitors cause angioedema more frequently in black patients than in patients of other races. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in black patients than in patients of other races. This may be due to the higher prevalence of low-renin hypertension in black patients with arterial hypertension.

Sportsmen. Hydrochlorothiazide may result in a positive doping test.

Metabolic and endocrine effects. Thiazide therapy may impair glucose tolerance. In some patients with diabetes mellitus, dosage adjustment of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus may become overt during thiazide treatment.

Thiazide diuretic therapy may be associated with increased cholesterol and triglyceride levels. In some patients, thiazide diuretics may precipitate hyperuricaemia or an acute attack of gout.

Cough. Cough has been reported with ACE inhibitors. This cough is typically non-productive and persistent, and resolves after discontinuation of treatment. When performing differential diagnosis of cough, ACE inhibitor-induced cough should be considered.

Acute myopia and secondary acute angle-closure glaucoma. Hydrochlorothiazide is a sulfonamide derivative. Sulfonamides and their derivatives may cause idiosyncratic reactions leading to transient myopia and acute angle-closure glaucoma. Symptoms include acute onset, decreased visual acuity, or eye pain, and usually occur within hours to weeks after starting treatment.

Untreated acute glaucoma may lead to permanent vision loss. The primary treatment step is prompt discontinuation of the drug. Prompt medical or surgical intervention may be required if intraocular pressure remains uncontrolled. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Non-melanoma skin cancer (NMSC). Two epidemiological studies based on data from the Danish National Cancer Registry have shown an increased risk of NMSC [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide. A possible mechanism for NMSC development may be the photosensitising effect of hydrochlorothiazide.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and advised to regularly examine their skin for new lesions and promptly report any suspicious skin changes to their physician. To reduce the risk of skin cancer, patients should be informed about preventive measures, such as limiting exposure to sunlight and ultraviolet radiation and ensuring adequate skin protection when such exposure occurs. Suspicious skin lesions should be promptly evaluated, including biopsy with histological examination. Patients with a history of NMSC may also require reassessment of the continued need for hydrochlorothiazide (see also section "Adverse reactions").

Acute respiratory toxicity. Very rare, severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary oedema typically develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnoea, fever, worsening pulmonary status, and hypotension. If ARDS is suspected, hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who have previously experienced ARDS after taking hydrochlorothiazide.

Other. Hypersensitivity reactions may occur in patients, regardless of history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported.

The drug may affect the results of the following laboratory tests:

• the drug may reduce plasma protein-bound iodine levels;
• treatment should be discontinued before laboratory testing to assess parathyroid function;
• the drug may increase free bilirubin concentration in serum.

Use in pregnancy or lactation.

The medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this product, therapy should be discontinued immediately and replaced with another agent approved for use during pregnancy.

Lactation. Ramises® Com is contraindicated during breastfeeding. The amounts of ramipril and hydrochlorothiazide excreted in breast milk are sufficient to potentially affect a breastfed infant when therapeutic doses of ramipril and hydrochlorothiazide are administered. As adequate data on the use of ramipril during breastfeeding are lacking, it is preferable to use alternative medicinal products known to be safer during lactation, especially when breastfeeding newborns or preterm infants. Hydrochlorothiazide is excreted in breast milk. Thiazide use in breastfeeding women has been associated with reduced or even complete cessation of milk production. Increased sensitivity to sulfonamide derivatives, hypokalaemia, and kernicterus may occur. Since use of both active substances may lead to serious adverse effects in breastfed infants, a decision should be made whether to discontinue breastfeeding or to discontinue therapy, taking into account the importance of the treatment for the woman.

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted. Some adverse effects (e.g. symptoms of low blood pressure such as dizziness) may impair a patient's concentration and reaction speed, posing a risk in situations where these abilities are particularly important (e.g. driving a vehicle or operating machinery). This is especially relevant at the beginning of treatment or when switching to another medicinal product.

Driving or operating machinery should be avoided for several hours after taking the first dose or following any subsequent dose increase.

Method of Administration and Dosage

For oral use.

The medication should be taken once daily at the same time each day, preferably in the morning.

The drug may be taken before, during, or after meals, as food intake does not affect its bioavailability (see section "Pharmacokinetics"). Tablets should be swallowed whole with water. They must not be chewed or crushed.

Adults. The dose should be individually adjusted depending on the severity of arterial hypertension and the presence of other concomitant risk factors. Fixed-dose combination of ramipril and hydrochlorothiazide is generally recommended only after titration of the doses of each individual component.

Treatment should be initiated at the lowest possible dose. If necessary, the dose may be gradually increased until the target blood pressure is achieved. The maximum recommended daily dose is 10 mg of ramipril and 50 mg of hydrochlorothiazide.

Special Patient Groups .

Patients receiving diuretics. Caution is recommended, as patients receiving diuretics may develop arterial hypotension upon initiation of treatment with this drug. Prior to starting therapy, the diuretic dose should be reduced or its administration discontinued.

Patients with renal impairment. Due to the presence of hydrochlorothiazide, the drug is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications"). Lower doses of the drug may be required in patients with impaired renal function. Patients with creatinine clearance of 30–60 mL/min should only be treated with the lowest dose of the fixed combination ramipril/hydrochlorothiazide, following monotherapy with ramipril. The maximum recommended daily dose in such cases is 5 mg ramipril and 25 mg hydrochlorothiazide.

Patients with hepatic impairment. In patients with mild to moderate hepatic impairment, treatment should be initiated only under close medical supervision. The maximum daily dose in these cases is 2.5 mg ramipril and 12.5 mg hydrochlorothiazide. The drug is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Elderly patients. Initial dosage should be lower, and subsequent dose titration should be performed more gradually due to the increased risk of adverse reactions.

Children.

The drug is not recommended for use in children (under 18 years of age), as there is insufficient data on its efficacy and safety in this patient population.

Overdose.

Symptoms of ACE inhibitor overdose include persistent diuresis, excessive peripheral vasodilation (with marked arterial hypotension and shock), bradycardia, electrolyte imbalances, renal failure, cardiac arrhythmias, disturbances of consciousness including coma, epileptic seizures, cerebral convulsions, paresis, and paralytic ileus.

Overdose with hydrochlorothiazide may lead to acute urinary retention in predisposed patients (e.g., patients with prostatic hyperplasia), tachycardia, weakness, dizziness, muscle spasms, polyuria, oliguria, anuria, hypokalemia, hyponatremia, hypochloremia, alkalosis, and increased blood urea nitrogen (mainly due to renal failure).

Careful monitoring of the patient is required.

Treatment is symptomatic and supportive. Therapeutic measures include initial decontamination (gastric lavage, administration of adsorbents) and interventions aimed at restoring stable hemodynamics, including fluid and electrolyte replacement, administration of alpha-1 adrenergic agonists, or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed by hemodialysis. Elimination of thiazide diuretics by dialysis is minimal.

If dialysis or hemofiltration is nevertheless considered, the risk of anaphylactoid reactions associated with the use of high-flux membranes should be taken into account (see section "Special Warnings and Precautions for Use").

Adverse reactions

The safety profile of Ramises® Kom includes data on adverse effects arising from arterial hypotension and/or reduced circulating blood volume due to increased diuresis. The active ingredient ramipril may cause persistent cough, while the active ingredient hydrochlorothiazide may impair glucose, lipid, and uric acid metabolism. Both components exert irreversible effects on plasma potassium levels. Serious adverse reactions include angioneurotic edema or anaphylactoid reactions, hepatic or renal dysfunction, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

The frequency of adverse effects is classified as follows: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1/10000 to <1/1000); very rare (<1/10000); not known (cannot be estimated from available data). Within each category, adverse reactions are listed in order of decreasing severity.

System Organ Classes	Common	Uncommon	Very rare	Not known
Cardiac disorders		Myocardial ischaemia, including angina pectoris; tachycardia; arrhythmia; palpitations; peripheral oedema		Myocardial infarction, orthostatic hypotension
Blood and lymphatic system disorders		Decreased leukocyte count, decreased erythrocyte count, decreased haemoglobin level, haemolytic anaemia, decreased platelet count	Aplastic anaemia	Bone marrow depression; neutropenia, including agranulocytosis, pancytopenia, eosinophilia; haemoconcentration due to fluid retention
Nervous system disorders	Headache, dizziness	Vertigo, paraesthesia, tremor, disturbance in equilibrium, burning sensation, dysgeusia, ageusia		Cerebral ischaemia, including ischaemic stroke and transient ischaemic attack; psychomotor impairment, parosmia
Eye disorders		Visual disturbance, including blurred vision, conjunctivitis		Xanthopsia, decreased lacrimation due to hydrochlorothiazide, secondary acute angle-closure glaucoma and/or acute myopia due to hydrochlorothiazide, choroidal effusion
Ear and labyrinth disorders		Tinnitus		Hearing impairment
Respiratory, thoracic and mediastinal disorders	Non-productive irritating cough, bronchitis	Sinusitis, dyspnoea, nasal congestion	Acute respiratory distress syndrome (ARDS) (see section "Special precautions")	Bronchospasm, including exacerbation of bronchial asthma; allergic alveolitis; respiratory distress, including pneumonitis, non-cardiogenic pulmonary oedema due to hydrochlorothiazide
Gastrointestinal disorders		Inflammatory conditions in the gastrointestinal tract, digestive disorders, abdominal pain, abdominal discomfort, dyspepsia, gastritis, nausea, constipation, gingivitis due to hydrochlorothiazide	Vomiting, aphthous stomatitis, glossitis, diarrhoea, dry mouth, upper abdominal pain, thirst	Pancreatitis (in isolated cases fatal events have been reported with ACE inhibitors), increased levels of pancreatic enzymes, angioneurotic oedema of the small intestine, sialadenitis due to hydrochlorothiazide
Renal and urinary disorders		Renal function impairment, including acute renal failure; increased urine output; elevated blood urea and creatinine levels		Worsening of background proteinuria, interstitial nephritis due to hydrochlorothiazide
Skin and subcutaneous tissue disorders		Angioedema; in very rare cases - airway obstruction due to angioedema which may be fatal; psoriatic dermatitis; hyperhidrosis; rash, particularly maculopapular; pruritus; alopecia		Stevens-Johnson syndrome, toxic epidermal necrolysis, pemphigus, erythema multiforme, exacerbation of psoriasis, exfoliative dermatitis, photosensitivity, onycholysis, pemphigoid or lichenoid exanthema or enanthema, urticaria, systemic lupus erythematosus due to hydrochlorothiazide
Endocrine disorders				Syndrome of inappropriate antidiuretic hormone secretion
Musculoskeletal and connective tissue disorders		Myalgia		Arthralgia, muscle cramps, muscle weakness, musculoskeletal stiffness, tetanic convulsions due to hydrochlorothiazide
Metabolism and nutrition disorders	Decompensation of diabetes mellitus, decreased glucose tolerance, increased blood glucose levels, increased uric acid levels, gout exacerbation, increased cholesterol and/or triglyceride levels due to hydrochlorothiazide	Anorexia, decreased appetite, decreased plasma potassium levels due to hydrochlorothiazide	Increased plasma potassium levels due to ramipril	Decreased plasma sodium levels, glucosuria, metabolic alkalosis, hypochloraemia, hypomagnesaemia, hypercalcaemia, dehydration due to hydrochlorothiazide, hypochloraemic alkalosis which may induce hepatic encephalopathy or hepatic coma due to hydrochlorothiazide
Vascular disorders		Arterial hypotension, orthostatic hypotension, syncope, flushing		Thrombosis due to significant reduction in circulating blood volume, vascular stenosis, hypoperfusion, Raynaud's syndrome, vasculitis, necrotic angiitis
General disorders and administration site conditions	Fatigue, asthenia	Chest pain, pyrexia		Prostration
Immune system disorders				Anaphylactic or anaphylactoid reactions to ramipril or anaphylactic reactions to hydrochlorothiazide, increased levels of antinuclear antibodies
Hepatobiliary disorders		Cholestatic or cytolytic hepatitis (in very rare cases with fatal outcome), increased levels of liver enzymes and/or bilirubin conjugates, cholelithiasis due to hydrochlorothiazide		Acute liver failure, cholestatic jaundice, hepatic cell damage
Reproductive system and breast disorders		Transient erectile impotence		Decreased libido, gynaecomastia
Psychiatric disorders		Depressed mood, apathy, anxiety, restlessness, sleep disturbances, including somnolence		Confusion, attention disturbance
Neoplasms benign, malignant and unspecified (including cysts and polyps)				Non-melanoma skin cancer (NMSC): epidemiological data have shown an association between cumulative dose of hydrochlorothiazide and development of NMSC (see also sections "Pharmacological properties" and "Special precautions")

Reporting of suspected adverse reactions

Reporting adverse reactions after marketing authorization of a medicinal product is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 10 tablets in a blister. 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's name and address of the place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.