INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RAMI SANDOZÒ COMPOSITUM (RamiSANDOZÒcompositum)

Composition:

Active substances: ramipril, hydrochlorothiazide;

One tablet contains 5 mg of ramipril and 25 mg of hydrochlorothiazide;

Excipients: sodium hydrocarbonate, hypromellose, microcrystalline cellulose, pregelatinized starch, sodium stearyl fumarate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white, elongated, flat tablets with beveled edges and a score line on both sides. Embossing on one side: «R 30».

The score line on the tablet is intended to facilitate splitting the tablet into two parts to ease swallowing, but not for dividing the tablet into two equal doses.

Pharmacotherapeutic group.

Combined preparations of angiotensin-converting enzyme (ACE) inhibitors. Single-component ACE inhibitors. Ramipril. ATC code C09B A05.

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 ACE 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 typically characterized by low renin activity), the response to monotherapy with ACE inhibitors has generally been less pronounced than in patients of other racial groups.

Hydrochlorothiazide. Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive action of thiazide diuretics has not yet been fully elucidated. They 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, whereas excretion of uric acid is reduced. Possible mechanisms of the antihypertensive effect of hydrochlorothiazide include changes in sodium balance, reduction in extracellular fluid volume and plasma volume, alteration 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. Usually, no substantial changes in renal plasma flow or glomerular filtration rate occur. In patients with arterial hypertension, ramipril 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. The maximum effect after a single oral dose usually occurs within 3–6 hours. The antihypertensive effect after a single dose generally persists for 24 hours.

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

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

Hydrochlorothiazide. The onset of the diuretic effect of hydrochlorothiazide occurs approximately 2 hours after administration and lasts for 6–12 hours, with maximum effect achieved within 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 use of ramipril and hydrochlorothiazide. Clinical studies have shown that the use of this combination leads to a greater reduction in blood pressure than the use of either active ingredient alone. Concomitant administration of ramipril and hydrochlorothiazide reduces potassium loss associated with the diuretic effect, likely due to inhibition of the renin-angiotensin-aldosterone system (RAAS). The combination of an ACE inhibitor with a thiazide diuretic demonstrates a synergistic effect and also reduces the risk of hypokalemia induced by the diuretic alone.

Pharmacokinetics.

Ramipril

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration of ramipril is reached within 1 hour. Based on the amount of substance detected in urine, 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 a 2.5 mg or 5 mg dose of ramipril 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 of ramipril is approximately 73%, and of ramiprilat approximately 56%.

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

Excretion. Metabolite excretion occurs predominantly via renal excretion. The decline in ramiprilat plasma concentration is multiphasic. Due to strong saturable binding to ACE and slow dissociation from the enzyme complex, 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 enzyme's binding capacity for ramiprilat being saturable. After oral administration of a single 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. 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. In patients with impaired liver function, conversion of ramipril to ramiprilat is slower due to reduced activity of hepatic esterases. In such patients, increased plasma levels of ramipril are observed. However, the maximum plasma concentration of ramiprilat in these patients does not differ from that in individuals with normal liver function.

Hydrochlorothiazide

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

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

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

Excretion. 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. 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. In patients with liver cirrhosis, the pharmacokinetics of hydrochlorothiazide are not significantly altered.

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 combined product can be considered bioequivalent to products containing the individual active substances.

Non-melanoma skin cancer (NMSC)

Available epidemiological data suggest a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of NMSC. One study included 71,533 cases of basal cell carcinoma and 8,629 cases of squamous cell carcinoma, corresponding to 1,430,833 and 172,462 individuals in the control groups, respectively. High-dose hydrochlorothiazide (≥50,000 mg cumulative) was associated with an adjusted odds ratio (OR) of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A cumulative dose-response relationship was observed for both basal cell carcinoma and squamous cell carcinoma. Another study showed a possible association between lip cancer and hydrochlorothiazide use: 633 cases of lip cancer were matched with 63,067 population-based controls using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) for high dose (~25,000 mg) and OR 7.7 (5.7–10.5) for the highest dose (~100,000 mg). For example, a cumulative dose of 100,000 mg corresponds to daily administration of the defined daily dose of 25 mg over a period of more than 10 years.

Clinical characteristics.

Indications.

Treatment of arterial hypertension. This fixed-dose combination is indicated for patients whose blood pressure is not adequately controlled on monotherapy with ramipril or hydrochlorothiazide.

Contraindications.

Hypersensitivity to ramipril or other ACE inhibitors, hydrochlorothiazide, other thiazide diuretics, sulfonamides, or any of the excipients of the medicinal product.

History of angioedema (hereditary, idiopathic, or previously experienced during therapy with ACE inhibitors or angiotensin II receptor antagonists). Patients with arterial hypotension or hemodynamically unstable conditions.

Extracorporeal therapy methods involving contact of blood with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction").

Severe bilateral renal artery stenosis or unilateral renal artery stenock with a single functioning kidney.

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

Clinically significant electrolyte imbalances that may worsen during treatment with the medicinal product (see section "Special precautions for use"). Refractory hypokalemia or hypercalcemia. Refractory hyponatremia.

Symptomatic hyperuricemia (gout).

Severe hepatic impairment, hepatic encephalopathy.

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

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

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

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

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations

Extracorporeal therapy methods involving contact of blood 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 — due to 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.

Concomitant use with aliskiren-containing medicinal products is contraindicated in patients with diabetes or in patients with moderate to severe renal impairment (creatinine clearance <60 mL/min) and is not recommended for all other patients.

Concomitant use with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended for all other patients.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use"). Ramipril therapy should be initiated only 36 hours after the last dose of sacubitril/valsartan. Sacubitril/valsartan therapy should be initiated only 36 hours after the last dose of ramipril.

Combinations requiring special caution

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

Antihypertensive medicinal products (e.g., diuretics), other medicinal products that may lower blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin), and alcohol. Increased risk of arterial hypotension is possible.

Vasopressor sympathomimetics and other medicinal products (e.g., epinephrine) that may reduce the antihypertensive effect of ramipril. Regular monitoring of blood pressure is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other medicinal products 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 monitored regularly. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity. Therefore, concomitant use of ramipril/hydrochlorothiazide and lithium is not recommended.

Antidiabetic medicinal products, including insulin. Hypoglycemic reactions may occur. Hydrochlorothiazide may reduce the effect of antidiabetic medicinal products. Therefore, glucose levels should be closely monitored at the beginning of concomitant therapy. Metformin should be used with caution due to the risk of lactic acidosis associated with possible functional renal impairment caused by hydrochlorothiazide.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. A reduced antihypertensive effect of the medicinal product is expected. Also, concomitant use of ACE inhibitors and NSAIDs may be associated with an increased risk of renal impairment and elevated blood potassium levels.

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

Corticosteroids, adrenocorticotropic hormone (ACTH), amphotericin B, carbenoxolone, excessive licorice consumption, laxatives (with prolonged use), and other potassium-depleting medicinal products or active substances that reduce plasma potassium levels. Increased risk of hypokalemia.

Cardiac glycosides, active substances that may prolong the QT interval, antiarrhythmic agents. Proarrhythmic effects may be enhanced and antiarrhythmic effects diminished in the presence of electrolyte imbalances (e.g., hypokalemia, hypomagnesemia).

Medicinal products whose effects are influenced by changes in serum potassium levels.

Periodic monitoring of serum potassium levels and ECG examination are recommended if hydrochlorothiazide is used concomitantly with medicinal products whose effects are influenced by changes in serum potassium levels (e.g., cardiac glycosides and antiarrhythmic agents), and the following medicinal products that may cause polymorphic ventricular tachycardia of the torsade de pointes type (including certain antiarrhythmic agents), since hypokalemia is a contributing factor for torsade de pointes tachycardia:

Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
Class III antiarrhythmic agents (e.g., 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 vinca alkaloids).

Methyldopa. Isolated cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.

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 concentration may be expected when used concomitantly with hydrochlorothiazide; therefore, plasma calcium levels should be closely monitored.

Carbamazepine. Risk of hyponatremia due to enhanced effect of hydrochlorothiazide.

Contrast agents containing iodine. In cases of dehydration caused by diuretics, including hydrochlorothiazide, there is an increased risk of acute renal failure, especially when large doses of iodine-containing contrast agents are administered.

Penicillin. Hydrochlorothiazide is excreted in the distal tubules of the nephron, thereby reducing penicillin excretion.

Quinine. Hydrochlorothiazide reduces quinine excretion.

Vildagliptin. Increased incidence of angioedema has been observed in patients concurrently taking ACE inhibitors and vildagliptin.

mTOR inhibitors (e.g., temsirolimus). Increased incidence of angioedema has been observed in patients concurrently taking ACE inhibitors and mTOR inhibitors (mammalian target of rapamycin).

Heparin. Possible increase in serum potassium concentrations.

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 risk of complications such as gout increased when used concomitantly with cyclosporine.

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

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

Salt. Possible reduction of 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 adverse effects caused by amantadine.

Pressor amines (e.g., adrenaline). Possible reduction of pressor amine effects, but not to the extent that their use must be discontinued.

Antigout agents (probenecid, sulfinpyrazone, and 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. 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.

Cytoxic agents (e.g., cyclophosphamide, methotrexate). Thiazides may reduce renal excretion of cytotoxic agents and potentiate their myelosuppressive effect.

Effect of medicinal products on laboratory test results. Due to effects on calcium metabolism, thiazides may influence 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 are increased. This effect is also considered possible with other allergens.

Neprilysin inhibitors. Increased risk of angioedema has been reported with concomitant use of ACE inhibitors and neprilysin inhibitors, e.g., racecadotril.

Special precautions for use.

Patients at high risk of developing arterial hypotension

Patients with increased activity of the RAAS. In patients with increased RAAS activity, there is a risk of sudden, significant reduction in arterial pressure and impaired renal function due to ACE inhibition. This is particularly relevant when an ACE inhibitor or concomitant diuretic is initiated or its dose is increased for the first time. A significant increase in RAAS activity, requiring medical supervision including continuous monitoring of arterial pressure, may be expected, for example, in patients:

with severe arterial hypertension;
with decompensated congestive heart failure;
with hemodynamically significant obstruction of inflow or outflow pathways of blood 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 anesthesia with agents that may cause arterial hypotension.

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

In patients with hepatic impairment, the response to treatment with the medicinal product may be either enhanced or diminished. Furthermore, in patients with severe liver cirrhosis associated with edema and/or ascites, renin-angiotensin system activity may be markedly increased; therefore, special caution is required when treating these patients.

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 ischemia in case of acute arterial hypotension. At the beginning of treatment, close medical supervision is required.

Primary hyperaldosteronism. The combination ramipril + hydrochlorothiazide is not the treatment of choice for primary hyperaldosteronism. However, if used in patients with primary hyperaldosteronism, plasma potassium levels must be closely monitored.

Elderly patients. See section "Dosage and administration".

Patients with hepatic disorders. In patients with liver disease, disturbances in electrolyte balance caused by diuretics such as hydrochlorothiazide may lead to the development of hepatic encephalopathy.

Thiazides should be used with caution in patients with hepatic disorders or progressive liver disease, as these agents may induce intrahepatic cholestasis, and even minor changes in fluid and electrolyte balance may precipitate hepatic coma. Hydrothiazide 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 careful monitoring. There is a risk of impaired renal function, especially in patients with congestive heart failure or after kidney transplantation.

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

Electrolyte imbalance. During diuretic therapy, plasma electrolyte levels should be measured regularly at appropriate intervals. Thiazides, including hydrochlorothiazide, may cause disturbances in fluid and electrolyte balance (hypovolemia, hypokalemia, hypomagnesemia, hyponatremia, hypochloremic alkalosis).

It is important to promptly recognize clinical signs of fluid and electrolyte imbalance, which may develop during episodes of diarrhea or vomiting. In such patients, periodic monitoring of serum electrolyte levels is necessary.

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

In hot weather, hyponatremia may occur in patients with edema due to hemodilution (dilutional hyponatremia). Low sodium levels may initially be asymptomatic, so regular monitoring is essential. In elderly patients and patients with liver cirrhosis, such monitoring should be performed more frequently.

In some patients receiving ramipril, syndrome of inappropriate antidiuretic hormone secretion (SIADH) with subsequent hyponatremia has been observed; therefore, regular monitoring of serum sodium levels is recommended in elderly patients and other patients at risk of hyponatremia.

Thiazides increase urinary magnesium excretion, which may lead to hypomagnesemia.

Hyperkalemia. Hyperkalemia has been observed in some patients receiving ACE inhibitors. Risk groups include patients with renal impairment, elderly patients (aged 70 years and older), patients with untreated or poorly controlled diabetes mellitus, those taking potassium salts, potassium-sparing diuretics, or other active substances that increase plasma potassium levels, as well as patients with conditions such as dehydration, acute heart failure, or metabolic acidosis. If concomitant use of the above-mentioned agents is indicated, regular monitoring of plasma potassium levels is recommended.

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"). Ramipril therapy should be initiated only 36 hours after the last dose of sacubitril/valsartan. Sacubitril/valsartan therapy should be initiated only 36 hours after the last dose of ramipril.

The risk of angioedema may be increased in patients receiving concomitant medications such as mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, everolimus, sirolimus), vildagliptin, or racecadotril (symptoms may include, for example, swelling of the airways or tongue with or without respiratory distress – see section "Adverse reactions"). Therefore, caution should be exercised when administering mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus), vildagliptin, or racecadotril to patients already receiving ACE inhibitors.

Hepatic encephalopathy. In patients with liver disease, disturbances in electrolyte balance caused by diuretic therapy, including hydrochlorothiazide, may lead to the development of hepatic encephalopathy. If hepatic encephalopathy occurs, treatment should be discontinued immediately.

Hypercalcemia. Hydrochlorothiazide enhances calcium reabsorption in the kidneys, potentially leading to hypercalcemia. This may interfere with test results when assessing parathyroid gland function.

Angioedema. Angioedema has been reported in patients receiving ACE inhibitors such as ramipril. In the event of angioedema, treatment with the medicinal product 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.

Angioedema of the intestine has been reported in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). These patients presented with abdominal pain (with or without nausea/vomiting).

Anaphylactic reactions during desensitization. The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased during ACE inhibitor therapy. The medicinal product should be temporarily discontinued prior to desensitization.

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis have been reported rarely. Bone marrow suppression has also been reported. To detect possible leukopenia, monitoring of white blood cell count is recommended. More frequent monitoring is advisable at the beginning of treatment and in patients with renal impairment, concomitant collagenosis (e.g., systemic lupus erythematosus or scleroderma), or those receiving concomitant medications that may affect blood parameters.

Ethnic differences. ACE inhibitors cause angioedema more frequently in patients of Black race than in other racial groups. The antihypertensive effect of ramipril may be less pronounced in patients of Black race compared to other racial groups. This may be due to the higher prevalence of low-renin hypertension in Black patients with arterial hypertension.

Athletes. Hydrochlorothiazide may lead to a positive result in doping tests.

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

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

Cough. Cough has been reported with ACE inhibitor use. This cough is usually non-productive, persistent, and resolves after discontinuation of treatment. When differentially diagnosing cough, the possibility of ACE inhibitor-induced cough should be considered.

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

Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to 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 after starting the medicinal product. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, medical, or surgical intervention may be necessary. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Dual blockade of the RAAS. Dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended, as it is associated with an increased risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Combined use of the medicinal product and aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (creatinine clearance <60 mL/min). Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy (see section "Contraindications").

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

The medicinal product may affect the results of the following laboratory tests:

the medicinal product may reduce plasma protein-bound iodine levels;
treatment with the medicinal product should be discontinued prior to laboratory testing to assess parathyroid gland function;
the medicinal product may increase free bilirubin concentration in serum.

This medicinal product contains sodium. Caution is advised when prescribing to patients on a sodium-restricted diet.

Non-melanoma skin cancer (NMSC)

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

Patients taking hydrochlorothiazide should be informed about the risk of NMSC. Regular skin examination for new lesions is recommended, and any suspicious skin changes should be reported immediately. Preventive measures to minimize the risk of skin cancer, such as limiting exposure to sunlight and ultraviolet radiation, are recommended; adequate sun protection is advised when exposed to sunlight. Suspicious skin lesions should be promptly evaluated, potentially including histological examination of biopsies. The use of hydrochlorothiazide should also be reconsidered in patients who have previously experienced NMSC.

Acute respiratory toxicity

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

Use during pregnancy or breastfeeding.

Pregnancy. The medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy occurs during therapy, treatment with the medicinal product should be discontinued immediately and, if necessary, alternative therapy initiated.

It is known that treatment with ACE inhibitors/angiotensin receptor antagonists during the second and third trimesters of pregnancy has fetotoxic effects (impaired renal function, oligohydramnios, delayed skull ossification) and may provoke neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

Prolonged use of hydrochlorothiazide during the third trimester of pregnancy may lead to fetoplacental ischemia and carries a risk of growth retardation. Additionally, isolated cases of hypoglycemia and thrombocytopenia have been observed in neonates exposed to the medicinal product shortly before birth. Hydrochlorothiazide may reduce plasma volume and uteroplacental circulation.

Breastfeeding. The medicinal product is contraindicated during breastfeeding. It is preferable to use other medicinal products that are safer during lactation, especially when breastfeeding newborns or premature infants.

Ability to affect reaction speed when driving or operating machinery.

Some adverse effects (e.g., dizziness) may impair a patient's ability to concentrate and reaction speed, posing a risk when driving vehicles or operating machinery. This is particularly relevant at the beginning of treatment or when switching to other medicinal products. Driving vehicles or operating machinery is not recommended for several hours after taking the first dose or after any subsequent dose increase.

Method of Administration and Dosage.

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

The medication may be taken before, during, or after meals, as food intake does not affect its bioavailability. Tablets should be swallowed whole with water. They must not be chewed or crushed. To facilitate swallowing, the tablet may be divided into two parts. However, the tablet does not split into two equal doses.

Adults. The dose should be individually adjusted depending on patient characteristics and blood pressure levels. Fixed-dose combination of ramipril and hydrochlorothiazide is generally recommended only after dose titration 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 daily dose is 10 mg of ramipril and 25 mg of hydrochlorothiazide (to achieve the required dosage, a combination of medications with appropriate strengths should be used).

Special Patient Groups.

Patients receiving diuretics. Caution is recommended, as patients receiving diuretics may experience arterial hypotension at the beginning of treatment with this medication. The dose of diuretic should be reduced or its administration discontinued before initiating treatment.

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

Patients with hepatic impairment. Treatment should be initiated only under close medical supervision in patients with mild to moderate hepatic impairment. The maximum daily dose in such cases is 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide. The medication is contraindicated in cases of severe hepatic impairment.

Elderly patients. The initial dose should be lower, especially in very elderly and frail patients, and subsequent dose titration should be performed more gradually due to the increased risk of adverse reactions.

Children.

Not recommended.

Overdose.

Symptoms of overdose are primarily due to significant fluid and electrolyte loss. Symptoms of ACE inhibitors overdose include excessive peripheral vasodilation (with marked arterial hypotension, shock), electrolyte imbalances (hypokalemia, hyponatremia, hypochloremia), cardiac arrhythmias (bradycardia, tachycardia), renal failure, weakness, dizziness, muscle cramps, paresthesia, fatigue, nausea, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, elevated blood urea nitrogen levels (primarily due to renal failure), disturbances of consciousness including coma, epileptic seizures, paresis, and paralytic ileus.

Overdose of hydrochlorothiazide may lead to acute urinary retention in predisposed patients (e.g., those with prostate hyperplasia).

Close monitoring of the patient is required.

Treatment is symptomatic and supportive. Therapeutic measures include initial detoxification (gastric lavage, administration of adsorbents), as well as interventions aimed at restoring stable hemodynamics, including restoration of fluid and electrolyte volume (potassium, sodium, magnesium), and administration of alpha-1 adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed by hemodialysis.

In cases of arterial hypotension and shock, administration of fluids and electrolytes (potassium, sodium, magnesium) is recommended. Until the patient's condition normalizes, monitoring of fluid and electrolyte balance and renal function is required.

Adverse reactions.

The safety profile of the ramipril + hydrochlorothiazide medicinal product includes data on adverse effects resulting from arterial hypotension and/or reduction in circulating blood volume (CBV) due to increased diuresis. The active substance ramipril may cause a persistent cough, while the active substance hydrochlorothiazide may affect glucose, lipid, and uric acid metabolism. Both substances have an irreversible effect on plasma potassium levels. Serious adverse reactions include angioedema 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, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

Cardiac disorders: uncommon – myocardial ischemia, including angina pectoris; tachycardia, arrhythmia, palpitations, peripheral edema; frequency not known – myocardial infarction.

Vascular disorders: uncommon – arterial hypotension, orthostatic hypotension, syncope, flushing; frequency not known – thrombosis due to marked reduction in CBV, vascular stenosis, hypoperfusion, Raynaud's syndrome, vasculitis, necrotizing angiitis.

Blood and lymphatic system disorders: uncommon – decreased leukocyte and erythrocyte counts, reduced hemoglobin levels, hemolytic anemia, thrombocytopenia; very rare – aplastic anemia; frequency not known – bone marrow suppression, neutropenia including agranulocytosis; pancytopenia, eosinophilia, hemoconcentration in case of fluid retention.

Nervous system disorders: common – headache, dizziness; uncommon – vertigo, paresthesia, tremor, loss of balance, burning sensation, dysgeusia, ageusia; frequency not known – cerebral ischemia, including ischemic stroke and transient ischemic attack; psychomotor impairment, parosmia, seizures, confusion.

Eye disorders: uncommon – visual disturbances, including blurred vision, conjunctivitis; frequency not known – xanthopsia, decreased lacrimation, closed-angle glaucoma due to hydrochlorothiazide; frequency not known – choroidal effusion.

Ear and labyrinth disorders: uncommon – tinnitus; frequency not known – hearing disturbances.

Respiratory, thoracic and mediastinal disorders: common – non-productive irritating cough, bronchitis; uncommon – sinusitis, dyspnea, nasal congestion; frequency not known – bronchospasm, including exacerbation of bronchial asthma; allergic alveolitis; respiratory distress, including pneumonitis; non-cardiogenic pulmonary edema due to hydrochlorothiazide; very rare: acute respiratory distress syndrome (ARDS).

Gastrointestinal disorders: uncommon – gastrointestinal inflammatory symptoms, digestive disturbances, abdominal discomfort, dyspepsia, gastritis, nausea, constipation, gingivitis due to hydrochlorothiazide; very rare – vomiting, aphthous stomatitis, glossitis, diarrhea, upper abdominal pain, dry mouth, thirst; frequency not known – pancreatitis (in isolated cases fatal outcomes have been reported with ACE inhibitors), increased pancreatic enzyme levels, angioedema of the small intestine, sialadenitis due to hydrochlorothiazide.

Renal and urinary disorders: uncommon – renal dysfunction, including acute renal failure; increased urine output, elevated plasma urea and creatinine levels; frequency not known – worsening of background proteinuria, interstitial nephritis due to hydrochlorothiazide, hyperuricemia which may trigger gout attacks in patients with asymptomatic disease.

Skin and subcutaneous tissue disorders: uncommon – angioedema (in very rare cases airway obstruction due to angioedema, which may be fatal); psoriatic dermatitis, hyperhidrosis, rash (including maculopapular), pruritus, alopecia; frequency not known – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, exfoliative dermatitis, photosensitivity, onycholysis, pemphigoid or lichenoid exanthema or enanthema, urticaria, systemic lupus erythematosus due to hydrochlorothiazide.

Musculoskeletal and connective tissue disorders: uncommon – myalgia; frequency not known – arthralgia, muscle cramps, muscle weakness, musculoskeletal stiffness, tetany-like cramps due to hydrochlorothiazide.

Endocrine disorders: frequency not known – syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders: common – decompensation of diabetes mellitus, reduced glucose tolerance, elevated blood glucose, elevated uric acid levels, gout exacerbation, increased cholesterol and/or triglyceride levels due to hydrochlorothiazide; uncommon – anorexia, decreased appetite, decreased plasma potassium levels due to hydrochlorothiazide; very rare – increased plasma potassium levels due to ramipril; frequency not known – decreased plasma sodium levels, glucosuria, metabolic alkalosis, hypochloremia, hypomagnesemia, hypercalcemia, dehydration, hypochloremic alkalosis which may induce hepatic encephalopathy or hepatic coma due to hydrochlorothiazide.

General disorders: common – increased fatigue, asthenia; uncommon – chest pain, pyrexia; frequency not known – exhaustion.

Immune system disorders: frequency not known – anaphylactic or anaphylactoid reactions to ramipril or anaphylactic reactions to hydrochlorothiazide, increased antinuclear antibody levels, anaphylactic shock, purpura.

Hepatobiliary disorders: uncommon – cholestatic or cytolytic hepatitis (in very rare cases with fatal outcome), elevated liver enzymes and/or bilirubin conjugates, cholelithiasis due to hydrochlorothiazide; frequency not known – acute liver failure, cholestatic jaundice, hepatocellular injury.

Reproductive system disorders: uncommon – transient erectile impotence; frequency not known – decreased libido, gynecomastia, sexual dysfunction.

Psychiatric disorders: uncommon – depression and mood changes, apathy, anxiety, restlessness, sleep disturbances including somnolence; frequency not known – confusion, attention disturbances, agitation.

Benign and malignant neoplasms, including cysts and polyps:

frequency not known: NMSC (basal cell carcinoma and squamous cell carcinoma).

Reporting of suspected adverse reactions after medicinal product authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance System at: https://aisf.dec.gov.ua/.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 3 blisters (10 × 3) in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

LEK S.A., Poland.

Manufacturer's location and address of place of business.

95-010 Strzegom, Podlipie Street 16, Poland (unpacked product manufacturing, batch release authorization).

Domaniewska Street 50C, Warsaw, 02-672, Poland (primary and secondary packaging, batch release authorization).