Ramimed combo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RAMIMED® COMBI (RAMIMEDCOMBI)

Composition:

Active substances: 1 tablet contains 2.5 mg ramipril / 12.5 mg hydrochlorothiazide or 5 mg ramipril / 25 mg hydrochlorothiazide;

Excipients: pregelatinized starch; sodium stearyl fumarate; sodium hydrogencarbonate; lactose monohydrate; sodium croscarmellose.

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets 2.5 mg / 12.5 mg – white or almost white, capsule-shaped, uncoated, flat tablets with beveled edges, with a score line on one side, approximately 4.0 × 8.0 mm in size. Marked "12.5".

tablets 5 mg / 25 mg – white or almost white, capsule-shaped, uncoated, flat tablets with beveled edges, with a score line on one side and on the lateral surfaces, approximately 5.0 × 10.0 mm in size. Marked "25".

Pharmacotherapeutic group. Combined angiotensin-converting enzyme (ACE) inhibitors. Ramipril and diuretics. ATC code C09BA05.

Pharmacological Properties.

Mechanism of Action.

Ramipril. Ramiprilat, the active metabolite of the prodrug ramipril, is an inhibitor of angiotensin-converting enzyme (ACE), also known as dipeptidyl carboxypeptidase I or kininase II. In plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, and the degradation of bradykinin, a potent vasodilator. By reducing the formation of angiotensin II and inhibiting the breakdown of bradykinin, ramiprilat leads to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat reduces 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 exact mechanism of its antihypertensive action has not yet been fully elucidated. Thiazide diuretics inhibit the reabsorption of sodium and chloride ions in the distal renal tubules. Enhanced renal excretion of these ions is accompanied by increased urine output (due to osmotic water retention). Excretion of potassium and magnesium is also increased, whereas excretion of uric acid is reduced. Possible mechanisms of hydrochlorothiazide’s hypotensive effect include changes in sodium balance, reduction in extracellular fluid and plasma volume, alterations 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 significant changes in renal plasma flow or glomerular filtration rate (GFR) occur. In patients with arterial hypertension, ramipril reduces blood pressure in both supine and upright positions, without compensatory increases 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 is typically achieved within 3–6 hours. The antihypertensive effect after a single dose persists for 24 hours.

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

Abrupt discontinuation of ramipril does not cause a rapid or excessive increase in 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 peak effect occurring at about 4 hours. The antihypertensive effect is achieved within 3–4 days of treatment and may persist for up to 1 week after discontinuation.

The antihypertensive effect is accompanied by a slight increase in GFR, renal vascular resistance, and plasma renin activity.
Non-melanoma skin cancer. Based on available epidemiological data, there is an association between the development of non-melanoma skin cancer and the use of high cumulative doses of hydrochlorothiazide. One study included 71,533 cases of basal cell carcinoma and 8,629 cases of squamous cell carcinoma among 1,430,833 and 172,462 individuals, respectively. The use of high-dose hydrochlorothiazide (≥50,000 mg cumulative) was associated with an adjusted 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 clear dose-response relationship was observed for both basal cell and squamous cell carcinoma. Another study indicated a possible association between lip cancer and hydrochlorothiazide exposure: 633 cases of lip cancer were compared 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 use (~25 mg) and OR 7.7 (5.7–10.5) for the highest cumulative dose (~100 mg) (see section "Special Warnings and Precautions for Use").

Concomitant use of ramipril and hydrochlorothiazide. Administration of this combination results in a greater reduction in blood pressure than either active component 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 (RAAS). Combining an ACE inhibitor with a thiazide diuretic produces 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. Peak plasma concentration of ramipril is reached within 1 hour. Based on the amount of substance recovered 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 2.5 mg and 5 mg doses is 45%.

Peak plasma concentration of ramiprilat, the sole active metabolite of ramipril, is achieved 2–4 hours after ramipril administration. After administration of usual daily doses of ramipril once daily, steady-state plasma concentrations of ramiprilat are reached 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 the diketopiperazine ester, diketopiperazine acid, and glucuronides of ramipril and ramiprilat.

Elimination. 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 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 renal impairment (see section "Dosage and Administration"). In patients with impaired renal function, renal excretion of ramiprilat is reduced, and the renal clearance of ramiprilat is proportional to creatinine clearance. This results in higher plasma concentrations of ramiprilat, which decline more slowly than in individuals with normal renal function.

Patients with hepatic impairment (see section "Dosage and Administration"). In patients with impaired liver function, conversion of ramipril to ramiprilat is slower due to reduced activity of hepatic esterases. In these 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 liver function.

Hydrochlorothiazide.

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

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

Metabolism. Hydrochlorothiazide undergoes minimal metabolism in the liver.

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 renal impairment (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 increased plasma concentrations of hydrochlorothiazide, which decline more slowly than in individuals with healthy kidneys.

Patients with hepatic impairment (see section "Dosage and Administration"). 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 fixed-dose combination can be considered bioequivalent to formulations containing the individual active substances.

Clinical characteristics.

Indications.

Treatment of arterial hypertension. The use of this fixed combination is indicated in patients whose blood pressure is not adequately controlled with monotherapy with ramipril or hydrochlorothiazide.

Contraindications.

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

Ramipril should not be used in patients with arterial hypotension or hemodynamically unstable conditions.

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

Anuria, treatment-resistant hypokalemia or hypercalcemia, refractory hyponatremia, symptomatic hyperuricemia (gout).

Use of extracorporeal therapies involving blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction").

Significant 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").

Severe hepatic impairment, hepatic encephalopathy.

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

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

Concomitant use of RAMIMED® COMBI with medicinal products containing aliskiren in patients with diabetes mellitus or renal dysfunction (eGFR < 60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

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

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 events such as arterial hypotension, hyperkalemia, and worsening of renal function (including development of acute renal failure), compared to use of a single agent affecting the RAAS (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Food. Concomitant food intake does not significantly affect ramipril absorption.

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"). Ramipril therapy 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 RAMIMED® COMBI.

Extracorporeal therapies involving 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—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 an alternative class of antihypertensive agents.

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

Combinations requiring special caution.

Potassium salts, heparin, potassium-sparing diuretics, and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim and its fixed combinations with sulfamethoxazole, tacrolimus, cyclosporine). Hyperkalemia may occur; therefore, plasma potassium levels should be closely 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 is possible (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, cytostatics, and other substances that may alter 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 further increase the risk of lithium toxicity caused by ACE inhibitors; therefore, concomitant use of ramipril/hydrochlorothiazide and lithium is not recommended.

Antidiabetic agents (oral hypoglycemic agents and insulin). Hypoglycemic reactions may occur. Hydrochlorothiazide may reduce the effectiveness of antidiabetic agents. Therefore, blood glucose levels should be closely monitored when initiating concomitant therapy.

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. A reduced antihypertensive effect of RAMIMED® COMBI is expected. Concomitant use of ACE inhibitors and NSAIDs may also be associated with an increased risk of renal function impairment and elevated blood potassium levels.

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

Corticosteroids, adrenocorticotropic hormone, amphotericin B, carbenoxolone, licorice in large quantities, laxatives (with prolonged use), and other potassium-wasting 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. In the presence of electrolyte imbalances (e.g., hypokalemia, hypomagnesemia), proarrhythmic effects may be enhanced and antiarrhythmic effects weakened.

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

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (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 for oral use. 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 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.

Vildagliptin. Increased incidence of angioedema has been observed in patients concomitantly receiving ACE inhibitors and vildagliptin.

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

Heparin. Possible increase in serum potassium concentrations.

mTOR inhibitors or DPP-4 inhibitors. Increased risk of angioedema is possible in patients concomitantly receiving mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or DPP-4 inhibitors (vildagliptin, and possibly saxagliptin or linagliptin). Caution should be exercised when initiating such therapy (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. Concomitant use of cyclosporine may enhance hyperuricemia and increase the risk of complications such as gout.

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

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

Salt. The antihypertensive effect of the medicinal product may be weakened by 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). The effect of pressor amines may be reduced, but not to the extent that their use is precluded.

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

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

Effect of medicinal products on laboratory test results. Due to effects on calcium metabolism, thiazides may influence the assessment of parathyroid gland function (see section "Special precautions for use").

Patients require rehydration prior to administration of iodine-containing agents.

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.

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 absolutely necessary, women planning pregnancy should be switched to another antihypertensive agent considered safe during pregnancy. As soon as pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be stopped immediately and, if necessary, treatment with another agent should be initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Double blockade of the RAAS. Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and impaired 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 "Pharmacological properties" and "Interaction with other medicinal products and other forms of interaction").

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

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

Patients at high risk of hypotension.

Patients with increased RAAS activity. Patients with increased RAAS activity are at risk of sudden and significant drop in blood pressure and impaired renal function due to ACE inhibition. This is particularly relevant when an ACE inhibitor or a concomitant diuretic is used for the first time or when the dose is increased for the first time. Increased RAAS activity, requiring medical supervision including continuous blood pressure monitoring, may be expected in patients:

• with severe arterial hypertension;
• with decompensated congestive heart failure;
• with hemodynamically 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 extensive surgery or receiving anesthesia with agents that may cause hypotension.

Prior to initiating therapy, correction of dehydration, hypovolemia, 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).

In patients with hepatic impairment, the response to treatment with RAMIMED® COMBI may be either enhanced or reduced. Additionally, in patients with severe cirrhosis associated with edema and/or ascites, RAAS activity may be markedly increased; therefore, particular caution is required during treatment of 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 hypotension. During the initial phase of treatment, close medical supervision is required.

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

Elderly patients. See section "Posology and method of administration".

Patients with hepatic disorders. In patients with hepatic disorders, electrolyte imbalances caused by diuretics such as hydrochlorothiazide may lead to hepatic encephalopathy.

In patients with hepatic impairment, the response to treatment may be either enhanced or reduced. Additionally, in patients with severe cirrhosis associated with edema and/or ascites, RAAS activity may be markedly increased; therefore, particular caution is required during treatment of these patients.

Thiazides should be used with caution in patients with liver disorders or progressive liver disease, as these agents may cause intrahepatic cholestasis, and even minimal changes 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 "Posology and method of administration") require particularly close monitoring. There is a risk of impaired renal function, particularly in patients with congestive heart failure or after kidney transplantation, or with renal vascular disease, including patients with hemodynamically significant unilateral renal artery stenosis.

Patients with renal impairment. 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").

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

Electrolyte imbalance. As in all patients receiving diuretic therapy, plasma electrolyte levels should be measured regularly at appropriate intervals. Thiazides, including hydrochlorothiazide, may cause disturbances in water and electrolyte balance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Although hypokalemia may develop during thiazide diuretic therapy, concomitant use of ramipril may reduce diuretic-induced hypokalemia. The risk of hypokalemia is highest in patients with liver cirrhosis, those with increased diuresis, those receiving inadequate electrolyte intake, and those receiving concomitant corticosteroids or adrenocorticotropic hormone (see section "Interaction with other medicinal products and other forms of interaction"). Plasma potassium levels should be determined during the first week of treatment. If low potassium levels are detected, correction is required.

Dilutional hyponatremia may occur. Low sodium levels may initially be asymptomatic, so regular monitoring is essential. Such monitoring should be performed more frequently in elderly patients and patients with liver cirrhosis.

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

Monitoring of electrolytes: hyperkalemia. Hyperkalemia has been observed in some patients receiving ACE inhibitors such as RAMIMED® COMBI. Patients at risk of hyperkalemia include those with renal impairment, elderly patients (aged 70 years or 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, or patients with conditions such as dehydration, acute heart decompensation, 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: hyponatremia. In isolated patients receiving ramipril, syndrome of inappropriate antidiuretic hormone secretion (SIADH) with subsequent hyponatremia has been observed. Regular monitoring of serum sodium levels is recommended in elderly patients and other patients at risk of hyponatremia.

Hepatic encephalopathy. In patients with liver disorders, electrolyte imbalances caused by diuretic therapy, including hydrochlorothiazide, may lead to 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 tests assessing parathyroid function.

Angioedema. Angioedema has been reported in patients receiving ACE inhibitors such as ramipril (see section "Undesirable effects"). The risk may be higher in patients concurrently taking medicinal products capable of causing angioedema, such as mTOR inhibitors (mammalian target of rapamycin) (e.g., temsirolimus, everolimus, sirolimus) or DPP-4 inhibitors (dipeptidyl peptidase-4) (vildagliptin and possibly saxagliptin or linagliptin) or neprilysin (NEP) inhibitors such as racecadotril. Combination therapy with ramipril and sacubitril/valsartan is contraindicated due to the risk of angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

In case of angioedema, treatment with RAMIMED® COMBI 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 RAMIMED® COMBI (see section "Undesirable effects"). These patients presented with abdominal pain (with or without nausea/vomiting). Symptoms of intestinal angioedema resolved after discontinuation of the ACE inhibitor.

Anaphylactic reactions during desensitization. The use of ACE inhibitors increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens. Administration of RAMIMED® COMBI 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, in patients with renal impairment, patients with concomitant collagenosis (e.g., systemic lupus erythematosus or scleroderma), and in those receiving concomitant medicinal products that may affect blood counts (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Choroidal effusion, acute myopia, and secondary acute angle-closure glaucoma. Hydrochlorothiazide, a sulfonamide derivative, may cause idiosyncratic reactions leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms are characterized by acute onset of decreased visual acuity or eye pain and typically develop within hours to weeks after starting treatment. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Initial management includes prompt discontinuation of hydrochlorothiazide. If intraocular pressure remains uncontrolled, immediate medical or surgical intervention may be required. Risk factors for acute angle-closure glaucoma include a history of sulfonamide use or penicillin allergy.

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

Athletes. Hydrochlorothiazide may result in a positive doping test.

Metabolic and endocrine effects. Thiazide therapy may impair glucose tolerance. In some diabetic patients, 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 acute gout attacks.

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

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 serum unconjugated bilirubin concentration.

Non-melanoma skin cancer. In two epidemiological studies from the Danish National Cancer Registry, an increased risk of non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) was observed with high cumulative doses of hydrochlorothiazide. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for non-melanoma skin cancer.

Patients taking hydrochlorothiazide should be informed about the risk of non-melanoma skin cancer and should regularly examine their skin for new lesions and promptly report any suspicious skin changes. Preventive measures, such as limiting exposure to sunlight and ultraviolet radiation, and using appropriate protection when exposure occurs, should be recommended to minimize the risk of skin cancer. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsies. The use of hydrochlorothiazide may also be reconsidered in patients with a previous history of non-melanoma skin cancer (see section "Undesirable effects").

Since the drug contains lactose, patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Use during pregnancy or breastfeeding.

Pregnancy. This medicinal product is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this drug, its use must be discontinued immediately and replaced with another medicinal product permitted during pregnancy.

Period of breastfeeding. RAMIMED® COMBI is contraindicated during breastfeeding. The amounts of ramipril and hydrochlorothiazide that pass into breast milk are sufficient that an infant who is breastfed may be exposed to their effects when therapeutic doses are used. Due to the lack of adequate data on ramipril use during breastfeeding, preference should be given to other medicinal products considered safer during breastfeeding, especially when breastfeeding newborns or preterm infants. Hydrochlorothiazide passes into breast milk. Use of thiazides by breastfeeding mothers has been associated with reduced or even complete cessation of milk production. Increased sensitivity to sulfonamide derivatives, hypokalemia, and kernicterus may occur. Since the 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/withhold therapy, depending on the importance of the treatment for the mother.

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect of the drug 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, which may be hazardous in situations where these abilities are particularly important (e.g., driving vehicles or operating machinery).

This is especially relevant at the beginning of treatment or when switching to another medication. After taking the first dose or any subsequent dose increase, driving vehicles or operating machinery should be avoided for several hours.

Dosage and Administration.

For oral use.

The drug 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 "Pharmacological Properties"). Tablets should be swallowed whole with water. They must not be chewed or crushed.

Adults. The dose should be individually adjusted depending on patient characteristics (see section "Special Warnings and Precautions for Use") and blood pressure levels. Fixed-dose combination therapy with ramipril and hydrochlorothiazide is generally recommended only after individual titration of each 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 dose is 10 mg ramipril and 25 mg hydrochlorothiazide per day (use combination products with corresponding dosage strengths).

Special patient groups.

Patients receiving diuretics. Caution is recommended, as patients receiving diuretics may experience arterial hypotension at the start of treatment with this drug. Prior to initiating therapy, the diuretic dose should be reduced or its administration discontinued. If discontinuation of the diuretic is not feasible, treatment should be initiated at the lowest possible dose of ramipril (1.25 mg daily) as an unformulated combination. Subsequently, transition to an initial daily dose not exceeding 2.5 mg ramipril/12.5 mg hydrochlorothiazide is recommended.

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 renal impairment. Patients with creatinine clearance of 30–60 mL/min should only be treated with the lowest dose of fixed combination ramipril/hydrochlorothiazide after monotherapy with ramipril. The maximum recommended daily dose is 5 mg ramipril and 25 mg 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 ramipril and 12.5 mg hydrochlorothiazide. The drug is contraindicated in cases of severe hepatic impairment (see section "Contraindications").

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 increased risk of adverse reactions.

* To achieve the required dosage, combination products with appropriate dosage strengths should be used.

Children. The drug is not recommended for use in children and adolescents due to insufficient data on efficacy and safety in these patient populations.

Overdose.

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

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

Close monitoring of the patient is required.

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

Adverse reactions.

The safety profile of ramipril + hydrochlorothiazide includes adverse effects resulting from arterial hypotension and/or reduced circulating blood volume due to increased diuresis. The active ingredient ramipril may cause a persistent dry cough, while the active ingredient hydrochlorothiazide may affect glucose, lipid, and uric acid metabolism. Both components 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 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each category, adverse reactions are listed in order of decreasing severity.

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

Blood and lymphatic system disorders: uncommon – decreased leukocyte count, decreased erythrocyte count, 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.

Eye disorders: uncommon – visual disturbances, including blurred vision, conjunctivitis; frequency not known – xanthopsia, decreased lacrimation, secondary acute angle-closure glaucoma and/or acute myopia due to hydrochlorothiazide, choroidal effusion.

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

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

Gastrointestinal disorders: uncommon – inflammatory gastrointestinal events, digestive disorders, 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 reported with ACE inhibitors), elevated pancreatic enzymes, angioedema of the small intestine, sialadenitis due to hydrochlorothiazide.

Renal and urinary disorders: uncommon – renal dysfunction, including acute renal failure; renal failure; increased urine output; elevated blood urea and creatinine levels; frequency not known – worsening of background proteinuria, interstitial nephritis due to hydrochlorothiazide.

Skin and subcutaneous tissue disorders: uncommon – angioedema; in very rare cases – airway obstruction due to angioedema, which may be fatal; psoriatic dermatitis; hyperhidrosis; rash, particularly 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 exanthem or enanthem, urticaria, systemic lupus erythematosus due to hydrochlorothiazide.

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

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

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

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

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.

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

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

Benign, malignant and unspecified neoplasms (including cysts and polyps): non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) associated with hydrochlorothiazide use.

Description of selected adverse reactions.

Non-melanoma skin cancer: based on available epidemiological data, there is an association between the development of non-melanoma skin cancer and the use of high cumulative doses of hydrochlorothiazide (see sections "Pharmacological properties" and "Special precautions for use").

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is an important step. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any adverse reactions via the pharmacovigilance system of Ukraine.

Shelf life. 2 years.

Storage conditions. Store at a temperature not exceeding 30 °C in the original packaging, in a place inaccessible to children.

Packaging. 10 tablets per blister. 3 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer.

1. Medocemie LTD (Central Plant)/Medochemie LTD (Central Factory).
2. Actavis LTD/Actavis LTD.

Manufacturer's address and location of business operations.

1. 1-10 Constantinoupoleos Street, Limassol, 3011, Cyprus.
2. BLB015, BLB016, Bulebel Industrial Estate, Zejtun ZTN3000, Malta.