Ramises® com

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RAMiZES COM (RAMiZES COM)

Composition:

Active substances: ramipril, hydrochlorothiazide;

One tablet contains ramipril equivalent to 100% dry substance 5 mg and hydrochlorothiazide equivalent to 100% dry substance 12.5 mg, or ramipril equivalent to 100% dry substance 10 mg and hydrochlorothiazide equivalent to 100% dry substance 12.5 mg, or ramipril equivalent to 100% dry substance 10 mg and hydrochlorothiazide equivalent to 100% dry substance 25 mg;

Excipients:

5 mg/12.5 mg and 10 mg/25 mg: lactose monohydrate; silicified microcrystalline cellulose; iron oxide red (E 172); crospovidone; hypromellose; magnesium stearate;

10 mg/12.5 mg: lactose monohydrate; silicified microcrystalline cellulose; iron oxide red (E 172); iron oxide yellow (E 172); crospovidone; hypromellose; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

5 mg/12.5 mg: round-shaped tablets with flat surface, beveled edge and a score line on one side, light pink in color. Speckles on the surface are permissible.

10 mg/12.5 mg: round-shaped tablets with biconvex surface and a score line on one side, light orange with a slight pinkish tint. Speckles on the surface are permissible.

10 mg/25 mg: round-shaped tablets with flat surface, beveled edge and a score line on one side, light pink in color. Speckles on the surface are permissible.

Pharmacotherapeutic group. Combined angiotensin-converting enzyme (ACE) inhibitors. 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 angiotensin-converting enzyme [ACE] or kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor substance, and the breakdown of bradykinin, which is a potent vasodilator. Reduced formation of angiotensin II 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 (African-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 precise mechanism of the antihypertensive effect of thiazide diuretics has not yet been fully elucidated. These agents inhibit the reabsorption of sodium and chloride ions in the distal renal tubules. Enhanced renal excretion of these ions is accompanied by increased urine production (due to osmotic water retention). Excretion of potassium and magnesium is also increased, whereas excretion of uric acid is reduced. Possible mechanisms of the hypotensive effect of hydrochlorothiazide include changes in sodium balance, reduction in extracellular fluid volume and plasma volume, alterations in renal vascular resistance, or decreased responsiveness to norepinephrine and angiotensin II.

Pharmacodynamics.

Ramipril. Administration of ramipril leads to a significant reduction in peripheral arterial resistance. Generally, no substantial 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 causing 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 is usually achieved 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 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 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 GFR, renal vascular resistance, and plasma renin activity.

Concomitant use of ramipril and hydrochlorothiazide. Clinical studies have shown that the combination of these two agents results in a greater reduction in blood pressure than either component used alone. Concomitant administration of ramipril and hydrochlorothiazide reduces potassium loss associated with the diuretic effect, likely due to suppression of the renin-angiotensin-aldosterone system (RAAS). The combination of an ACE inhibitor with a thiazide diuretic produces a synergistic effect and also reduces the risk of diuretic-induced hypokalemia.

Clinical Efficacy and Safety

Essential Hypertension of Mild to Moderate Severity. The efficacy of ramipril and hydrochlorothiazide has been demonstrated in two studies involving patients with mild to moderate essential hypertension. The first study (534 patients) aimed to determine the optimal dose by comparing ramipril (at doses from 2.5 mg to 10 mg) and hydrochlorothiazide (at doses of 12.5 mg or 25 mg) administered separately and in combination. The study medications were administered for 6 weeks following a 2–4 week placebo lead-in phase. Efficacy was assessed based on the reduction in blood pressure measured in the supine and standing positions from the end of the placebo phase to the study endpoint (last measurement for each patient). It was confirmed that 10 mg of ramipril is an effective antihypertensive dose. Combination therapy with ramipril and hydrochlorothiazide provided statistically significant greater blood pressure reduction compared to either ramipril or hydrochlorothiazide as monotherapy (p < 0.05 for most comparisons); ramipril 10 mg was more effective when used in combination with hydrochlorothiazide 12.5 mg or 25 mg than as monotherapy. Overall, the greatest mean reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were achieved with ramipril 5 mg or 10 mg in combination with hydrochlorothiazide 12.5 mg or 25 mg.

The second study (192 patients) was a double-blind, randomized, parallel-group study with a 4-week placebo lead-in phase followed by 12 weeks of active treatment. During the first 6 weeks of active treatment, patients received monotherapy with either ramipril 10 mg or hydrochlorothiazide 50 mg. Efficacy was assessed by measuring SBP and DBP in the supine and standing positions. Treatment efficacy was defined as achieving a DBP ≤ 90 mm Hg in both supine and standing positions at the end of the monotherapy phase. During the second phase of active treatment, patients who did not respond to monotherapy at the end of the 6-week monotherapy phase received a non-fixed combination of ramipril 10 mg and hydrochlorothiazide 50 mg. At the end of the first 6-week monotherapy phase, the mean reduction in SBP in the supine position was 15.5 mm Hg in the hydrochlorothiazide 50 mg group and 11.1 mm Hg in the ramipril 10 mg group; corresponding SBP reductions in the standing position were 14.5 and 8.4 mm Hg. Mean reductions in DBP in the supine position were 10.7 mm Hg in the hydrochlorothiazide 50 mg group and 9.0 mm Hg in the ramipril 10 mg group; corresponding DBP reductions in the standing position were 11.3 and 7.9 mm Hg. The response rate after 6 weeks of treatment was 52.1% in the hydrochlorothiazide 50 mg group and 37.7% in the ramipril 10 mg group (Fisher’s exact test, p=0.061). Of the 49 patients who did not respond to ramipril 10 mg monotherapy at the end of the 6-week phase, 21 (42.9%) responded after adding hydrochlorothiazide 50 mg. Similarly, of the 35 patients who did not respond to hydrochlorothiazide 50 mg monotherapy, 13 (37.1%) responded after adding ramipril 10 mg.

HOPE Study. In addition to its antihypertensive effect, ramipril at a dose of 10 mg demonstrates beneficial protective effects on the cardiovascular system and kidneys independent of blood pressure reduction.

A placebo-controlled study evaluating the preventive properties of the drug (the HOPE study) was conducted, in which ramipril was added to standard therapy in over 9,200 patients. Patients included in this study had an increased risk of cardiovascular disease due to either established atherothrombotic cardiovascular disease (history of ischemic heart disease, stroke, or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented microalbuminuria, arterial hypertension, elevated total cholesterol, low HDL cholesterol, or smoking).

The study demonstrated that ramipril significantly reduces the incidence of myocardial infarction, cardiovascular mortality, and stroke (composite primary endpoint events), both as monotherapy and in combination regimens.

Table 1

HOPE Study: Key Results

Double blockade of the RAS. Two large randomized controlled trials [ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)] investigated the use of a combination of an ACE inhibitor with an angiotensin II receptor antagonist.

The ONTARGET trial was conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.

These trials did not demonstrate significant benefits of combination therapy regarding renal and/or cardiovascular morbidity and mortality. However, an increased risk of hyperkalemia, acute renal failure, and/or arterial hypotension was observed compared to monotherapy. Given the similar pharmacodynamic profiles of these drugs, these findings are also applicable to other ACE inhibitors and angiotensin II receptor antagonists.

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

The ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Endpoints) evaluated the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor antagonist in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. This trial was terminated prematurely due to an increased risk of adverse clinical outcomes. A numerically higher frequency of fatal events due to cardiovascular causes and stroke, as well as an increased incidence of serious adverse reactions (hyperkalemia, arterial hypotension, and renal dysfunction), were observed in the aliskiren group compared to the placebo group.

Non-melanoma skin cancer (NMSC). Epidemiological data have shown an association between cumulative dose of hydrochlorothiazide and the development of NMSC. One study included 71,533 patients with basal cell carcinoma (BCC) and 8,629 patients with squamous cell carcinoma (SCC), matched with 1,430,833 and 172,462 patients in the control group, respectively. At high levels of hydrochlorothiazide use (cumulative dose ≥ 50,000 mg), an adjusted odds ratio (OR) of 1.29 (95% CI: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC was observed. A clear dose-effect relationship was observed for both BCC and SCC. Another study demonstrated a possible association between lip cancer (SCC) and hydrochlorothiazide use: 633 cases of lip cancer were identified among 63,067 patients in the control group (using a risk-set sampling strategy). A dose-effect relationship was demonstrated by an adjusted OR of 2.1 (95% CI: 1.7–2.6). The OR increased to 3.9 (3.0–4.9) with high cumulative doses of hydrochlorothiazide (~25,000 mg) and to 7.7 (5.7–10.5) with the highest cumulative doses (~100,000 mg) (see also section "Special precautions").

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 drug 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. With repeated once-daily dosing of ramipril, 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 diketopiperazine ester, diketopiperazine acid, and glucuronides of ramipril and ramiprilat.

Elimination. Metabolite excretion occurs predominantly via renal excretion. The decline in plasma ramiprilat concentration is multiphasic. Due to strong saturable binding to ACE and slow dissociation from the enzyme, ramiprilat exhibits a prolonged terminal elimination phase at very low plasma concentrations. The effective half-life of ramipril after repeated doses of 5–10 mg ramipril once daily is 13–17 hours, and 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 renal clearance of ramiprilat is proportional to creatinine clearance. This results in elevated 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 hepatic esterase activity. In these patients, increased plasma levels of ramipril are observed. However, peak plasma concentrations of ramiprilat in these patients do not differ from those in individuals with normal liver function.

Hydrochlorothiazide

Absorption. Approximately 70% of hydrochlorothiazide is absorbed from the gastrointestinal tract after oral administration. Peak 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 very minor extent.

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

Patients with 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 results in elevated 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 pharmacokinetic studies of hydrochlorothiazide have been conducted in patients with heart failure.

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

Preclinical safety data. In rats and mice, administration of the combination of ramipril and hydrochlorothiazide at doses up to 10,000 mg/kg body weight did not result in acute toxic effects. Repeated-dose studies in rats and monkeys demonstrated only disturbances in electrolyte balance. Mutagenicity and carcinogenicity studies of this combination were not performed, as studies of the individual components revealed no risks. Reproductive toxicity studies showed that the combination was slightly more toxic than either active substance alone, but none of the studies demonstrated teratogenic effects of this combination.

Clinical characteristics.

Indications.

Treatment of arterial hypertension. This fixed-dose combination is indicated in patients whose blood pressure is not adequately controlled on 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 contained in the medicinal product.
• History of angioedema (hereditary, idiopathic, or previously occurred during treatment with ACE inhibitors or angiotensin II receptor antagonists).
• Arterial hypotension or hemodynamically unstable conditions.
• Concomitant use with sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").
• Concomitant use of ACE inhibitors and extracorporeal treatment methods involving blood contact with negatively charged surfaces, as such use may lead to severe anaphylactoid reactions. These extracorporeal treatment methods include dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis with dextran sulfate (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 disturbances, which may worsen during treatment with the medicinal product (see section "Special warnings and precautions for use").
• Refractory hypokalemia or hypercalcemia.
• Refractory hyponatremia.
• Symptomatic hyperuricemia (gout).
• Anuria.
• Severe hepatic dysfunction, hepatic encephalopathy.
• Pregnancy and planned pregnancy (see section "Use during pregnancy or lactation").
• Lactation period (see section "Use during pregnancy or lactation").
• Concomitant use with aliskiren-containing medicinal products 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 with angiotensin II receptor antagonists in patients with diabetic nephropathy.

Interaction with other medicinal products and other forms of interaction.

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

Contraindicated combinations

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special warnings and 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 Ramizes® Com.

Extracorporeal treatment methods 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 with dextran sulfate, are contraindicated 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 switching to an antihypertensive agent from another class.

Combinations requiring special caution

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

Antihypertensive agents (e.g., diuretics) and other active substances that may reduce blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, high-dose 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 blood pressure monitoring is recommended. Additionally, hydrochlorothiazide may reduce the effect of vasopressor sympathomimetics.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other substances that may alter blood counts. Increased risk of hematological reactions (see section "Special warnings and 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 already elevated by ACE inhibitors. Therefore, concomitant use of ramipril/hydrochlorothiazide and lithium is not recommended.

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

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

Oral anticoagulants. 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 agents or active substances that reduce plasma potassium levels. Increased risk of hypokalemia.

Cardiac glycosides, active substances capable of prolonging the QT interval, antiarrhythmic agents. Proarrhythmic effects may be enhanced and antiarrhythmic effects reduced 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 is recommended when 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 with the following medicinal products associated with polymorphic ventricular tachycardia (torsades de pointes), 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. Hemolysis is possible.

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

Curare-like muscle relaxants. Potentiation and prolonged duration of action of muscle relaxants are possible.

Calcium salts and medicinal products that increase plasma calcium levels. Increased plasma calcium concentration may occur 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 case of dehydration caused by diuretic therapy, including hydrochlorothiazide, there is an increased risk of acute renal failure, especially with administration of large doses of iodine-containing contrast agents.

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

Quinine. Hydrochlorothiazide reduces quinine excretion.

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

Heparin. Possible increase in serum potassium concentrations.

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

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

Cyclosporine. Hyperuricemia may be exacerbated 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, or antidepressants. May potentiate orthostatic arterial hypotension.

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

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

Amantadine. Thiazides, including hydrochlorothiazide, increase the risk of adverse reactions caused by amantadine.

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

Antigout agents (probenecid, sulfinpyrazone, allopurinol). Dose adjustment of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid levels. Increased doses of probenecid or sulfinpyrazone may be needed. 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 diuretics increases.

Effect of medicinal products on laboratory test results

Due to effects on calcium metabolism, thiazides may influence assessment of parathyroid function (see section "Special warnings and 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 believed to possibly extend to 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 immediately discontinued and, if necessary, treatment with another agent should be initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Dual blockade of the RAAS. Evidence supports that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of arterial hypotension, hyperkalaemia, and impaired renal function (including development of acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections "Pharmacodynamics" 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 arterial hypotension

Patients with increased RAAS activity. Patients with increased RAAS activity are at risk of sudden and significant blood pressure reduction and impaired renal function due to ACE inhibition. This is particularly relevant when initiating or increasing the dose of an ACE inhibitor or concomitant diuretic. 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 of blood from the left ventricle (e.g., aortic or mitral valve stenosis);
• with unilateral renal artery stenosis and a functioning second kidney;
• with existing or potential fluid or electrolyte depletion (including patients receiving diuretics);
• with liver cirrhosis and/or ascites;
• undergoing major surgery or receiving anaesthesia with agents that may cause arterial hypotension.

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

In patients with hepatic impairment, response to treatment with RamisesÒ Com may be either enhanced or reduced. Additionally, in patients with severe liver cirrhosis associated with oedema and/or ascites, renin-angiotensin system activity may be markedly increased; therefore, particular 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 ischaemia in case of acute arterial hypotension. During the initial phase of treatment, close medical supervision is required.

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

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

Patients with hepatic disease. Electrolyte imbalances caused by diuretics such as hydrochlorothiazide may lead to the development of hepatic encephalopathy in patients with liver disorders.

Thiazides should be used with caution in patients with liver disorders or progressive liver disease, as these agents may cause intrahepatic cholestasis, and even minor alterations 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 should be adjusted accordingly, especially during the first weeks of therapy. Patients with impaired renal function (see section "Posology and method of administration") require particularly careful monitoring. There is a risk of impaired renal function, particularly in patients with congestive heart failure or after kidney transplantation, and in those with renal vascular disease, including patients with hemodynamically significant unilateral renal artery stenosis.

Patients with impaired renal function. In patients with renal disease, thiazides may precipitate the onset of uraemia. Cumulative effects of active substances may occur in patients with impaired renal function. If progression of renal dysfunction becomes evident, as indicated by increasing blood urea nitrogen, the continuation of treatment should be carefully reconsidered. Discontinuation of diuretic therapy should be considered (see sections "Contraindications" and "Posology and method of administration").

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 fluid and electrolyte balance (hypokalaemia, hyponatraemia, and hypochloraemic alkalosis).

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

Dilutional hyponatraemia may occur. In patients with low sodium levels, symptoms may initially be absent; therefore, regular measurement of sodium levels is essential. Such monitoring should be performed more frequently in elderly patients and in patients with liver cirrhosis.

Thiazides have been shown to increase urinary magnesium excretion, which may lead to hypomagnesaemia.

Monitoring of electrolytes: hyperkalaemia. Hyperkalaemia has occurred in some patients receiving ACE inhibitors such as RamisesÒ Com. Patients at risk of hyperkalaemia include those with renal impairment, elderly individuals (aged 70 years or older), patients with uncontrolled diabetes mellitus, those taking potassium salts, potassium-sparing diuretics, or other active substances that increase plasma potassium levels, and patients with conditions such as dehydration, acute cardiac decompensation, or metabolic acidosis. If concomitant use of the above-mentioned agents is indicated, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Hypercalcaemia. Hydrochlorothiazide enhances calcium reabsorption in the kidneys, which may lead to hypercalcaemia. This may interfere with test results used to assess parathyroid function.

Angioedema. Angioedema has been observed in patients receiving ACE inhibitors such as ramipril (see section "Adverse reactions"). This 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), DPP-4 inhibitors (dipeptidyl peptidase-4) (vildagliptin and possibly saxagliptin or linagliptin), or neprilysin 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 the event of angioedema, treatment with RamisesÒ Com should be immediately discontinued 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 RamisesÒ Com (see section "Adverse reactions"). 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 desensitisation. The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased during treatment with ACE inhibitors. RamisesÒ Com should be temporarily discontinued prior to desensitisation procedures.

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

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma. Medicinal products containing sulfonamides or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms are characterized by sudden onset of decreased visual acuity or eye pain and typically develop within hours to weeks after starting the drug. 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 is 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 patients of Black race than in other racial groups. As with other ACE inhibitors, 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 result in a positive doping test.

Metabolic and endocrine effects. Thiazide treatment may impair glucose tolerance. In some patients with diabetes mellitus, adjustment of insulin or oral hypoglycaemic agent dosage 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 hyperuricaemia or acute gout attacks.

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

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

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

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

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

This medicinal product contains lactose; therefore, patients with known intolerance to certain sugars should consult their physician before taking this medicinal product.

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 product, therapy should be immediately discontinued and replaced with another medicinal product permitted during pregnancy.

Breastfeeding

RamisesÒ Com is contraindicated during breastfeeding. The amount of ramipril and hydrochlorothiazide that passes into breast milk is sufficient that an infant who is breastfed may be exposed to their effects when therapeutic doses of ramipril and hydrochlorothiazide are administered. As there are insufficient data on the use of ramipril 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. Thiazide use in breastfeeding women has been associated with reduced or even complete cessation of milk production. Increased sensitivity to sulfonamide derivatives, hypokalaemia, and kernicterus may occur. Since the use of both active substances may lead to serious adverse reactions in breastfed infants, a decision should be made whether to discontinue breastfeeding or treatment, depending on the importance of the therapy for the woman.

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted. Some adverse reactions (e.g., symptoms of low blood pressure such as dizziness) may impair a patient's ability to concentrate 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 medicinal product. Driving or operating machinery should be avoided for several hours after taking the first dose or any subsequent dose increase.

Method of Administration and Dosage

For oral use. To achieve the recommended dosage, tablets containing the appropriate amounts of active substances should be used.

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

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

Adults. The dose should be individually adjusted depending on 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 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.

Special Patient Groups

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

If discontinuation of the diuretic is not possible, treatment should be initiated with the lowest possible dose of ramipril (1.25 mg daily) as a non-fixed 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 dysfunction. Patients with creatinine clearance of 30–60 mL/min should only be treated with the lowest dose of the fixed combination of ramipril/hydrochlorothiazide after monotherapy with ramipril. The maximum daily dose* is 5 mg ramipril and 25 mg hydrochlorothiazide; therefore, the medicinal product Ramises® Com 10 mg/12.5 mg is contraindicated in patients with moderate renal impairment.

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. Therefore, higher doses, including the medicinal product Ramises® Com 10 mg/12.5 mg, are contraindicated in patients with mild to moderate hepatic impairment. 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 the increased risk of adverse reactions.

* To achieve the required dosage, a combination of medications in appropriate strengths should be used.

Children.

The drug is not recommended for use in children due to insufficient data on efficacy and safety in this patient population.

Overdose.

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

Careful monitoring of the patient is required.

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

Adverse reactions.

The safety profile of ramipril + hydrochlorothiazide includes adverse reactions resulting from arterial hypotension and/or reduced blood volume due to increased diuresis. The active substance ramipril may cause a persistent cough, whereas the active substance hydrochlorothiazide may affect glucose, lipid, and uric acid metabolism. Both substances exert an irreversible effect on plasma potassium levels. Severe adverse reactions include angioedema or anaphylactoid reactions, hepatic or renal dysfunction, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

The frequency of adverse reactions is classified as follows: very common (≥1/10); common (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data). Within each category, adverse reactions are listed in order of decreasing severity.

Shelf life. 2 years.

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

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets per blister. 3 blisters per pack.

Prescription status. Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.