Cartil®-n

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HARTIL®-N (HARTIL®-N)

Composition:

Active substances:
ramipril, hydrochlorothiazide;

1 tablet contains: 5 mg ramipril and 25 mg hydrochlorothiazide;

Excipients:
lactose monohydrate, hypromellose, crospovidone, microcrystalline cellulose, sodium stearyl fumarate.

Pharmaceutical form.
Tablets.

Main physico-chemical properties:

White oval tablets with a score line on both sides; on one side of the tablet – engraved numbers "5" and "25" on both sides of the score line.

The tablet can be divided into two equal parts.

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

ATC code C09BA05.

Pharmacological properties.

Pharmacodynamics. The combination of ramipril/hydrochlorothiazide has antihypertensive and diuretic effects. The antihypertensive effects of both substances complement each other, and the hypokalemic effect of hydrochlorothiazide is reduced by ramipril. Mechanism of action Ramipril Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidyl-carboxypeptidase I (synonyms: angiotensin-converting enzyme, kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of tissue angiotensin I into the active vasoconstrictor angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduction in angiotensin II levels and inhibition of bradykinin degradation lead to vasodilation. Since angiotensin II also stimulates aldosterone release, ramiprilat leads to reduced aldosterone secretion. Increased bradykinin activity contributes to the cardioprotective effects of ramipril and protects the endothelium. 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 races. Hydrochlorothiazide Hydrochlorothiazide is a thiazide diuretic. The mechanism of its antihypertensive action has not yet been fully elucidated. Thiazide diuretics inhibit reabsorption of sodium and chloride ions in the distal tubules. Enhanced renal excretion of these ions is accompanied by increased urine production (due to osmotic water binding). Excretion of potassium and magnesium is also increased, while excretion of uric acid is decreased. Possible mechanisms of hydrochlorothiazide's antihypertensive effect include changes in sodium balance, reduction in extracellular fluid and plasma volume, alteration in renal vascular resistance, or decreased responsiveness to norepinephrine and angiotensin II. Pharmacodynamics. Ramipril Administration of ramipril causes a pronounced reduction in peripheral arterial resistance. Significant changes in renal plasma flow and glomerular filtration rate are usually not observed. In patients with arterial hypertension, ramipril leads to a reduction in blood pressure without compensatory tachycardia. In most patients, the antihypertensive effect is achieved within 1–2 hours after a single dose. The maximum effect is reached 3–6 hours after administration. Generally, the antihypertensive effect after a single dose lasts for at least 24 hours. With prolonged ramipril therapy, the maximum antihypertensive effect is usually achieved within 3–4 weeks. It has been demonstrated that the antihypertensive effect is maintained for up to 2 years during long-term therapy. Abrupt discontinuation of ramipril does not cause rapid or excessive elevation of blood pressure. Hydrochlorothiazide Excretion of electrolytes and water begins approximately 2 hours after administration, with maximum effect reached within 4 hours and lasting for 6–12 hours. The antihypertensive effect develops within 3–4 days of treatment and persists for up to 1 week after discontinuation of the drug. During long-term treatment, blood pressure reduction is achieved with lower doses than those required for diuretic effect. Blood pressure reduction is accompanied by a slight increase in glomerular filtration rate, renal vascular resistance, and plasma renin activity. Concomitant use of ramipril and hydrochlorothiazide. Clinical studies have shown that the use of this combination leads to a more significant reduction in blood pressure than the use of either active ingredient alone. Concomitant administration of ramipril and hydrochlorothiazide reduces potassium loss associated with the diuretic effect, likely due to inhibition of the renin-angiotensin-aldosterone system (RAAS). Combining an ACE inhibitor with a thiazide diuretic results in a synergistic effect and also reduces the risk of hypokalemia caused by the diuretic alone. Pharmacokinetics. Ramipril Absorption After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract, and maximum plasma concentration is reached within 1 hour. Based on the amount of substance detected in urine, absorption is at least 56%, and is not significantly affected by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of 2.5 mg and 5 mg doses is 45%. Maximum plasma concentrations of ramiprilat, the sole active metabolite of ramipril, are reached 2–4 hours after ramipril administration. After repeated daily dosing of ramipril, steady-state plasma concentrations of ramiprilat are achieved within approximately 4 days of treatment. Distribution Plasma protein binding of ramipril is approximately 73%, and of ramiprilat is 56%. Metabolism Ramipril is almost completely metabolized to ramiprilat, diketopiperazine ester, diketopiperazine acid, and glucuronides of ramipril and ramiprilat. Elimination Metabolite elimination 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 has a prolonged terminal elimination phase at very low plasma concentrations. The effective half-life of ramipril after repeated doses of 5–10 mg ramipril once daily is 13–17 hours, and is longer with lower doses (1.25–2.5 mg). This difference is due to the enzyme's binding capacity for ramiprilat being saturable. After 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 In patients with impaired renal function, renal excretion of ramiprilat is reduced, and renal clearance of ramiprilat is proportional to creatinine clearance. This leads to elevated plasma concentrations of ramiprilat, which decline more slowly than in individuals with normal renal function. Patients with hepatic impairment In patients with impaired liver function, conversion of ramipril to ramiprilat occurs more slowly due to reduced activity of hepatic esterases. In such patients, increased plasma levels of ramipril are observed. However, the maximum plasma concentration of ramiprilat in these patients does not differ from that in individuals with normal liver function. Hydrochlorothiazide Absorption After oral administration, 70% of hydrochlorothiazide is absorbed in the duodenum and upper small intestine. Maximum plasma concentration 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 negligible 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 In patients with impaired renal function, renal excretion of hydrochlorothiazide is reduced, and renal clearance of hydrochlorothiazide is proportional to creatinine clearance. This leads to elevated plasma concentrations of hydrochlorothiazide, which decline more slowly than in individuals with healthy kidneys. Patients with hepatic impairment 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 combination product can be considered bioequivalent to products containing the individual active substances. Non-melanoma skin cancer (NMSC) Available epidemiological data indicate a cumulative, dose-dependent association between hydrochlorothiazide exposure and the development of NMSC. One study included 71,533 cases of basal cell carcinoma and 8,629 cases of squamous cell carcinoma, corresponding to 1,430,833 and 172,462 individuals in the control groups, respectively. High-dose hydrochlorothiazide (≥50,000 mg cumulative) was associated with an adjusted odds ratio (OR) of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A cumulative dose-response relationship was observed for both basal cell and squamous cell carcinoma. Another study showed a possible association between lip cancer and hydrochlorothiazide use: 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 (~25,000 mg) and OR 7.7 (5.7–10.5) for the highest dose (~100,000 mg). For example, a cumulative dose of 100,000 mg corresponds to daily use of the defined daily dose of 25 mg over a period of more than 10 years.

Clinical characteristics.

Indications.

Essential hypertension in patients for whom combination therapy (ramipril and hydrochlorothiazide) is recommended.

Contraindications.

• Hypersensitivity to the active substance ramipril or to other angiotensin-converting enzyme (ACE) inhibitors, hydrochlorothiazide, other thiazide diuretics, sulfonamides, or to any of the excipients contained in the medicinal product (see section "Composition").
• History of angioedema (hereditary, idiopathic, or previously experienced during treatment with ACE inhibitors or angiotensin II receptor antagonists).
• Concomitant use with sacubitril/valsartan (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use").
• Patients with arterial hypotension or hemodynamically unstable conditions.
• Concomitant use of ACE inhibitors and extracorporeal treatment methods that result in 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) and low-density lipoprotein apheresis using dextran sulfate (see section "Interaction with other medicinal products and other types of interactions").
• Significant bilateral renal artery stenosis or unilateral renal artery stenosis in the presence of a single functioning kidney.
• Pregnancy and planned pregnancy (see section "Use during pregnancy or breastfeeding").
• Breastfeeding period (see section "Use during pregnancy or breastfeeding").
• Severe renal impairment (creatinine clearance <30 mL/min) in patients not undergoing hemodialysis.
• Clinically significant electrolyte imbalances, the course of which may worsen during treatment with the medicinal product (see section "Special precautions for use").
• Refractory hypokalemia or hypercalcemia.
• Refractory hyponatremia.
• Symptomatic hyperuricemia (gout).
• Anuria.
• Severe hepatic impairment, hepatic encephalopathy.

Concomitant use with aliskiren-containing medicinal products in patients with diabetes or in patients with moderate or severe renal impairment (eGFR <60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other types of interactions").

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

Interaction with other medicinal products and other types of interactions.

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

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

Contraindicated combinations.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections "Contraindications" and "Special precautions for use"). Treatment with ramipril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan. Initiation of sacubitril/valsartan therapy should not occur earlier than 36 hours after the last dose of Hartil®-N.

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 using dextran sulfate, are contraindicated due to an increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or switching to another class of antihypertensive agents.

Combinations requiring special caution

Potassium salts, heparin, potassium-sparing diuretics, and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim, trimethoprim/sulfamethoxazole fixed-dose combination, tacrolimus, cyclosporine): Hyperkalemia may occur; therefore, careful monitoring of plasma potassium levels is required.

Antihypertensive agents (e.g., diuretics) and other agents that may reduce blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): An increased risk of arterial hypotension is expected.

Vasopressor sympathomimetics and other substances (e.g., isoproterenol, dobutamine, dopamine, epinephrine, norepinephrine) that may reduce the antihypertensive effect of ramipril: Blood pressure monitoring is recommended. Additionally, hydrochlorothiazide may attenuate the effect of vasopressor sympathomimetics.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatic agents, and other substances that may alter blood cell counts: Increased risk of hematological reactions.

Thiazide diuretics may increase the risk of severe hypersensitivity reactions associated with allopurinol therapy, particularly in patients with renal impairment.

Lithium salts: ACE inhibitors may reduce lithium excretion, thereby increasing its toxicity. Regular monitoring of plasma lithium levels is required. 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 effectiveness 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 ramipril is expected. Therefore, concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function and elevated blood potassium levels.

Oral anticoagulants: Hydrochlorothiazide reduces anticoagulant effect. Corticosteroids, ACTH, amphotericin B, carbenoxolone, large amounts of licorice, laxatives (with prolonged use), other potassium-sparing diuretics, or low plasma potassium levels: Increased risk of hypokalemia.

Cardiac glycosides, 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 may be diminished.

Methyldopa: Hemolysis is possible.

Cholestyramine or other orally administered ion-exchange resins: Impaired absorption of hydrochlorothiazide.

Sulfonamide diuretics should be taken 1 hour before or 4–6 hours after administration of the medicinal product.

Neuromuscular blocking agents (curare-type): Possible potentiation and prolonged duration of neuromuscular blockers.

Calcium salts and agents that increase plasma calcium levels: Serum calcium concentration may increase when used concomitantly with hydrochlorothiazide; therefore, monitoring is not required.

Carbamazepine: Risk of hyponatremia due to additive effects with hydrochlorothiazide.

Contrast agents containing iodine: In cases of diuretic-induced dehydration, including by hydrochlorothiazide, there is an increased risk of renal failure, particularly during administration of iodine-containing contrast agents.

Penicillin: Hydrochlorothiazide is excreted in the distal tubules and reduces penicillin excretion.

Quinine: Hydrochlorothiazide reduces quinine excretion.

Heparin. Possible increase in serum potassium concentrations.

mTOR inhibitors (mammalian target of rapamycin) or vildagliptin: An increased incidence of angioedema has been observed in patients concomitantly taking ACE inhibitors and mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin. Caution is advised when initiating such therapy (see section "Special precautions for use").

Vildagliptin. An increased incidence of angioedema has been observed in patients concomitantly taking ACE inhibitors and vildagliptin.

Heparin. Possible increase in serum potassium concentrations.

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

Salicylates

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

Cyclosporine

Concomitant use with cyclosporine may exacerbate hyperuricemia and increase the risk of complications such as gout.

Alcohol. Ramipril may cause enhanced vasodilation and thereby potentiate the effects of alcohol.

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

Salt. The antihypertensive effect of the medicinal product may be reduced with increased dietary salt intake.

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

Amantadine.

Thiazides, including hydrochlorothiazide, may increase the risk of adverse effects caused by amantadine.

Pressor amines (e.g., adrenaline). The effect of pressor amines may be reduced, but not to an extent that precludes their use.

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

Effect of medicinal products on laboratory test results

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

Specific hyposensitization. Due to ACE inhibition, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom are increased. This effect may also apply 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 discontinued immediately and, if necessary, replaced with another suitable medication (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Special warnings.

Patients at risk of arterial hypotension.

Patients with increased activity of the renin-angiotensin-aldosterone system.

A marked decrease in blood pressure and worsening of renal function may occur with ACE inhibitors in patients with increased activity of the renin-angiotensin-aldosterone system, particularly when initiating therapy with an ACE inhibitor or a concomitant diuretic, or when increasing the dose.

Medical monitoring and blood pressure control are required in patients with increased activity of the renin-angiotensin-aldosterone system:

• patients with severe arterial hypertension;
• patients with decompensated congestive heart failure;
• patients with hemodynamically significant obstruction to inflow or outflow of the left ventricle (e.g. aortic or mitral valve stenosis);
• patients with unilateral renal artery stenosis of the only functioning kidney;
• patients with existing or potential excessive fluid or sodium chloride loss (including patients taking diuretics);
• patients with liver cirrhosis and/or ascites;
• patients who have undergone major surgery or are under anesthesia with agents causing arterial hypotension.

Prior to initiating therapy, conditions such as dehydration, hypovolemia, or excessive sodium chloride loss should be corrected (however, in patients with heart failure, the feasibility of such corrective measures should be carefully weighed against the risk of volume overload).

Surgery

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

Patients at risk of cardiac or cerebral ischemia due to acute arterial hypotension.

The initial phase of treatment requires special medical supervision.

Primary hyperaldosteronism

The combination of ramipril and hydrochlorothiazide is not the drug of choice for treating primary hyperaldosteronism. If this combination is used to treat patients with primary hyperaldosteronism, plasma potassium levels do not need to be monitored.

Elderly patients

See section "Dosage and administration".

Patients with hepatic disease

Electrolyte disturbances due to diuretic therapy, including hydrochlorothiazide, may lead to hepatic encephalopathy in patients with liver disease.

Monitoring of renal function .

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

Renal impairment

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

Electrolyte imbalance

As with 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 treatment with thiazide diuretics, concomitant use of ramipril may reduce diuretic-induced hypokalemia. The risk of hypokalemia is highest in patients with liver cirrhosis, those with marked diuresis, those receiving inadequate electrolyte intake, and those receiving concomitant corticosteroid or ACTH therapy (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; therefore, regular monitoring is essential. Such monitoring should be performed more frequently in elderly patients and those 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 taking ACE inhibitors, including XARIL®-H. Patients at risk of developing hyperkalemia include the following groups: patients with renal impairment, patients aged

(>70 years), patients with uncontrolled diabetes mellitus, patients taking potassium supplements, potassium-sparing diuretics, or other agents that increase serum potassium levels, and conditions leading to elevated active substance levels such as dehydration, acute heart failure, or metabolic acidosis. If concomitant use under these conditions is considered appropriate, regular monitoring of serum potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Monitoring of electrolytes: hyponatremia

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) and resulting hyponatremia has been observed in patients receiving ramipril.

Hepatic encephalopathy

Electrolyte imbalance due to diuretic therapy, including hydrochlorothiazide, may lead to hepatic encephalopathy in patients with liver disease, with symptoms of impaired liver function, particularly during the first weeks or months. If hepatic encephalopathy occurs, treatment must be discontinued immediately.

Hypercalcemia

Hydrochlorothiazide enhances calcium reabsorption in the kidneys and may lead to hypercalcemia. This may alter parathyroid function test results.

Angioedema

Angioedema has been reported in patients treated with ACE inhibitors, including 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. Combined treatment 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").

If angioedema occurs, treatment with XARIL®-H should be discontinued. Symptomatic treatment should be initiated promptly. Patients should remain under medical supervision for 12 to 24 hours and should only be discharged after complete resolution of symptoms.

Cases of intestinal angioedema have been observed in patients receiving ACE inhibitors such as XARIL®-H (see section "Adverse reactions"). These patients reported abdominal pain (with or without nausea/vomiting). Symptoms of intestinal angioedema resolved after discontinuation of the ACE inhibitor.

Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased during treatment with ACE inhibitors. Treatment with XARIL®-H should be discontinued prior to desensitization.

Neutropenia/Agranulocytosis

Neutropenia/agranulocytosis has been observed rarely; no reports of bone marrow suppression have been received. Monitoring of white blood cell count is recommended, with possible development of leukopenia. Monitoring is recommended at the start of treatment and in patients with renal impairment, and particularly in patients with collagen vascular disease (e.g. systemic lupus erythematosus or scleroderma), as well as in patients taking medicinal products that may affect blood counts.

Ethnic differences

ACE inhibitors cause angioedema more frequently in black patients than in white patients.

Like other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black patients, possibly due to the high prevalence of low-renin hypertension in this population.

Athletes

Hydrochlorothiazide may result in a positive doping test.

Metabolic and endocrine effects

Thiazide diuretics may reduce glucose tolerance. Diabetic patients may require adjustment of insulin or oral hypoglycemic agent dosage. Latent diabetes mellitus may become overt during treatment with thiazide diuretics.

Thiazide diuretics may also increase cholesterol and triglyceride levels.

Hyperuricemia or acute gout attacks may occur in some patients during treatment with thiazide diuretics.

Cough

Cough may occur during treatment with ACE inhibitors. Typically, the cough is non-productive, persistent, and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Others

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

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with aliskiren-containing medicinal products

Dual blockade of the renin-angiotensin-aldosterone system by combining XARIL®-H with aliskiren is not recommended, as it increases the risk of arterial hypotension, hyperkalemia, and changes in renal function (including acute renal failure).

Combination of XARIL®-H with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min) (see section "Contraindications").

If dual blockade therapy is considered necessary, it should be initiated under close specialist supervision with regular monitoring of renal function, electrolyte levels, and blood pressure.

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

Lactose intolerance

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

Alcoholic beverages are not recommended during treatment with this medicinal product.

The product should be used with caution in patients with gout, as well as in those with diabetes mellitus, particularly those using insulin or oral antidiabetic agents.

Extracorporeal treatment methods that involve blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g. polyacrylonitrile), or low-density lipoprotein apheresis with dextrin sulfate, may lead to severe anaphylactoid reactions. If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (BCC and SCC) with increasing cumulative dose of hydrochlorothiazide has been observed in two epidemiological studies. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for the development of these conditions. Patients taking hydrochlorothiazide alone or in combination with other medicinal products should be informed of the risk of non-melanoma skin cancer and advised to regularly check their skin for new lesions or changes in existing lesions and to promptly report any suspicious skin changes. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsy material. Patients should be advised to limit exposure to sunlight and ultraviolet radiation, and to use appropriate sun protection when exposed to sunlight or UV radiation to minimize the risk of skin cancer. Additionally, caution should be exercised when prescribing hydrochlorothiazide-containing products to patients with a history of skin cancer (see also section "Adverse reactions").

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

Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and typically occur within hours to weeks after starting the medicinal product.

Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, medical or surgical interventions may be required. Risk factors for developing acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

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 taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening lung condition, and hypotension. If ARDS is suspected, XARIL®-H should be discontinued and appropriate treatment initiated.

Hydrochlorothiazide should not be administered to patients who previously experienced ARDS after taking hydrochlorothiazide.

Use during pregnancy or breastfeeding

Pregnancy

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

Breastfeeding

XARIL®-H is contraindicated during breastfeeding. The amount of ramipril and hydrochlorothiazide excreted into breast milk is sufficient that breastfed infants may be exposed to these substances when therapeutic doses are administered. Due to the lack of adequate data on the use of ramipril during breastfeeding, preference should be given to other medicinal products with a more favorable safety profile during breastfeeding, especially when breastfeeding newborns or preterm infants. Hydrochlorothiazide is excreted into breast milk. Thiazide use in breastfeeding mothers has been associated with decreased 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 therapy, taking into account the importance of the treatment for the mother.

Effect on ability to drive and use machines

Some adverse effects (e.g. symptoms of low blood pressure such as dizziness) may impair concentration and reaction ability, thereby affecting the ability to drive or operate machinery.

These adverse reactions were observed at the beginning of treatment or when switching from other medications. Driving or operating machinery should be avoided for several hours after taking the first dose or increasing the dose.

Administration and Dosage.

For oral use.

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

The medication may be taken before, during, or after meals, as food intake does not affect its bioavailability (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 titrating the doses of each individual component.

Treatment should be initiated at the lowest possible dose. If necessary, the dose may be gradually increased until the target blood pressure is achieved. The maximum daily dose is 10 mg ramipril and 25 mg hydrochlorothiazide per day.

Special patient populations.

Patients receiving diuretics.
Caution is advised, as patients receiving diuretics may experience arterial hypotension at the start 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 feasible, treatment should be initiated with 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 the hydrochlorothiazide component, the medication is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min) (see section "Contraindications"). Lower doses of the medication may be required in patients with impaired renal function. Patients with a creatinine clearance of 30–60 mL/min should be treated only with the lowest dose of the fixed combination of ramipril/hydrochlorothiazide following monotherapy with ramipril. The maximum daily dose\* is 5 mg ramipril and 25 mg hydrochlorothiazide. Patients with hepatic impairment. Treatment should be initiated only under careful 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 medication 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.

Children.

The medication is not recommended for use in children and adolescents under 18 years of age due to insufficient data on efficacy and safety in this 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, convulsions, 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 elevated blood urea nitrogen levels (primarily due to renal failure).

Careful monitoring of the patient is required.

Treatment is symptomatic and supportive. Therapeutic measures include primary detoxification (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 the medicinal product ramipril + hydrochlorothiazide includes adverse effects resulting from arterial hypotension and/or reduction in circulating blood volume due to increased diuresis. The active substance ramipril may cause a persistent cough, whereas the active substance hydrochlorothiazide may impair glucose, lipid, and uric acid metabolism. Both substances have an irreversible effect on plasma potassium levels. Serious adverse reactions include angioneurotic edema or anaphylactoid reactions, hepatic or renal dysfunction, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

The frequency of adverse reactions is classified as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥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.

	Frequent	Uncommon	Rare	Frequency not known
Cardiac disorders		Myocardial ischemia, including angina pectoris; tachycardia; arrhythmia; palpitations; peripheral edema		Myocardial infarction, orthostatic hypotension
Blood and lymphatic system disorders		Decreased leukocyte count, decreased erythrocyte count, decreased hemoglobin level, hemolytic anemia, decreased platelet count	Aplastic anemia	Bone marrow suppression; neutropenia, including agranulocytosis, pancytopenia, eosinophilia hemoconcentration in case of fluid retention
Nervous system disorders	Headache, dizziness	Vertigo, paresthesia, tremor, loss of balance, burning sensation, dysgeusia, ageusia		Cerebral ischemia, including ischemic stroke and transient ischemic attack; psychomotor impairment, parosmia
Eye disorders		Visual disturbances, including blurred vision, conjunctivitis		Xanthopsia, decreased tear production due to hydrochlorothiazide, secondary acute angle-closure glaucoma and/or acute myopia due to hydrochlorothiazide, choroidal effusion
Ear and labyrinth disorders		Tinnitus		Hearing impairment
Respiratory, thoracic and mediastinal disorders	Non-productive irritating cough, bronchitis	Sinusitis, dyspnea, nasal congestion		Bronchospasm, including exacerbation of bronchial asthma; allergic alveolitis; respiratory distress, including pneumonitis and non-cardiogenic pulmonary edema due to hydrochlorothiazide
Gastrointestinal disorders		Inflammatory conditions in the gastrointestinal tract, digestive disorders, abdominal discomfort, dyspepsia, gastritis, nausea, constipation, gingivitis due to hydrochlorothiazide	Vomiting, aphthous stomatitis, glossitis, diarrhea, upper abdominal pain, dry mouth	Pancreatitis (in isolated cases fatal outcomes have been reported with ACE inhibitors), increased pancreatic enzyme levels, angioedema of the small intestine, sialadenitis due to hydrochlorothiazide
Renal and urinary disorders		Renal function impairment, including acute renal failure; increased urine production; elevated blood urea and creatinine levels		Worsening of underlying proteinuria, interstitial nephritis due to hydrochlorothiazide
Skin and subcutaneous tissue disorders		Angioedema; in very rare cases – airway obstruction due to angioedema, which may be fatal; psoriatic dermatitis; hyperhidrosis; rash, including maculopapular; pruritus; alopecia		Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, exfoliative dermatitis, photosensitivity, onycholysis, pemphigoid or lichenoid exanthema or enanthema, urticaria, systemic lupus erythematosus due to hydrochlorothiazide
Musculoskeletal and connective tissue disorders		Myalgia		Arthralgia, muscle cramps, muscle weakness, musculoskeletal stiffness, tetanic convulsions due to hydrochlorothiazide
Endocrine disorders				Syndrome of inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders	Poor control of diabetes mellitus, decreased glucose tolerance, increased blood glucose levels, increased uric acid levels, gout exacerbation, increased cholesterol and/or triglyceride levels due to hydrochlorothiazide	Anorexia, decreased appetite, decreased plasma potassium levels, thirst sensation due to hydrochlorothiazide	Increased plasma potassium levels due to ramipril	Decreased plasma sodium levels, glucosuria, metabolic alkalosis, hypochloremia, hypomagnesemia, hypercalcemia, dehydration, hypochloremic alkalosis which may induce hepatic encephalopathy or hepatic coma due to hydrochlorothiazide
Vascular disorders		Arterial hypotension, orthostatic hypotension, syncope, flushing		Thrombosis due to significant reduction in circulating blood volume, vascular stenosis, hypoperfusion, Raynaud's syndrome, vasculitis, necrotizing angiitis
General disorders	Increased fatigue, asthenia	Chest pain, pyrexia		Exhaustion
Immune system disorders				Anaphylactic or anaphylactoid reactions to ramipril or anaphylactic reactions to hydrochlorothiazide, increased levels of antinuclear antibodies
Hepatobiliary disorders		Cholestatic or cytolytic hepatitis (in exceptional cases with fatal outcome), increased levels of liver enzymes and/or conjugated bilirubin, cholelithiasis-induced cholecystitis due to hydrochlorothiazide		Acute liver failure, cholestatic jaundice, liver cell damage
Reproductive system and breast disorders		Transient erectile impotence		Decreased libido, gynecomastia
Psychiatric disorders		Depressed mood, apathy, anxiety, restlessness, sleep disturbances, including somnolence		Confusion, agitation, attention disturbances
Benign, malignant and unspecified neoplasms (including cysts and polyps)				NMSC (BCC and SCC): Based on epidemiological data, an association has been found between cumulative dose of hydrochlorothiazide and the development of NMSC (see also sections "Pharmacological properties" and "Special precautions").

Shelf life.
3 years.

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

Storage conditions.
Store at a temperature not exceeding 25 °C in a place inaccessible to children.

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

Prescription status.
Prescription only.

Manufacturer.

Egis Pharmaceuticals Ltd.

Location of the manufacturer and its registered business address.

1165 Budapest, Bekenyefeldi str. 118-120, Hungary.