Ampril® hl

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMPRIL® HL (AMPRIL® HL)

Composition:

Active substance: 1 tablet contains 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide;

Excipients: sodium bicarbonate, lactose monohydrate, sodium croscarmellose, pregelatinized starch, sodium stearyl fumarate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: flat, uncoated tablets, capsule-shaped, white or almost white, with a score line on one side and the mark "12.5" on the other side.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Ramipril

Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidyl carboxypeptidase I (angiotensin-converting enzyme or kininase II).

In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I into the vasoconstrictive substance angiotensin II, and also promotes the breakdown of the active vasodilator bradykinin. 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 (of Afro-Caribbean origin) with arterial hypertension (typically characterized by low renin activity in this population), the response to monotherapy with angiotensin-converting enzyme (ACE) inhibitors has generally been less pronounced than in patients of other races.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive action of thiazide diuretics is not fully elucidated. They inhibit reabsorption of sodium and chloride ions in the distal tubules. Enhanced excretion of these ions via the kidneys is accompanied by increased urine production (due to osmotic binding of water). Excretion of potassium and magnesium is increased, while excretion of uric acid is reduced. Possible mechanisms of the antihypertensive effect of hydrochlorothiazide include: altered sodium balance, reduced extracellular water and plasma volume, altered renal vascular resistance, and reduced sensitivity to angiotensin II.

Pharmacodynamic effect.

Ramipril

Administration of ramipril results in a marked reduction in peripheral arterial resistance. Typically, there are no significant changes in renal plasma flow or glomerular filtration rate. In patients with arterial hypertension, administration of ramipril leads to a reduction in blood pressure in both supine and standing positions without compensatory increase in heart rate. In most patients, the onset of the hypotensive effect after a single dose occurs within 1–2 hours following oral administration. The peak effect of a single dose is usually reached within 3–6 hours after oral administration. The hypotensive effect of a single dose typically lasts for 24 hours. With prolonged ramipril treatment, the maximum antihypertensive effect is usually achieved within 3–4 weeks of therapy. 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 arterial blood pressure.

Hydrochlorothiazide

After hydrochlorothiazide administration, the onset of diuretic effect occurs within 2 hours, with peak effect at approximately 4 hours; the effect lasts for 6–12 hours.

The antihypertensive effect begins on days 3–4 of therapy and may persist for up to 1 week after discontinuation of treatment.

The reduction in arterial blood pressure is accompanied by a slight increase in glomerular filtration rate, renal vascular resistance, and plasma renin activity.

Concomitant use of ramipril-hydrochlorothiazide

Clinical studies have shown that the combination therapy leads to a greater reduction in arterial blood pressure than either component alone. Possibly due to blockade of the renin-angiotensin-aldosterone system (RAAS), the concomitant use of ramipril with hydrochlorothiazide reduces potassium loss associated with the diuretic effect. Combining an ACE inhibitor with a thiazide diuretic results in a synergistic effect and also reduces the risk of diuretic-induced hypokalemia.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Two large randomized controlled trials ("ONTARGET" [telmisartan alone and in combination with ramipril] and "VA NEPHRON-D" [patients with diabetic nephropathy]) evaluating the use of a combination of an ACE inhibitor with angiotensin II receptor blockers have been reported.

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

These studies did not demonstrate a beneficial effect on renal function and/or cardiovascular complications and mortality, but an increased risk of hyperkalemia, acute renal failure, and/or hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these findings are also applicable to other ACE inhibitors and angiotensin II receptor blockers.

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

The "ALTITUDE" trial (aliskiren use in type 2 diabetes with cardiovascular and renal endpoints) evaluated the benefits of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was prematurely terminated due to an increased risk of adverse outcomes. Cardiovascular death, stroke, and serious adverse events (hyperkalemia, hypotension, and renal impairment) occurred more frequently with aliskiren than with placebo.

Non-melanoma skin cancer

Results from two pharmacoepidemiological studies based on data from the Danish National Cancer Registry demonstrated a cumulative dose-dependent association between hydrochlorothiazide and the occurrence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). One study included a population of 71,533 patients with BCC and 8,629 patients with SCC, whose data were compared with those of 1,430,833 and 172,462 control subjects, respectively. High-dose hydrochlorothiazide use (cumulative dose ≥ 50,000 mg) was associated with an adjusted risk coefficient (RR) of 1.29 (95% confidence interval [CI]: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear cumulative dose-dependent association was observed for both BCC and SCC. Another study indicated a possible association between lip cancer (SCC) and hydrochlorothiazide use: data from 633 cases of lip cancer (SCC) were compared with data from 63,067 control subjects using a random sampling strategy. A cumulative dose-dependent association was demonstrated with an adjusted RR of 2.1 (95% CI: 1.7–2.6), increasing to RR 3.9 (3.0–4.9) for high doses (~25,000 mg) and RR 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see section "Special precautions for use").

Pharmacokinetics.

Ramipril

After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract. Absorption is 50–60% and is independent of food intake. Maximum plasma concentration is reached within 1 hour. The elimination half-life of ramipril is 1 hour. Ramipril is metabolized in the liver. The main metabolite is ramiprilat, which is 6 times more potent as an angiotensin-converting enzyme inhibitor than ramipril. Maximum plasma concentration of ramiprilat is reached 2–4 hours after administration, and steady-state plasma concentration is achieved within 4 days.

Approximately 73% of ramipril and 56% of ramiprilat are bound to plasma proteins.

Ramipril and ramiprilat are primarily excreted in urine (approximately 60%), mainly as metabolites, with less than 2% of the administered dose excreted unchanged as ramipril.

Ramiprilat is eliminated in multiple phases. After administration of ramipril at therapeutic doses, the terminal elimination half-life ranges from 13 to 17 hours.

In patients with renal impairment, elimination of ramipril, ramiprilat, and their metabolites is delayed; therefore, dosage adjustment is required according to renal function (see section "Dosage and administration").

In patients with hepatic impairment, metabolic conversion of ramipril to ramiprilat may be slowed due to reduced activity of hepatic esterases, resulting in increased serum concentration of ramipril (see section "Dosage and administration").

Hydrochlorothiazide

After oral administration, approximately 70% of hydrochlorothiazide is absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 1.5–5 hours. It is approximately 40% bound to plasma proteins. Hydrochlorothiazide undergoes minimal hepatic metabolism. 95% of hydrochlorothiazide is excreted unchanged by the kidneys. Excretion occurs via tubular secretion. After a single oral dose, 50–70% is excreted within 24 hours. The elimination half-life ranges from 5 to 6 hours.

Patients with impaired renal function (see section "Dosage and administration")

Renal excretion of hydrochlorothiazide is reduced in patients with impaired renal function; hydrochlorothiazide clearance is proportional to creatinine clearance. This leads to increased plasma concentrations of hydrochlorothiazide, which decline more slowly than in patients with normal renal function.

Patients with impaired hepatic function (see section "Dosage and administration")

The pharmacokinetics of hydrochlorothiazide were not significantly altered in patients with liver cirrhosis. The pharmacokinetics of hydrochlorothiazide have not been studied 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 with this combination have not been conducted. Reproductive toxicity studies showed that the combination is slightly more toxic than either active substance alone, but none of the studies demonstrated teratogenic effects of the combination.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to ramipril or other angiotensin-converting enzyme (ACE) inhibitors, hydrochlorothiazide, other thiazide diuretics, sulfonamides, or to any other component of the medicinal product;
• Hepatic encephalopathy, severe impairment of liver function;
• Hypotension or hemodynamically unstable state;
• Anuria;
• History of angioedema (hereditary, idiopathic, or previously experienced during treatment with ACE inhibitors or angiotensin II receptor antagonists);
• Primary hyperaldosteronism;
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see "Interaction with other medicinal products and other forms of interaction");
• Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney;
• Severe renal impairment (creatinine clearance < 30 mL/min) in patients not undergoing hemodialysis;
• Clinically significant electrolyte imbalances that may worsen after treatment with the medicinal product;
• Symptomatic hyperuricemia (gout);
• Pregnancy or planned pregnancy (see "Use in pregnancy or lactation");
• Breastfeeding (see "Use in pregnancy or lactation").

Concomitant use with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) (see "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

Concomitant use with sacubitril/valsartan is contraindicated. Ampril® HL must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

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

Contraindicated combinations

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see "Contraindications", "Special precautions for use").

Extracorporeal treatments leading to contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate, increase the risk of severe anaphylactoid reactions. If such treatment is required, a decision should be made to use a different type of dialysis membrane or another class of antihypertensive agents.

Combinations requiring caution

Potassium salts, heparin, potassium-sparing diuretics, and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim, tacrolimus, cyclosporine): although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving ramipril/hydrochlorothiazide. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium concentration. Caution should also be exercised when ramipril/hydrochlorothiazide is used concomitantly with other agents that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic, similar to amiloride. Therefore, combination of ramipril/hydrochlorothiazide with the above-mentioned agents is not recommended. If concomitant use is indicated, it should be done with caution and frequent monitoring of serum potassium levels.

Co-trimoxazole (trimethoprim/sulfamethoxazole): increased risk of hyperkalemia in patients receiving co-trimoxazole (trimethoprim/sulfamethoxazole) concomitantly (see "Special precautions for use").

Antihypertensive agents (e.g., diuretics) and other substances that may reduce blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, large amounts of alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): potential for hypotension should be anticipated (see section "Dosage and administration").

Vasoconstrictive sympathomimetics and other active substances (epinephrine) that may reduce the antihypertensive effect of ramipril: blood pressure monitoring is recommended.

In addition, the effect of vasopressor sympathomimetics may be diminished by hydrochlorothiazide.

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

Litium salts: lithium excretion may be reduced by ACE inhibitors, potentially increasing lithium toxicity. Serum lithium levels should be monitored. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and further enhance the already elevated risk due to ACE inhibitors. Therefore, combination of ramipril and hydrochlorothiazide with lithium is not recommended.

Antidiabetic agents, including insulin: hypoglycemic reactions may occur. Hydrochlorothiazide may potentiate the effect of antidiabetic agents; therefore, careful monitoring of blood glucose is recommended, especially during initial treatment.

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid: reduced antihypertensive effect of Ampril® HL should be anticipated. Moreover, concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function and hyperkalemia.

Oral anticoagulants: anticoagulant effect may be reduced due to concomitant use of hydrochlorothiazide.

Corticosteroids, adrenocorticotropic hormone, amphotericin B, carbenoxolone, large amounts of licorice, laxatives (in case of prolonged use), and other potassium-wasting agents and agents that reduce plasma potassium levels: increased risk of hypokalemia.

Cardiac glycosides, active substances known to prolong the QT interval, and antiarrhythmic agents: their proarrhythmic toxicity may be increased or their antiarrhythmic effect reduced in the presence of electrolyte imbalances (e.g., hypokalemia or hypomagnesemia).

Methyldopa: hemodialysis may be required.

Cholestyramine or other enteral ion-exchange substances: absorption of hydrochlorothiazide is reduced. Sulfonamide diuretics should be taken at least 1 hour before or 4–6 hours after administration of these agents.

Muscle relaxants, curare-like agents: possible potentiation and prolongation of muscle relaxation effect.

Calcium salts and medicinal products that increase plasma calcium levels: increased serum calcium concentration should be anticipated during concomitant administration of hydrochlorothiazide; therefore, careful monitoring of serum calcium levels is necessary.

Carbamazepine: risk of symptomatic hyponatremia due to additive effect of hydrochlorothiazide.

Contrast media containing iodine: in cases of dehydration caused by diuretics, including hydrochlorothiazide, there is an increased risk of acute renal failure, especially with high doses of contrast agent.

Penicillin: hydrochlorothiazide is secreted into the distal tubules of the nephron and slows penicillin excretion.

Quinine: hydrochlorothiazide slows quinine excretion.

Cyclosporine: hyperkalemia may develop when ACE inhibitors are used concomitantly with cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin: hyperkalemia may develop when ACE inhibitors are used concomitantly with heparin. Monitoring of serum potassium levels is recommended.

mTOR (mammalian target of rapamycin) inhibitors or vildagliptin: increased risk of angioedema in patients receiving concomitant therapy with mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin. Initiation of such therapy should be done cautiously (see "Special precautions for use").

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

Special precautions for use.

Special patient groups

• Pregnancy: treatment with angiotensin-converting enzyme (ACE) inhibitors such as ramipril or angiotensin II receptor antagonists (ARBs) should not be initiated during pregnancy. If antihypertensive therapy is considered necessary, women planning pregnancy should switch to alternative treatments with established safety profiles during pregnancy. If pregnancy is confirmed while taking Ampril® HL, treatment should be discontinued immediately and, if necessary, alternative therapy initiated (see sections "Interaction with other medicinal products and other forms of interaction" and "Contraindications").

• Patients at risk of arterial hypotension

• Patients with increased activity of the renin-angiotensin-aldosterone system (RAAS)

Patients with increased RAAS activity are at risk of significant blood pressure reduction and worsening renal function due to ACE inhibition. This is particularly relevant when initiating ACE inhibitor therapy or concomitant diuretic therapy, or when increasing their doses.

Significant RAAS activation should be anticipated, requiring medical supervision including blood pressure monitoring, for example in patients:

• with severe arterial hypertension;
• with decompensated heart failure with signs of congestion;
• with hemodynamically significant obstruction of inflow or outflow from the left ventricle (e.g. aortic or mitral valve stenosis);
• with unilateral renal artery stenosis and a functioning contralateral kidney;
• who have or may develop fluid and electrolyte imbalance (including patients taking diuretics);
• with liver cirrhosis and/or ascites;
• undergoing major surgery or receiving anesthesia with agents that may cause arterial hypotension.

Generally, appropriate treatment for dehydration, hypovolemia, or electrolyte depletion should be administered before initiating therapy (however, in patients with heart failure, such corrective measures should be carefully weighed against the risk of volume overload).

• Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

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

If 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.

• Unstable or stable heart failure following myocardial infarction.
• Patients at risk of cardiac or cerebral ischaemia in case of acute arterial hypotension

The initial phase of treatment requires special medical supervision.

• Primary hyperaldosteronism

The combination of ramipril and hydrochlorothiazide is not a preferred treatment for primary hyperaldosteronism. If ramipril/hydrochlorothiazide combination is used in patients with primary hyperaldosteronism, plasma potassium levels should be carefully monitored.

• Elderly patients

Initial doses should be lower and subsequent dose titration more gradual, due to increased likelihood of adverse effects, especially in frail elderly patients.

• Patients with hepatic disorders

In patients with liver disease, electrolyte imbalances caused by diuretic therapy, including hydrochlorothiazide, may lead to hepatic encephalopathy.

Surgery

It is recommended to discontinue ACE inhibitors such as ramipril at least 1 day prior to surgery, if possible.

Monitoring of renal function

Renal function should be assessed before and during treatment, and dose adjustments made accordingly, especially during the first weeks of therapy. Careful monitoring is particularly required in patients with impaired renal function (see section "Dosage and administration"). There is a risk of worsening renal function, particularly in patients with congestive heart failure or after kidney transplantation, as well as in patients with renovascular disease, including those with hemodynamically significant unilateral renal artery stenosis.

Renal impairment

In patients with impaired renal function, thiazides may lead to uraemia. Cumulative effects of active substances may develop in patients with impaired renal function. If progression of renal impairment becomes evident, as indicated by increasing blood urea nitrogen levels, careful re-evaluation of therapy is required, including consideration of discontinuing diuretic therapy (see section "Contraindications").

Electrolyte imbalance

As with any patient receiving diuretic therapy, plasma electrolyte levels should be periodically measured at appropriate intervals. Thiazides, including hydrochlorothiazide, may cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Although hypokalaemia may occur with thiazide diuretics, concomitant ramipril therapy may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients with liver cirrhosis, those undergoing rapid diuresis, those receiving inadequate electrolyte intake, and those receiving concomitant corticosteroid or adrenocorticotropic hormone therapy (see section "Interaction with other medicinal products and other forms of interaction"). The first measurement of plasma potassium should be performed within the first week after starting treatment. If low potassium levels are detected, dose adjustment is required.

Dilutional hyponatraemia may occur. Decreased sodium levels may initially be asymptomatic, making regular monitoring essential. More frequent testing is recommended in elderly patients and patients with liver cirrhosis.

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

Hyperkalaemia

ACE inhibitors may cause hyperkalaemia due to inhibition of aldosterone release. This effect is usually not significant in patients with normal renal function. Hyperkalaemia has been observed in some patients taking ACE inhibitors, including Ampril® HL. Risk factors for hyperkalaemia include: renal impairment; age over 70 years; uncontrolled diabetes mellitus; concomitant use of potassium salts, potassium-sparing diuretics, or other agents that increase plasma potassium levels, or agents associated with increased serum potassium (e.g. heparin, trimethoprim or co-trimoxazole, also known as trimethoprim/sulfamethoxazole combination), particularly aldosterone antagonists or angiotensin receptor blockers; and conditions such as dehydration, acute heart failure, or metabolic acidosis. Patients receiving ACE inhibitors should be used cautiously with potassium-sparing diuretics and angiotensin receptor blockers, and serum potassium and renal function should be monitored. If concomitant use of the above-mentioned agents is considered appropriate, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Hyponatraemia

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) and subsequent hyponatraemia has been observed in some patients taking ramipril. Regular monitoring of plasma sodium levels is recommended in elderly patients and those at risk of hyponatraemia.

Hepatic encephalopathy

Electrolyte imbalances due to diuretic therapy, including hydrochlorothiazide, may precipitate hepatic encephalopathy in patients with liver disease. If hepatic encephalopathy occurs, treatment should be discontinued immediately.

Hypercalcaemia

Hydrochlorothiazide enhances renal calcium reabsorption and may cause hypercalcaemia. This may affect parathyroid function test results.

Hypersensitivity / angioedema

Angioedema has been reported in patients taking ACE inhibitors, including ramipril (see section "Adverse reactions").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Treatment with sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of ramipril/hydrochlorothiazide. Treatment with ramipril/hydrochlorothiazide should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see "Adverse reactions", "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus), or vildagliptin increases the risk of angioedema (including airway or tongue swelling with or without respiratory distress) (see "Interaction with other medicinal products and other forms of interaction"). Caution is advised when using racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving an ACE inhibitor.

In case of angioedema, Ampril® HL should be discontinued.

Immediate emergency treatment should be initiated. The patient should remain under medical supervision for at least 12–24 hours until symptoms have completely resolved.

Intestinal angioedema has been reported in patients taking ACE inhibitors, including Ampril® HL (see section "Adverse reactions"). These patients presented with abdominal pain (with or without nausea and vomiting). Symptoms of intestinal angioedema resolve after discontinuation of the ACE inhibitor.

Anaphylactic reactions during desensitization

The use of ACE inhibitors increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom or other allergens. These reactions resolve when Ampril® HL is temporarily discontinued prior to desensitization.

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis has been rarely observed; bone marrow suppression has also been reported. Leukocyte counts should be monitored to detect possible leukopenia. More frequent monitoring is recommended during initial treatment, and in patients with renal impairment, those with concomitant collagenosis (e.g. systemic lupus erythematosus or scleroderma), and those receiving other medicinal products that may affect blood counts (see sections "Adverse reactions" and "Interaction with other medicinal products and other forms of interaction").

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

Hydrochlorothiazide is a sulfonamide derivative. Sulfonamides and sulfonamide derivatives may cause idiosyncratic reactions 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 medication.

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

Ethnic differences

ACE inhibitors cause a higher incidence of angioedema in black patients compared to other ethnic groups. This may be due to the higher prevalence of low-renin hypertension in black patients with arterial hypertension.

Cough

Cough has been reported during ACE inhibitor therapy. It is typically non-productive, persistent, and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be differentiated from other types of cough.

Athletes

Hydrochlorothiazide may cause a positive doping test.

Metabolic and endocrine effects

Thiazide therapy may affect glucose tolerance. Patients with diabetes may require insulin or oral hypoglycaemic agent dose adjustments. Latent diabetes mellitus may become manifest during thiazide therapy.

Increased cholesterol and triglyceride levels have been associated with thiazide diuretic therapy.

In some patients, thiazide diuretics may precipitate hyperuricaemia or acute gout attacks.

Non-melanoma skin cancer (NMSC)

An increased risk of non-melanoma skin cancer (NMSC) with increasing cumulative dose of hydrochlorothiazide was identified in two pharmacoepidemiological studies (see section "Pharmacological properties"). The photosensitizing effect of hydrochlorothiazide may be a mechanism underlying this condition.

Patients taking hydrochlorothiazide, alone or in combination with other medicinal products, should be informed about the risk of NMSC (especially with long-term use), the need for regular skin examination, and the importance of promptly reporting any new or changing skin lesions/moles or suspicious skin growths to their physician. To reduce the risk of skin cancer, patients should avoid exposure to sunlight and UV radiation and adequately protect their skin when outdoors. Suspicious skin lesions should be evaluated promptly, including histological examination of biopsy material. The appropriateness of hydrochlorothiazide therapy should be reconsidered in patients with a history of NMSC.

Other

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

Acute respiratory toxicity

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

Special warnings regarding inactive ingredients

The product contains lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

The medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and, if necessary, replaced with another medicinal product permitted during pregnancy.

The medicinal product is contraindicated during breastfeeding.

Ability to affect reaction speed when driving or operating machinery

Especially at the beginning of treatment, during dose escalation, when switching medicinal products, and depending on individual response to treatment, adverse reactions (such as reduced blood pressure, dizziness) may occur. In such cases, patients should refrain from driving or operating machinery for several hours after taking the medicinal product.

Method of Administration and Dosage

Fixed-dose combination of ramipril and hydrochlorothiazide should be used only after prior individual titration of doses and monitoring of arterial pressure.

Treatment should be initiated at the lowest possible dose. If necessary, the daily dose may be gradually increased over 2–3 weeks until the target blood pressure level is achieved. The usual maintenance dose is 2.5 mg ramipril and 12.5 mg hydrochlorothiazide once daily in the morning. The maximum dose is 5 mg ramipril and 25 mg hydrochlorothiazide per day.

The drug should be taken once daily at the same time each day, preferably in the morning. It may be taken before, during, or after meals, as food intake does not affect the bioavailability of the drug. The tablet must not be chewed or crushed but should be swallowed whole with liquid.

Missed Doses

If a dose is missed, it should be taken as soon as possible. However, if the missed dose is noticed close to the time of the next scheduled dose, the missed dose should not be taken; instead, the patient should continue with the regular dosing schedule. The dose should not be doubled.

Patients Receiving Diuretics

Special attention should be paid to patients who are concurrently receiving diuretics, as arterial hypotension may develop after initiation of treatment. Prior to starting therapy with this drug, it is recommended to reduce the dose of the diuretic or discontinue its use.

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").

Patients with renal impairment may require dose reduction of Amlipril® HL. Patients with creatinine clearance levels between 30 and 60 mL/min should only be treated with the fixed combination of the lowest doses of ramipril and hydrochlorothiazide, following monotherapy with ramipril. The maximum permitted daily doses are 5 mg ramipril and 25 mg hydrochlorothiazide.

Patients with Hepatic Impairment

In patients with mild to moderate hepatic impairment, treatment should be initiated under close medical supervision. The maximum daily doses are 2.5 mg ramipril and 12.5 mg hydrochlorothiazide.

Amlipril® HL is contraindicated in cases of severe hepatic impairment (see section "Contraindications").

Elderly Patients

The initial dose should be lower, and subsequent dose titration should be more gradual due to the increased risk of adverse reactions, especially in frail patients aged 70 years and older.

Children

The drug 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

Depending on the degree of overdose, the following symptoms may occur: excessive peripheral vasodilation (with marked arterial hypotension, shock), impaired consciousness up to coma and cerebral convulsions, paresis, arrhythmia, bradycardia, acute renal failure, electrolyte imbalance, and paralytic intestinal obstruction.

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

Careful monitoring of the patient is essential.

Treatment is symptomatic and supportive. In case of hypotension, the patient should be placed in a supine position with the head lowered and legs elevated. Gastric lavage and administration of adsorbents and sodium sulfate are recommended (within the first 30 minutes, if possible). Careful monitoring of blood pressure, renal function, and serum potassium levels is required. If necessary, plasma volume should be expanded by intravenous infusion of 0.9% NaCl solution. In addition to volume and electrolyte replacement, catecholamines and angiotensin II may be administered. Ramipril is poorly removed by dialysis.

In case of persistent bradycardia, treatment with cardiac pacing should be initiated. Continuous monitoring of electrolyte and acid-base balance, glucose levels, and other blood constituents is essential. In case of hypokalemia, potassium replacement therapy should be administered.

In the event of life-threatening angioedema, emergency treatment should include subcutaneous injection of 0.3–0.5 mg epinephrine (adrenaline) or slow intravenous administration of adrenaline (according to dilution instructions!) with continuous ECG monitoring and blood pressure measurement. Systemic glucocorticoids should be administered subsequently. Intravenous antihistamines and H2-receptor antagonists are also recommended.

Adverse Reactions

The safety profile of the ramipril and hydrochlorothiazide combination includes adverse reactions associated with hypotension and/or hypovolemia due to enhanced diuresis. The active substance ramipril may cause a persistent dry cough, and the active substance hydrochlorothiazide may affect glucose, lipid, and uric acid metabolism. The two active substances have opposing effects on plasma potassium levels. Serious adverse reactions include angioedema or anaphylactic reaction, impairment of renal or hepatic function, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

The frequency of adverse reactions was determined using the following classification:

• Very common (≥1/10);
• Common (≥1/100 to <1/10);
• Uncommon (≥1/1,000 to <1/100);
• Rare (≥1/10,000 to <1/1,000);
• Very rare (<1/10,000);
• Not known (cannot be estimated from available data).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

1 Non-melanoma skin cancer: according to data from epidemiological studies, there is a cumulative dose-dependent association between hydrochlorothiazide and non-melanoma skin cancer (see "Special precautions for use" and "Pharmacological properties").

Reporting of suspected adverse reactions

Reporting of adverse reactions after registration of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 30 °C. Keep out of reach and sight of children.

Packaging.

10 tablets per blister; 3, 6, or 9 blisters per carton.

7 tablets per blister; 2, 4, 8, 12, or 14 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and location of its business operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.