Laceran nst

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LACERAN HCT (LACERANHCT)

Composition:

Active substances: ramipril, hydrochlorothiazide;

One tablet contains ramipril 2.5 mg and hydrochlorothiazide 12.5 mg or ramipril 5 mg and hydrochlorothiazide 25 mg;

Excipients:

LACERAN HCT 2.5 mg/12.5 mg: hypromellose, microcrystalline cellulose (Avicel PH 112), microcrystalline cellulose (Avicel PH 101), pregelatinized starch, sodium stearyl fumarate;

LACERAN HCT 5 mg/25 mg: hypromellose, microcrystalline cellulose (Avicel PH 112), microcrystalline cellulose (Avicel PH 101), pregelatinized starch, sodium stearyl fumarate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

LACERAN HCT 2.5 mg/12.5 mg: elongated tablets of white or almost white color with markings “R” and “21” on both sides of the break line on one side and a break line on the other side.

LACERAN HCT 5 mg/25 mg: elongated tablets of white or almost white color with markings “R” and “22” on both sides of the break line on one side and a break line on the other side.

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

Pharmacological Properties

Mechanism of Action

Ramipril. Ramiprilat, the active metabolite of the prodrug ramipril, is an inhibitor of 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, and the degradation of bradykinin, a potent vasodilator. By reducing the formation of angiotensin II and inhibiting the breakdown of bradykinin, ramiprilat leads to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. In patients of non-Caucasian race (of Afro-Caribbean origin) with arterial hypertension (a population typically characterized by low renin activity), the response to monotherapy with ACE inhibitors has generally been less pronounced than in patients of other racial groups.

Hydrochlorothiazide. Hydrochlorothiazide is a thiazide diuretic. The precise mechanism of its antihypertensive action has not yet been fully elucidated. Thiazide diuretics inhibit the reabsorption of sodium and chloride ions in the distal renal tubules. Increased renal excretion of these ions is accompanied by enhanced diuresis (due to osmotic water retention). Excretion of potassium and magnesium is also increased, whereas excretion of uric acid is reduced. Possible mechanisms of the antihypertensive effect of hydrochlorothiazide include changes in sodium balance, reduction in extracellular fluid and plasma volume, alterations in renal vascular resistance, or decreased responsiveness to norepinephrine and angiotensin II.

Pharmacodynamics

Ramipril. Administration of ramipril results in a significant reduction in peripheral arterial resistance. Generally, no major changes in renal plasma flow or glomerular filtration rate (GFR) occur. In patients with arterial hypertension, ramipril reduces blood pressure in both supine and upright positions, without compensatory increases in heart rate.

In most patients, the antihypertensive effect begins approximately 1–2 hours after oral administration of a single dose. The maximum effect after a single oral dose is usually achieved within 3–6 hours. The antihypertensive effect following a single dose typically lasts for 24 hours.

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

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

Hydrochlorothiazide. For hydrochlorothiazide, the onset of diuretic effect occurs approximately 2 hours after administration and lasts for 6–12 hours, with peak effect reached at about 4 hours.

The antihypertensive effect begins within 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 alone. The concomitant use of ramipril and hydrochlorothiazide reduces potassium loss associated with the diuretic effect, likely due to suppression of the renin-angiotensin-aldosterone system (RAAS). Combining an ACE inhibitor with a thiazide diuretic produces a synergistic effect and also reduces the risk of diuretic-induced hypokalemia.

Clinical Efficacy and Safety

Essential mild to moderate hypertension. The efficacy of the combination ramipril + 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 of 2.5 to 10 mg) and hydrochlorothiazide (at doses of 12.5 mg or 25 mg), administered separately and in combination. The study drugs were given for 6 weeks following a 2–4 week placebo lead-in period. Efficacy was assessed by the reduction in blood pressure measured in the supine and standing positions from the end of the placebo period to the end of the study (last measurement for each patient). The antihypertensive dose of ramipril was confirmed to be 10 mg. Combination therapy with ramipril and hydrochlorothiazide provided statistically significant greater reductions in blood pressure compared to either ramipril or hydrochlorothiazide as monotherapy (p < 0.05 for most comparisons); ramipril 10 mg was more effective when combined 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 period followed by 12 weeks of active treatment. During the first 6 weeks of the active treatment phase, patients received either monotherapy with ramipril 10 mg or hydrochlorothiazide 50 mg. Efficacy was assessed by measuring SBP and DBP in both supine and standing positions. Treatment response was defined as a DBP ≤ 90 mm Hg in both supine and standing positions at the end of the first monotherapy phase. During the second phase of active treatment, patients who did not respond by 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 supine SBP was 15.5 mm Hg in the hydrochlorothiazide 50 mg group and 11.1 mm Hg in the ramipril 10 mg group; corresponding standing SBP reductions were 14.5 and 8.4 mm Hg. Mean reductions in supine DBP were 10.7 mm Hg in the hydrochlorothiazide 50 mg group and 9.0 mm Hg in the ramipril 10 mg group; corresponding standing DBP reductions 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 has demonstrated favorable protective effects on the cardiovascular system and kidneys that are independent of blood pressure reduction.

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

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

Table 1

HOPE Study: Key Results

Parameters	Ramipril, % (n = 4645)	Placebo, % (N = 4652)	Relative risk (95 % confidence interval)	p value
Events of the combined primary endpoint	14.0	17.8	0.78 (0.70–0.86)	< 0.001
Myocardial infarction	9.9	12.3	0.80 (0.70–0.90)	< 0.001
Death due to cardiovascular causes	6.1	8.1	0.74 (0.64–0.87)	< 0.001
Stroke	3.4	4.9	0.68 (0.56–0.84)	< 0.001
Secondary endpoints
Death from any cause	10.4	12.2	0.84 (0.75–0.95)	0.005
Need for revascularization	16.0	18.3	0.85 (0.77–0.94)	0.002
Hospitalization due to unstable angina	12.1	12.3	0.98 (0.87–1.10)	Not statistically significant
Hospitalization due to heart failure	3.2	3.5	0.88 (0.70–1.10)	0.25
Diabetes complications	6.4	7.6	0.84 (0.72–0.98)	0.03

Double blockade of the renin-angiotensin-aldosterone system (RAAS). Two large randomized controlled trials [ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (Veterans Affairs Nephropathy in Diabetes Trial)] evaluated 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 concomitant 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 outcomes and mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or arterial hypotension was observed compared to monotherapy. Given the similar pharmacodynamic characteristics 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. In the aliskiren group compared to the placebo group, there was a numerically higher incidence of cardiovascular death and stroke, as well as an increased frequency of serious adverse events (hyperkalemia, arterial hypotension, and renal dysfunction).

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), adjusted odds ratios (OR) were 1.29 (95% CI: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. For both BCC and SCC, a clear dose-effect relationship with cumulative dose was observed. 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). The 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 hydrochlorothiazide dose (~25,000 mg) and to 7.7 (5.7–10.5) with the highest cumulative dose (~100,000 mg) (see also section "Special precautions").

Pharmacokinetics

Ramipril

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration of ramipril is reached within 1 hour. Based on the amount of substance 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%.

Maximum plasma concentration of ramiprilat, the sole active metabolite of ramipril, is reached 2–4 hours after ramipril intake. After administration of usual once-daily doses of ramipril, steady-state plasma concentration of ramiprilat is achieved after approximately 4 days of treatment.

Distribution. Plasma protein binding is approximately 73% for ramipril and 56% for ramiprilat.

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

Elimination. Metabolite excretion occurs predominantly via renal excretion. The decline in ramiprilat plasma concentration is multiphasic. Due to strong saturable binding to ACE and slow dissociation from the enzyme complex, ramiprilat exhibits a prolonged terminal elimination phase at very low plasma concentrations. The effective half-life of ramipril after repeated doses of 5–10 mg ramipril once daily is 13–17 hours, and longer with lower doses (1.25–2.5 mg). This difference is due to the saturable binding capacity of the enzyme for ramiprilat. After a single oral dose of ramipril, neither ramipril nor its metabolites were detected in breast milk. However, the effect of repeated dosing is unknown.

Patients with renal impairment (see section "Dosage and administration"). In patients with impaired renal function, renal excretion of ramiprilat is reduced, and 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 (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 such patients, increased plasma levels of ramipril are observed. However, maximum plasma concentration of ramiprilat in these patients does not differ from that in individuals with normal liver function.

Hydrochlorothiazide

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

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

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

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

Patients with renal impairment (see section "Dosage and administration"). In patients with impaired renal function, renal excretion of hydrochlorothiazide is reduced, and renal clearance of hydrochlorothiazide is proportional to creatinine clearance. This leads to 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 animals, 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 dosing in animals showed only disturbances in electrolyte balance. Mutagenicity and carcinogenicity studies of this combination were not performed, as administration of the individual components did not reveal any risks. Reproductive toxicity studies demonstrated that the combination is slightly more toxic than either active substance alone, but none of the studies showed teratogenic effects of this combination.

Ramipril

Extensive mutagenicity studies in several test models showed no evidence of mutagenic or genotoxic properties of ramipril.

Long-term studies in rats and mice did not reveal any tumorigenic effects.

Renal tubules with oxyphilic cells and tubules with oxyphilic cell hyperplasia in rats are considered a response to functional and morphological changes, not a neoplastic or pre-neoplastic reaction.

Hydrochlorothiazide

Hydrochlorothiazide was not genotoxic in vitro in the Ames test for mutagenicity using Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538, or in the Chinese hamster ovary (CHO) chromosomal aberration test, or in vivo in mouse sex cell chromosome analyses, Chinese hamster bone marrow cell chromosomes, and the sex-linked lethal test in Drosophila. Positive results were obtained only in in vitro sister chromatid exchange tests in CHO cells (clastogenicity) and in mouse lymphoma cell tests (mutagenicity) using hydrochlorothiazide concentrations from 43 to 1300 µg/mL, and in the Aspergillus nidulans nondisjunction test at undefined concentrations.

Two-year feeding studies in mice and rats conducted under the U.S. National Toxicology Program (NTP) showed no evidence of carcinogenic potential of hydrochlorothiazide in female mice (doses up to approximately 600 mg/kg/day) or in male and female rats (doses up to approximately 100 mg/kg/day). However, NTP found equivocal evidence of hepatocarcinogenicity in male mice.

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 the active substance ramipril or to other angiotensin-converting enzyme (ACE) inhibitors, hydrochlorothiazide, other thiazide diuretics, sulfonamides, or to any of the excipients of the medicinal product (see section "Composition").
• History of angioedema (hereditary, idiopathic, or previously experienced 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 (hemofiltration) that involve 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 forms of interaction").
• Significant bilateral renal artery stenosis or unilateral renal artery stenosis in the presence of a single functioning kidney.
• Severe renal impairment (creatinine clearance < 30 mL/min) in patients not undergoing hemodialysis.
• Clinically significant electrolyte imbalances that 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 impairment, hepatic encephalopathy.
• Pregnancy or planned pregnancy (see section "Use in pregnancy or breastfeeding").
• Breastfeeding period (see section "Use in pregnancy or breastfeeding").
• Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or in patients with moderate to severe renal impairment (creatinine clearance < 60 mL/min).
• Concomitant use with angiotensin II receptor antagonists in patients with diabetic nephropathy.
• Pediatric population (under 18 years of age).

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 renal dysfunction (including acute renal failure), compared to using a single RAAS-acting medicinal product (see sections "Pharmacodynamics", "Contraindications", and "Special warnings and precautions for use").

Food. Co-administration with food does not significantly affect the absorption of ramipril.

Contraindicated combinations

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections "Contraindications" and "Special warnings and 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 should not occur earlier than 36 hours after the last dose of Laceren NCT.

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 an alternative 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 in combination with sulfamethoxazole, tacrolimus, cyclosporine). Hyperkalemia may occur; therefore, plasma potassium levels should be closely monitored.

Antihypertensive medicinal products (e.g., diuretics) and other active substances that may lower 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 monitoring of blood pressure is recommended. Additionally, hydrochlorothiazide may reduce the effect of vasopressor sympathomimetics.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other substances that may alter blood parameters. Increased risk of hematological reactions (see section "Special 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 effectiveness of antidiabetic agents; therefore, blood glucose levels should be closely monitored at the beginning of concomitant therapy.

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. A reduced antihypertensive effect of Laceren NTS is expected. Moreover, concomitant use of ACE inhibitors and NSAIDs may be associated with an increased risk of renal dysfunction and elevated blood potassium levels.

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

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

Cardiac glycosides, active substances that may prolong the QT interval, antiarrhythmic agents. Proarrhythmic effects may be enhanced, and antiarrhythmic effects may be 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 monitoring are 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 that may cause polymorphic ventricular tachycardia (torsades de pointes), including certain antiarrhythmics, since hypokalemia is a risk factor for 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 may occur.

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 may occur.

Calcium salts and medicinal products that increase plasma calcium levels. Concomitant use with hydrochlorothiazide may increase plasma calcium concentration; therefore, plasma calcium levels should be closely monitored.

Carbamazepine. Risk of hyponatremia due to potentiation of hydrochlorothiazide's effect.

Contrast agents containing iodine. In cases of dehydration caused by diuretic use, 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 tubules of the nephron, 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 taking ACE inhibitors concomitantly with mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin. Caution should be exercised at the beginning of such therapy (see section "Special warnings and precautions for use").

Heparin. Increased serum potassium concentrations may occur.

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

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

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

Salt. Increased salt intake may reduce the antihypertensive effect of the medicinal product.

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). The effect of pressor amines may be reduced, but not to the extent that their use is contraindicated.

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

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

Influence of medicinal products on laboratory test results

Due to their effect on calcium metabolism, thiazides may affect the assessment of parathyroid gland function (see section "Special warnings and precautions for use").

Specific hypersensitivity. Due to ACE inhibition, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom are increased. This effect may also occur with other allergens.

Special precautions for use

Special patient groups

Pregnancy. Treatment with ACE inhibitors or angiotensin II receptor antagonists should not be initiated during pregnancy. Except in cases where continued treatment with an ACE inhibitor/angiotensin II receptor antagonist is absolutely necessary, women who are planning to become pregnant should be switched to alternative antihypertensive agents with an established safety profile during pregnancy. As soon as pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be immediately discontinued and, if necessary, replaced with another suitable medication (see sections "Contraindications" and "Use in pregnancy or lactation").

Double blockade of the renin-angiotensin-aldosterone system (RAAS). Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

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

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

Patients at high risk of hypotension

Patients with increased activity of the renin-angiotensin-aldosterone system (RAAS). Patients with increased RAAS activity are at risk of sudden, significant reduction in blood pressure and impaired renal function due to ACE inhibition. This is particularly relevant when an ACE inhibitor or a concomitant diuretic is initiated or its dose is increased for the first time. Increased RAAS activity requiring medical supervision, including continuous blood pressure monitoring, may be expected, for example, 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 contralateral kidney;
• with marked or latent fluid or electrolyte depletion (including patients receiving diuretics);
• with liver cirrhosis and/or ascites;
• undergoing major surgery or anesthesia with agents that may cause hypotension.

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

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

Surgery. If possible, treatment with ACE inhibitors such as ramipril should be discontinued one day before surgery.

Patients at risk of cardiac or cerebral ischemia due to acute 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 closely monitored.

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

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

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

Patients with impaired renal function. In patients with kidney disease, thiazides may precipitate sudden onset of uremia. Cumulative effects of active substances may occur in patients with impaired renal function. If progression of renal dysfunction becomes evident, as indicated by increasing 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 in all patients receiving diuretic therapy, plasma electrolyte levels should be measured regularly at appropriate intervals. Thiazides, including hydrochlorothiazide, may cause disturbances in water and electrolyte balance (hypokalemia, hyponatremia, and hypochloremic alkalosis).

Although hypokalemia may occur 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, patients with increased diuresis, patients receiving inadequate electrolyte intake, and patients receiving concomitant corticosteroids or ACTH (see section "Interaction with other medicinal products and other forms of interaction"). Plasma potassium levels should be determined at the beginning of treatment. If low potassium levels are detected, correction is required.

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

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

Monitoring of electrolytes: hyperkalemia Hyperkalemia has been observed in some patients receiving ACE inhibitors such as the medicinal product Laceren NCT. Patients at risk of hyperkalemia include those with renal impairment, elderly patients (aged 70 years or older), patients with untreated or poorly controlled diabetes mellitus, patients taking potassium salts, potassium-sparing diuretics, or other active substances that increase plasma potassium levels, or patients with conditions such as dehydration, acute heart decompensation, or metabolic acidosis. If concomitant use of these agents is indicated, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Monitoring of electrolyte levels: hyponatremia. In some patients receiving ramipril, syndrome of inappropriate antidiuretic hormone secretion (SIADH) with subsequent hyponatremia has been observed. Regular monitoring of plasma sodium levels is recommended in elderly patients and other patients at risk of developing hyponatremia.

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

Hypercalcemia. Hydrochlorothiazide enhances calcium reabsorption in the kidneys, which may lead to hypercalcemia. This may interfere with tests assessing parathyroid function.

Angioedema. Angioedema has been reported in patients taking ACE inhibitors, including ramipril (see section "Undesirable effects"). The risk of angioedema (e.g., swelling of the airways or tongue, regardless of presence or absence of respiratory distress) may be increased in patients concomitantly taking medicinal products capable of causing angioedema, such as mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, everolimus, sirolimus), vildagliptin, or neprilysin inhibitors (such as racecadotril). Combination therapy with ramipril and sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

In case of angioedema, treatment with Laceren NCT 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 observed in patients receiving ACE inhibitors such as the medicinal product Laceren NCT (see section "Undesirable effects"). These patients presented with abdominal pain (with or without nausea/vomiting). Symptoms of intestinal angioedema resolved after discontinuation of the ACE inhibitor.

Anaphylactic reactions during desensitization. The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased during ACE inhibitor therapy. Prior to undergoing desensitization, treatment with Laceren NCT should be temporarily discontinued.

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

Choroidal effusion, acute myopia, and angle-closure glaucoma. Hydrochlorothiazide, a sulfonamide derivative, may cause idiosyncratic reactions leading to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma. Symptoms are characterized by acute onset of decreased visual acuity or eye pain and typically develop within hours to weeks after starting 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 black patients than in patients of other races. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in black patients 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 therapy may impair glucose tolerance. In some patients with diabetes mellitus, dose adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus may become manifest during thiazide therapy.

Thiazide diuretic therapy may be associated with increased cholesterol and triglyceride levels. In some patients, thiazide diuretics may precipitate hyperuricemia or acute gout attacks.

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

Non-melanoma skin cancer. Two epidemiological studies based on data from the Danish National Cancer Registry have shown an increased risk of non-melanoma skin cancer [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide. A possible mechanism for the development of non-melanoma skin cancer may be the photosensitizing effect of hydrochlorothiazide.

Patients taking hydrochlorothiazide should be informed about the risk of non-melanoma skin cancer and advised to regularly check their skin for new lesions and to 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 evaluated, including biopsy with histological examination. Patients with a history of non-melanoma skin cancer may also require reassessment of the continued need for hydrochlorothiazide (see also section "Undesirable effects").

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

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

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use in pregnancy or lactation

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

Lactation. The medicinal product Laceren NCT 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. Since adequate data on the use of ramipril during breastfeeding are lacking, it is preferable to use other medicinal products with a more favorable safety profile during lactation, especially when breastfeeding newborns or preterm infants. Hydrochlorothiazide passes into breast milk. Use of thiazides in breastfeeding mothers has been associated with reduced or even complete cessation of milk production. Increased sensitivity to sulfonamide derivatives, hypokalemia, and kernicterus may occur. Because use of both active substances may cause serious adverse reactions in breastfed infants, a decision should be made whether to discontinue breastfeeding or discontinue/modify therapy, depending on the importance of the treatment for the mother.

Ability to influence reaction speed when driving or operating machinery

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., when driving vehicles or operating machinery).

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

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 medication can 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 (to achieve the required dosage, a combination of medications in appropriate strengths should be used).

Special Patient Groups

Patients Receiving Diuretics
Caution is recommended, as patients receiving diuretics may experience arterial hypotension at the start of treatment with this medication. Before initiating therapy, the diuretic dose should be reduced or its administration discontinued. If discontinuation of the diuretic is not feasible, treatment should begin 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 medication is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications"). Lower doses of the medication may be indicated in patients with renal impairment. 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.

Patients with Hepatic Impairment
Treatment should be initiated only under close medical supervision in patients with mild to moderate hepatic impairment. The maximum daily dose in such cases is 2.5 mg ramipril and 12.5 mg hydrochlorothiazide. The 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, as there is insufficient data on its 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 intestinal obstruction.

Overdose with hydrochlorothiazide may lead to acute urinary retention in predisposed patients (e.g., those with benign prostatic hyperplasia), tachycardia, weakness, dizziness, muscle spasms, polyuria, oliguria, anuria, hypokalemia, hyponatremia, hypochloremia, alkalosis, and elevated blood urea nitrogen (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), as well as interventions aimed at restoring stable hemodynamics, including fluid and electrolyte replacement, and administration of alpha-1 adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed by hemodialysis.

Adverse reactions

The safety profile of ramipril/hydrochlorothiazide includes adverse reactions resulting from arterial hypotension and/or reduction of circulating blood volume due to increased diuresis. The active substance ramipril may cause a persistent cough, whereas the active substance hydrochlorothiazide may disturb 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 (≥ 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 the available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

System organ classes	Common	Uncommon	Very rare	Not known
Cardiac disorders		Myocardial ischaemia, including angina; tachycardia; arrhythmia; palpitations; peripheral oedema		Myocardial infarction, orthostatic hypotension
Blood and lymphatic system disorders		Decreased leukocyte count, decreased erythrocyte count, decreased haemoglobin level, haemolytic anaemia, decreased platelet count	Aplastic anaemia	Bone marrow suppression; neutropenia, including agranulocytosis, pancytopenia, eosinophilia; haemoconcentration in case of fluid retention
Nervous system disorders	Headache, dizziness	Vertigo, paraesthesia, tremor, impaired balance, burning sensation, dysgeusia, ageusia		Cerebral ischaemia, including ischaemic stroke and transient ischaemic attack; psychomotor impairment, parosmia
Eye disorders		Visual disturbances, including blurred vision, conjunctivitis		Xanthopsia, decreased lacrimation due to hydrochlorothiazide, choroidal effusion, secondary acute angle-closure glaucoma and/or acute myopia due to hydrochlorothiazide
Ear and labyrinth disorders		Tinnitus		Hearing impairment
Respiratory, thoracic and mediastinal disorders	Non-productive irritating cough, bronchitis	Sinusitis, dyspnoea, nasal congestion	Acute respiratory distress syndrome (ARDS) (see section "Special warnings and precautions for use")	Bronchospasm, including exacerbation of bronchial asthma; allergic alveolitis; respiratory distress, including pneumonitis and non-cardiogenic pulmonary oedema 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, diarrhoea, upper abdominal pain, dry mouth	Pancreatitis (in isolated cases fatal outcomes have been reported with ACE inhibitors), increased pancreatic enzyme levels, angioneurotic oedema of the small intestine, sialadenitis due to hydrochlorothiazide
Renal and urinary disorders		Renal function impairment, including acute renal failure; increased urine output; increased 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, tetany 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, increased uric acid levels, gout exacerbation, increased cholesterol and/or triglycerides due to hydrochlorothiazide	Anorexia, decreased appetite, decreased plasma potassium, thirst due to hydrochlorothiazide	Increased plasma potassium due to ramipril	Decreased plasma sodium, glucosuria, metabolic alkalosis, hypochloraemia, hypomagnesaemia, hypercalcaemia, dehydration, hypochloraemic alkalosis which may precipitate 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		Prostration
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 very rare cases with fatal outcome), increased levels of liver enzymes and/or conjugated bilirubin, cholelithiasis cholecystitis due to hydrochlorothiazide		Acute liver failure, cholestatic jaundice, liver cell damage
Reproductive system and breast disorders		Transient erectile impotence		Decreased libido, gynaecomastia
Psychiatric disorders		Depressed mood, apathy, anxiety, restlessness, sleep disturbances, including somnolence		Confusion, agitation, attention disturbances
Neoplasms benign, malignant and unspecified (including cysts and polyps)				Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) due to cumulative dose of hydrochlorothiazide (dose-effect relationship) (see also sections "Pharmacological properties" and "Special warnings and precautions for use")

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

Shelf life. 2 years.

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

Keep out of reach and sight of children.

Packaging. 7 tablets in a blister pack, 1 or 3 blisters per cardboard box;
10 tablets in a blister pack, 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer

Sun Pharmaceutical Industries Limited.

Manufacturer's location and address of place of business

V. Ganguwala, Paonta Sahib, District Sirmour, Himachal Pradesh 173025, India.