Tratace plus® 5 mg/12.5 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRITACE PLUSÒ 5 mg/12.5 mg (TRITACE PLUSÒ 5 mg/12.5 mg) TRITACE PLUSÒ 10 mg/12.5 mg (TRITACE PLUSÒ 10 mg/12.5 mg)

Composition:

Active substances: ramipril, hydrochlorothiazide;

One tablet contains ramipril 5 mg and hydrochlorothiazide 12.5 mg or ramipril 10 mg and hydrochlorothiazide 12.5 mg;

Excipients:

Tritace PlusÒ 5 mg/12.5 mg: hypromellose, pregelatinized corn starch, microcrystalline cellulose, sodium stearyl fumarate, red iron oxide (E 172);

Tritace PlusÒ 10 mg/12.5 mg: hypromellose, pregelatinized corn starch, microcrystalline cellulose, sodium stearyl fumarate, red iron oxide (E 172), yellow iron oxide (E 172).

Pharmaceutical form. Tablets.

Main physicochemical properties:

Tritace PlusÒ 5 mg/12.5 mg: elongated pink-colored tablets with a dividing line on both sides. Upper imprint: 41/AV. Lower imprint: absent.

Tritace PlusÒ 10 mg/12.5 mg: elongated orange-colored tablets with a dividing line on both sides. Upper imprint: 42/AV. Lower imprint: absent.

Pharmacotherapeutic group. Combined preparations of angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors in combination with 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, or kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to angiotensin II, an active vasoconstrictor substance, and the degradation of bradykinin, which is an active vasodilator. Reduction in angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilation.

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

Hydrochlorothiazide. Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics has not yet been fully elucidated. These agents inhibit the reabsorption of sodium and chloride ions in the distal tubules. Enhanced renal excretion of these ions is accompanied by increased urine production (due to osmotic water retention). Excretion of potassium and magnesium is also increased, while excretion of uric acid is decreased. Possible mechanisms of the antihypertensive effect of hydrochlorothiazide include changes in sodium balance, reduction in extracellular fluid and plasma volume, changes 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 significant changes in renal plasma flow or glomerular filtration rate occur. In patients with arterial hypertension, ramipril administration leads to a reduction in 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 usually occurs within 3–6 hours. The antihypertensive effect after 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 during prolonged therapy, the antihypertensive effect is maintained for up to 2 years.

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

Hydrochlorothiazide. Regarding hydrochlorothiazide, the onset of diuretic effect occurs approximately 2 hours after administration and lasts for 6–12 hours, with maximum effect achieved within 4 hours.

The antihypertensive effect begins 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 glomerular filtration rate, renal vascular resistance, and plasma renin activity.

Concomitant use of ramipril and hydrochlorothiazide. Clinical studies have demonstrated that the use of this combination leads to a greater reduction in blood pressure than either active ingredient alone. Concomitant administration of ramipril and hydrochlorothiazide reduces potassium loss associated with the diuretic effect, likely due to suppression of the renin-angiotensin-aldosterone system activity. Combining an ACE inhibitor with a thiazide diuretic results in 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 drug Tritace PlusÒ was demonstrated in two studies involving patients with mild to moderate essential arterial hypertension. The objective of the first study (534 patients) was to determine the optimal dose by comparing ramipril (at doses from 2.5 mg to 10 mg) and hydrochlorothiazide (at doses of 12.5 mg or 25 mg) administered separately and in combination. The investigational drugs were administered for 6 weeks following a 2–4 week initial phase during which patients received placebo. Efficacy was assessed based on the reduction in blood pressure in the supine and standing positions from the end of the placebo phase to the study endpoint (last measurement for each patient). It was confirmed that the effective antihypertensive dose of ramipril is 10 mg. Combination therapy with ramipril and hydrochlorothiazide provided statistically significant greater blood pressure reduction compared to ramipril or hydrochlorothiazide as monotherapy (p < 0.05 for most comparisons); ramipril at a dose of 10 mg was more effective when used in combination with hydrochlorothiazide at doses of 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 at doses of 5 mg or 10 mg in combination with hydrochlorothiazide at doses of 12.5 mg or 25 mg.

The second study (192 patients) was a double-blind, randomized, parallel-group study with a 4-week initial phase during which patients received placebo, 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 determined by measuring SBP and DBP in both supine and standing positions. Treatment response was defined as 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 to therapy at the end of the 6-week monotherapy phase received unfixed combination therapy of ramipril 10 mg and hydrochlorothiazide 50 mg. At the end of the first 6-week monotherapy phase, mean reductions in SBP in the supine position were 15.5 mm Hg in the hydrochlorothiazide 50 mg group and 11.1 mm Hg in the ramipril 10 mg group; corresponding SBP values in the standing position were 14.5 and 8.4 mm Hg. Mean reductions in DBP in the supine position were 10.7 mm Hg in the hydrochlorothiazide 50 mg group and 9.0 mm Hg in the ramipril 10 mg group; corresponding DBP values in the standing position were 11.3 and 7.9 mm Hg. The response rate after 6 weeks of treatment was 52.1% in the hydrochlorothiazide 50 mg group and 37.7% in the ramipril 10 mg group (Fisher's exact test, p = 0.061). Of the 49 patients who did not respond to treatment at the end of the 6-week monotherapy phase with ramipril 10 mg, 21 (42.9%) responded to treatment after adding hydrochlorothiazide 50 mg to ramipril. Similarly, of the 35 patients who did not respond to treatment at the end of the 6-week monotherapy phase with hydrochlorothiazide 50 mg, 13 (37.1%) responded to treatment after adding ramipril 10 mg to hydrochlorothiazide.

HOPE study. In addition to its antihypertensive effect, ramipril at a dose of 10 mg demonstrates 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 the drug (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 mellitus, with at least one additional risk factor (documented microalbuminuria, arterial hypertension, elevated total cholesterol, low HDL cholesterol, or smoking).

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

Table 1

HOPE study: main 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)	Statistically not significant
Hospitalization due to heart failure	3.2	3.5	0.88 (0.70–1.10)	0.25
Diabetic 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 evidence of target organ damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.

These trials did not demonstrate significant benefits of combination therapy regarding renal and/or cardiovascular 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 drug classes, 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) assessed 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 placebo, 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 cumulative exposure to hydrochlorothiazide (cumulative dose ≥ 50,000 mg), the adjusted odds ratio (OR) was 1.29 (95% CI: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-effect relationship was observed for both BCC and SCC. Another study demonstrated a potential 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 2.1 (95% CI: 1.7–2.6) at high cumulative doses of hydrochlorothiazide (~25,000 mg) and to 7.7 (5.7–10.5) at the highest cumulative dose (~100,000 mg) (see also section "Special precautions for use").

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 administration. After administration of usual daily doses of ramipril, steady-state plasma concentrations of ramiprilat are 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 diketopiperazine ester, diketopiperazine acid, and glucuronides of ramipril and ramiprilat.

Elimination. Metabolites are primarily excreted via renal excretion. The decline in plasma ramiprilat 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 is longer with lower doses (1.25–2.5 mg). This difference is due to the saturable nature of enzyme binding capacity for ramiprilat. After a single oral dose of ramipril, neither ramipril nor its metabolites were detected in breast milk. However, the effect of repeated dosing is unknown.

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

Hydrochlorothiazide.

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

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

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

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

Patients with renal impairment (see section "Dosage and administration"). In patients with impaired renal function, renal excretion of hydrochlorothiazide is reduced, and the 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 formulations containing the individual active substances.

Preclinical safety data. In rats and mice, administration of the combination of ramipril and hydrochlorothiazide at doses up to 10,000 mg/kg body weight did not result in acute toxic effects. Repeated-dose studies in rats and monkeys demonstrated only disturbances in electrolyte balance. Mutagenicity and carcinogenicity studies of this combination 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.

Ramipril

Extensive mutagenicity testing in multiple test systems showed no evidence of mutagenic or genotoxic properties of ramipril.

Long-term studies in rats and mice revealed no evidence of tumorigenic potential.

Renal tubules with oxyphilic cells and tubules with oxyphilic cell hyperplasia in rats are considered to be 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 chromosomal aberration test in Chinese hamster ovary (CHO) cells, 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 ranging from 43 to 1300 µg/mL, and in the asexual disjunction test in Aspergillus nidulans at undefined concentrations.

Two-year feeding studies in mice and rats conducted under the U.S. National Toxicology Program (NTP) did not show 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, the NTP found equivocal evidence of hepatocarcinogenicity in male mice.

Clinical characteristics.

Indications.

Treatment of arterial hypertension. This fixed-dose combination is indicated for 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 contained in the medicinal product (see section "Composition").
• History of angioedema (hereditary, idiopathic, or previously occurring 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 precautions for use").
• Concomitant use of ACE inhibitors and extracorporeal treatment methods leading to blood contact with negatively charged surfaces (such use may result in severe anaphylactoid reactions). These extracorporeal treatment methods include dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate (see section "Interaction with other medicinal products and other forms of interaction").
• Severe bilateral renal artery stenosis or unilateral renal artery stenosis of a solitary functioning kidney.
• Severe renal impairment (creatinine clearance <30 mL/min) in patients not undergoing hemodialysis.
• Clinically significant electrolyte imbalances, which may worsen during treatment with the medicinal product (see section "Special precautions for use").
• Refractory hypokalemia or hypercalcemia.
• Refractory hyponatremia.
• Symptomatic hyperuricemia (gout).
• Anuria.
• Severe hepatic dysfunction, hepatic encephalopathy.
• Pregnancy and planned pregnancy (see section "Use in pregnancy or breastfeeding").
• Breastfeeding period (see section "Use in pregnancy or breastfeeding").
• Concomitant use of Tritace Plus® with medicinal products containing aliskiren in patients with diabetes mellitus or renal dysfunction (glomerular filtration rate (GFR) <60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").
• Concomitant use with angiotensin II receptor antagonists in patients with diabetic nephropathy.

Interaction with other medicinal products and other forms of interaction.

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

Contraindicated combinations.

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

Extracorporeal therapies resulting in 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 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 another class of antihypertensive agents.

Combinations requiring special caution.

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

Antihypertensive medicinal products (e.g., diuretics) and other active substances that may reduce blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, 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 attenuate the effect of sympathomimetic vasopressors.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other substances that may alter blood parameters. Increased risk of hematological reactions (see section "Special precautions for use").

Lithium salts. Since ACE inhibitors may reduce lithium excretion, this may lead to increased lithium toxicity. Plasma lithium levels should be monitored regularly. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and further elevate the already increased risk caused by ACE inhibitors. Therefore, concomitant use of ramipril/hydrochlorothiazide and lithium is not recommended.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. A reduced antihypertensive effect of Tritace Plus® is expected. Moreover, concomitant use of ACE inhibitors and NSAIDs may be associated with an increased risk of impaired renal function 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.

Digitalis preparations, active substances capable of prolonging 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 if hydrochlorothiazide is used concomitantly with medicinal products whose effects are influenced by changes in serum potassium levels (e.g., digitalis 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 contributing factor in the development of torsades de pointes:

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Certain neuroleptics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Other medicinal products (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vinca alkaloids).

Methyldopa. Hemolysis is possible.

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

Curare-like muscle relaxants. Possible potentiation and prolonged duration of action of muscle relaxants.

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 enhanced effect of hydrochlorothiazide.

Contrast agents containing iodine. In cases of dehydration caused by diuretics, including hydrochlorothiazide, there is an increased risk of acute renal failure, especially with administration of large doses of iodine-containing contrast agents.

Penicillin. Hydrochlorothiazide is excreted 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 when initiating such therapy (see section "Special precautions for use").

Heparin. Possible increase in serum potassium concentrations.

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

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

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

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

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

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

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

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

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

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

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

Effect of medicinal products on laboratory test results

Due to effects on calcium metabolism, thiazides may affect assessment of parathyroid function (see section "Special 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 is believed to also apply to other allergens.

Special precautions for use.

Special patient groups

Pregnancy. Treatment with ACE inhibitors or angiotensin II receptor antagonists should not be initiated during pregnancy. Except in cases where continued treatment with an ACE inhibitor/angiotensin II receptor antagonist is absolutely necessary, patients planning pregnancy should be switched to another antihypertensive agent considered safe during pregnancy. As soon as pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be stopped immediately and, if necessary, treatment with another agent should be initiated (see sections "Contraindications" and "Use in pregnancy or lactation").

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 blockade of the RAAS 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 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 arterial hypotension.

Patients with increased renin-angiotensin-aldosterone system activity. In patients with increased renin-angiotensin-aldosterone system activity, there is a risk of sudden, significant reduction in blood pressure and worsening renal function due to ACE inhibition. This is particularly relevant when an ACE inhibitor or a concomitant diuretic is initiated or the dose is increased for the first time. Increased renin-angiotensin-aldosterone system 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 from the left ventricle (e.g., aortic or mitral valve stenosis);
• with unilateral renal artery stenosis in the presence of a second functioning kidney;
• with existing or potential fluid or electrolyte depletion (including patients receiving diuretics);
• with liver cirrhosis and/or ascites;
• undergoing major surgery or receiving anaesthesia with agents that may cause arterial hypotension.

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

In patients with hepatic impairment, the response to treatment with Tritace Plus® may be either enhanced or diminished. Additionally, in patients with severe liver cirrhosis associated with oedema and/or ascites, renin-angiotensin system activity may be markedly increased; therefore, particular caution is required when treating these patients.

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

Patients at risk of cardiac or cerebral ischaemia in case of acute arterial hypotension. During the initial phase of treatment, careful medical supervision is required.

Primary hyperaldosteronism. The combination ramipril + hydrochlorothiazide is not the drug of choice for the treatment of 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 "Dosage and administration".

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

Thiazides should be used with caution in patients with liver disorders or progressive liver disease, as these agents may cause intrahepatic cholestasis, and even minor changes in fluid and electrolyte balance may precipitate hepatic coma. Hydrochlorothiazide is contraindicated in patients with severe hepatic insufficiency (see section "Contraindications").

Monitoring of renal function. Renal function should be monitored before and during treatment, and dosage adjusted accordingly, especially during the first weeks of therapy. Patients with impaired renal function (see section "Dosage and administration") require particularly close monitoring. There is a risk of worsening renal function, particularly in patients with congestive heart failure or after kidney transplantation, with 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 the onset of uraemia. Cumulative effects of the active substances may occur in patients with impaired renal function. If progression of renal dysfunction becomes evident, as indicated by increasing blood urea nitrogen levels, the continuation of treatment should be carefully reconsidered. Discontinuation of diuretic therapy should be considered (see sections "Dosage and administration" and "Contraindications").

Electrolyte imbalance. As with all patients receiving diuretic therapy, plasma electrolyte levels should be measured regularly at appropriate intervals. Thiazides, including hydrochlorothiazide, may cause disturbances in water and electrolyte balance (hypokalaemia, hyponatraemia, and hypochloraemic alkalosis).

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

Dilutional hyponatraemia 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 hypomagnesaemia.

Monitoring of electrolytes: hyperkalaemia. Hyperkalaemia has been reported in some patients receiving ACE inhibitors such as Tritace Plus®. Patients at risk of developing hyperkalaemia include those with renal insufficiency, elderly patients (aged 70 years or older), patients with uncontrolled diabetes mellitus, or those taking potassium supplements, potassium-sparing diuretics, or other active substances that increase plasma potassium levels, as well as patients with conditions such as dehydration, acute heart decompensation, or metabolic acidosis. If concomitant use of these agents is indicated, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Monitoring of electrolytes: hyponatraemia. In isolated cases, patients receiving ramipril have developed the syndrome of inappropriate antidiuretic hormone secretion (SIADH), leading to hyponatraemia. Regular monitoring of serum sodium levels is recommended in elderly patients and in other patients at risk of developing hyponatraemia.

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.

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

Angioedema. Angioedema has been reported in patients receiving 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 receiving concomitant medicinal products capable of causing angioedema, such as mTOR (mammalian target of rapamycin) inhibitors (e.g., temsirolimus, everolimus, sirolimus), vildagliptin, or neprilysin (NEP) 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 Tritace Plus® should be discontinued immediately and emergency therapy initiated. The patient should remain under medical supervision for at least 12–24 hours and may be discharged only after complete resolution of symptoms.

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

Anaphylactic reactions during desensitization. The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased during treatment with ACE inhibitors. Prior to desensitization, temporary discontinuation of Tritace Plus® is recommended.

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis have been reported rarely. Bone marrow suppression has also been reported. To detect possible leucopenia, monitoring of white blood cell count is recommended. More frequent monitoring is advisable at the beginning of treatment, in patients with impaired renal function, in patients with concomitant collagenosis (e.g., systemic lupus erythematosus or scleroderma), and in those receiving concomitant medicinal products that may cause blood count changes (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 typically include acute onset of decreased visual acuity or eye pain and usually develop within hours to weeks after starting the drug. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Initial management includes immediate discontinuation of hydrochlorothiazide. If intraocular pressure remains uncontrolled, prompt 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 other ethnic groups. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced 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.

Athletes. Hydrochlorothiazide may result in a positive doping test.

Metabolic and endocrine effects. Thiazide therapy may impair glucose tolerance. In some diabetic patients, adjustment of insulin or oral hypoglycaemic agents may be required. Thiazide treatment may unmask latent diabetes mellitus.

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

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

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

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and advised to regularly examine their skin for new lesions and promptly report any suspicious skin changes to their physician. To reduce the risk of skin cancer, patients should be informed about preventive measures, such as limiting exposure to sunlight and ultraviolet radiation and ensuring adequate skin protection when such exposure occurs. Suspicious skin lesions should be promptly investigated, including biopsy with histological examination. Patients with a history of NMSC may also need to reconsider the appropriateness of hydrochlorothiazide use (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 oedema typically develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnoea, 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 previously experienced ARDS after taking hydrochlorothiazide.

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.

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

Lactation. Tritace Plus® 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 used. As adequate data on the use of ramipril during breastfeeding are lacking, preference should be given to other medicinal products considered safer during breastfeeding, especially when breastfeeding newborns or preterm infants. Hydrochlorothiazide passes into breast milk. Use of thiazides in breastfeeding women has been associated with reduced or even complete cessation of milk production. Increased sensitivity to sulfonamide derivatives, hypokalaemia, and kernicterus may occur. As use of both active substances may lead to serious adverse effects in breastfed infants, a decision should be made whether to discontinue breastfeeding or to discontinue therapy, taking into account the importance of the therapy for the woman.

Ability to influence the ability to drive and use machines.

No studies on the effect of the medicinal product on the ability to drive and use machines have been conducted. Some adverse effects (e.g., symptoms of low blood pressure such as dizziness) may impair the patient's ability to concentrate and reaction speed, which may be hazardous in situations where these abilities are of particular importance (e.g., driving vehicles or operating machinery).

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

Dosage and Administration.

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

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

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

Adults. The dosage 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 titration of the doses of each individual component.

Treatment should be initiated at the lowest possible dose. If necessary, the dose may be gradually increased until the target blood pressure is achieved. The maximum daily dose is 10 mg of ramipril and 25 mg of hydrochlorothiazide per day, corresponding to 2 tablets of Tritace Plus® 5 mg/12.5 mg.

Special Patient Groups.

Patients receiving diuretics. Caution is recommended, as arterial hypotension may occur at the beginning of treatment in patients receiving diuretics. The dose of diuretic should be reduced or its administration discontinued prior to initiating treatment with this medicine.

If discontinuation of the diuretic is not possible, treatment should be initiated at the lowest possible dose of ramipril (1.25 mg daily) as a non-fixed combination. Subsequently, the initial daily dose should not exceed 2.5 mg ramipril / 12.5 mg hydrochlorothiazide*.

Patients with renal impairment. Due to the presence of the hydrochlorothiazide component, the medicine is contraindicated in patients with severe renal impairment [(creatinine clearance <30 mL/min) (see section "Contraindications")]. Lower doses of the medicine may be required in patients with renal impairment. Patients with creatinine clearance of 30–60 mL/min should only be treated with the lowest dose of the fixed combination of ramipril/hydrochlorothiazide after monotherapy with ramipril. The maximum daily dose* is 5 mg ramipril and 25 mg hydrochlorothiazide; therefore, Tritace Plus® 10 mg/12.5 mg is contraindicated in patients with moderate to severe renal impairment.

Patients with hepatic impairment. In patients with mild to moderate hepatic impairment, treatment should be initiated only under close medical supervision. The maximum daily dose* in such cases is 2.5 mg ramipril and 12.5 mg hydrochlorothiazide. Therefore, higher doses, including Tritace Plus® 10 mg/12.5 mg, are contraindicated in patients with mild to moderate hepatic impairment. The medicine is contraindicated in cases of severe hepatic impairment (see section "Contraindications").

Elderly patients. The initial dose should be lower, especially in very elderly and frail patients, and subsequent dose titration should be performed more gradually due to the increased risk of adverse reactions.

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

Children. The medicine is not recommended for use in children, as there is insufficient data on efficacy and safety in this patient group.

Overdose.

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

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

Careful monitoring of the patient is required.

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

Adverse Reactions

Short description of safety profile

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

List of adverse effects in tabular form

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

Table 2

System Organ Classes	Common	Uncommon	Very rare	Unknown
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, thrombocytopenia	Aplastic anaemia	Bone marrow depression; neutropenia, including agranulocytosis, pancytopenia, eosinophilia; haemoconcentration in case of fluid retention
Nervous system disorders	Headache, dizziness	Vertigo, paraesthesia, tremor, loss of 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; elevated blood urea and creatinine levels		Worsening of underlying proteinuria, interstitial nephritis due to hydrochlorothiazide
Skin and subcutaneous tissue disorders		Angioedema; in very rare cases – airway obstruction due to angioedema, which may be fatal; psoriatic dermatitis; hyperhidrosis; rash, particularly maculopapular; pruritus; alopecia		Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, exfoliative dermatitis, photosensitivity, onycholysis, pemphigoid or lichenoid exanthema or enanthema, urticaria, systemic lupus erythematosus due to hydrochlorothiazide
Musculoskeletal and connective tissue disorders		Myalgia		Arthralgia, muscle cramps, muscle weakness, musculoskeletal stiffness, tetanic cramps due to hydrochlorothiazide
Endocrine disorders				Syndrome of inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders	Poor control of diabetes mellitus, reduced glucose tolerance, increased blood glucose levels, increased uric acid levels, gout exacerbation, increased cholesterol and/or triglyceride levels due to hydrochlorothiazide	Anorexia, decreased appetite, decreased plasma potassium levels, thirst due to hydrochlorothiazide	Increased plasma potassium levels due to ramipril	Decreased plasma sodium levels, glucosuria, metabolic alkalosis, hypochloraemia, hypomagnesaemia, hypercalcaemia, dehydration, hypochloraemic alkalosis, which may induce hepatic encephalopathy or hepatic coma due to hydrochlorothiazide
Vascular disorders		Arterial hypotension, orthostatic hypotension, syncope, flushing		Thrombosis due to significant reduction in circulating blood volume, vascular stenosis, hypoperfusion, Raynaud's syndrome, vasculitis, necrotizing angiitis
General disorders	Increased fatigue, asthenia	Chest pain, pyrexia		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 bilirubin conjugates, cholelithiasis due to hydrochlorothiazide		Acute liver failure, cholestatic jaundice, hepatic 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): epidemiological data have shown an association between cumulative dose of hydrochlorothiazide and development of NMSC (see also sections "Special warnings and precautions for use" and "Pharmacological properties").

Reporting of suspected adverse reactions. Reporting of suspected adverse reactions after authorization of the medicinal product is an important procedure. It allows continuous monitoring of the benefit-risk balance of the use of this medicinal product. Healthcare professionals are requested to report all suspected adverse reactions using pharmacovigilance systems.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 ºC.

Keep out of reach of children.

Packaging. No. 28 (14x2): 14 tablets in a blister, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. SANOFI S.R.L.

Manufacturer's address and location of its business operations.

S.S. 17 KM 22, SCOPIPETO (L'AQUILA), 67019, Italy.