Zokardis® plus 30/12,5
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOCARDIS® PLUS 30/12.5 (ZOCARDIS® PLUS 30/12.5)
Composition:
Active substances: zofenopril calcium, hydrochlorothiazide;
One film-coated tablet contains zofenopril calcium 30 mg, equivalent to zofenopril 28.7 mg, and hydrochlorothiazide 12.5 mg;
Excipients: microcrystalline cellulose, lactose monohydrate, maize starch, hypromellose, colloidal anhydrous silicon dioxide, magnesium stearate, titanium dioxide (E 171), polyethylene glycol 400, polyethylene glycol 6000, iron oxide red (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: pale red, round, slightly biconvex film-coated tablets with a score line on one side.
The score line is intended only to facilitate tablet splitting for easier swallowing and is not intended for dividing the tablet into equal doses.
Pharmacotherapeutic group.
ACE inhibitors and diuretics. ATC code C09B A15.
Pharmacological Properties.
Pharmacodynamics.
Zokardis® Plus 30/12.5 is a combination drug consisting of zofenopril, an angiotensin-converting enzyme (ACE) inhibitor, and hydrochlorothiazide, a thiazide-type diuretic. The mechanisms of action of both components are complementary, and their antihypertensive effects are mutually enhanced.
Zofenopril is a sulfhydryl-containing ACE inhibitor that suppresses the enzyme catalyzing the conversion of angiotensin I to angiotensin II—a vasoconstrictive peptide. This leads to reduced vasoconstrictive activity and decreased aldosterone secretion. The latter may result in increased serum potassium concentration with concomitant excretion of sodium and fluid from the body. Disruption of the negative feedback loop between angiotensin II and renin secretion leads to increased plasma renin activity. The mechanism of blood pressure reduction by zofenopril is primarily based on inhibition of the renin-angiotensin-aldosterone system. ACE is identical to kininase II, the enzyme responsible for bradykinin degradation—a potent vasodilatory peptide. This likely contributes to the therapeutic effect of ACE inhibitors.
Hydrochlorothiazide is a diuretic and antihypertensive agent. It affects electrolyte reabsorption in the distal portion of the renal tubules. Hydrochlorothiazide enhances the excretion of sodium and chloride in approximately equal amounts. Natriuresis may be accompanied by loss of potassium and bicarbonate. Due to blockade of the renin-angiotensin-aldosterone system, concomitant administration of hydrochlorothiazide with zofenopril likely counteracts potassium loss associated with diuretic therapy. Diuresis begins within 2 hours after hydrochlorothiazide administration, reaches its peak approximately 4 hours after intake, and lasts about 6–12 hours.
Other information.
Concomitant use of ACE inhibitors and angiotensin II receptor blockers (ARBs) has been investigated in two large-scale randomized controlled trials (ONTARGET [ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial], VA NEPHRON-D [The Veterans Affairs Nephropathy in Diabetes]).
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was a study conducted in patients with type 2 diabetes and diabetic nephropathy. The studies did not demonstrate a significant beneficial effect on renal and/or cardiovascular outcomes or mortality. However, compared to monotherapy, there was an increased risk of hyperkalemia, acute kidney injury, and/or hypotension. Given the similarity in their pharmacodynamic properties, these findings are also applicable to other ACE inhibitors and ARBs.
Therefore, patients with diabetic nephropathy should not receive concomitant treatment with ACE inhibitors and angiotensin II receptor blockers.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to evaluate the benefit of adding aliskiren to standard therapy with an ACE inhibitor or ARB in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular mortality and stroke occurred more frequently in the aliskiren group than in the placebo group, and reports of adverse events and serious adverse events (hyperkalemia, hypotension, and renal dysfunction) were more frequent in the aliskiren group compared to the placebo group.
Non-melanoma skin cancer (NMSC). Epidemiological data have shown an association between cumulative hydrochlorothiazide dose 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), compared with 1,430,833 and 172,462 control subjects, respectively. High-dose hydrochlorothiazide use (cumulative dose ≥ 50,000 mg) was associated with an adjusted odds ratio (OR) of 1.29 (95% confidence interval [CI]: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-response relationship was observed for both BCC and SCC. Another study suggested a possible link between lip cancer (SCC) and hydrochlorothiazide: 633 patients with lip cancer were compared with 63,067 control subjects using a risk-set sampling strategy. A dose-response relationship was demonstrated: the adjusted OR was 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) with high-dose exposure (~25,000 mg) and OR 7.7 (5.7–10.5) at the highest cumulative dose (~100,000 mg) (see also section "Special precautions for use").
Pharmacokinetics.
Concomitant administration of zofenopril and hydrochlorothiazide has little or no effect on the bioavailability of the individual active substances. The combination product is bioequivalent to the two individual components administered together.
ZOFENOPRIL.
Zofenopril is a prodrug, as the active inhibitor is the free sulfhydryl compound, zofenoprilat, formed via thioester hydrolysis.
Absorption. Zofenopril is rapidly and completely absorbed after oral administration and is almost entirely converted to zofenoprilat. Maximum plasma concentration is reached within 1.5 hours after oral administration of zofenopril. The pharmacokinetics of single doses are linear within the dose range of 10–80 mg of zofenopril. No accumulation occurs after repeated administration of 15–60 mg zofenopril over 3 weeks. The presence of food in the gastrointestinal tract reduces the rate but not the extent of absorption; the area under the plasma concentration-time curve (AUC) of zofenoprilat is nearly identical with and without food.
Distribution. Approximately 88% of the circulating radioactivity measured ex vivo after administration of radiolabeled zofenopril is protein-bound in plasma, and the steady-state volume of distribution is 96 liters.
Biotransformation. Eight metabolites were identified in human urine after administration of radiolabeled zofenopril, accounting for 76% of total urinary radioactivity. The main metabolite is zofenoprilat (22%), which is further metabolized via several pathways, including glucuronide conjugation (17%), cyclization and glucuronide conjugation (13%), conjugation with cysteine (9%), and S-methylation of the thiol group (8%).
Elimination. Radiolabeled zofenoprilat is eliminated via urine (76%) and feces (16%) after intravenous administration, and via urine (69%) and feces (26%) after oral administration, indicating dual elimination pathways through the kidneys and liver. The elimination half-life of zofenoprilat after oral administration of zofenopril is 5.5 hours, and total systemic clearance is 1300 mL/min.
Pharmacokinetics in specific patient populations.
Pharmacokinetics in elderly patients. Dose adjustment is not required in elderly patients with normal renal function.
Pharmacokinetics in renal impairment. Based on comparison of key pharmacokinetic parameters of zofenoprilat measured after oral administration of radiolabeled zofenopril, zofenopril is eliminated at the same rate in patients with mild renal impairment (creatinine clearance > 45 to < 90 mL/min) as in patients with normal renal function (creatinine clearance > 90 mL/min). In patients with moderate to severe renal impairment (7–44 mL/min), elimination is reduced to approximately 50% of normal. In patients with end-stage renal disease undergoing hemodialysis or peritoneal dialysis, elimination is reduced to 25% of normal.
Pharmacokinetics in hepatic impairment. In patients with mild to moderate hepatic impairment receiving a single dose of radiolabeled zofenopril, Cmax and Tmax values for zofenoprilat were similar to those in patients with normal liver function. However, AUC values in patients with hepatic cirrhosis were approximately twice as high as those in patients with normal liver function. Therefore, patients with mild to moderate hepatic impairment should receive half the initial dose recommended for patients with normal liver function. Pharmacokinetic data for zofenopril and zofenoprilat in patients with severe hepatic impairment are lacking; therefore, zofenopril is contraindicated in such patients.
HYDROCHLOROTHIAZIDE.
Absorption. Hydrochlorothiazide is well absorbed (65–75%) after oral administration. Plasma concentration is linearly related to the administered dose. Absorption of hydrochlorothiazide varies depending on intestinal transit time, increasing with prolonged transit, for example, when taken with food. Based on plasma concentration assessments over 24 hours, the plasma elimination half-life ranges from 5.6 to 14.8 hours, and maximum plasma concentration is reached 1–5 hours after administration.
Distribution. Thiazides are widely distributed in body fluids and are highly bound (92%) to plasma proteins, primarily albumin, with displaced molecules being most actively bound. This leads to lower renal clearance and thus a prolonged duration of action. A relationship between plasma hydrochlorothiazide levels and the degree of blood pressure reduction has not been established.
Elimination. Hydrochlorothiazide is primarily excreted by the kidneys. Most of the drug is excreted unchanged in urine, with more than 95% of unchanged hydrochlorothiazide recovered in urine within 3–6 hours after oral administration. In patients with kidney disease, plasma hydrochlorothiazide concentrations are increased and elimination half-life is prolonged. Hydrochlorothiazide crosses the placental barrier but does not cross the blood-brain barrier.
Preclinical safety data.
Acute toxicity, repeated-dose toxicity, and genotoxicity studies did not reveal any specific risks of Zokardis® Plus 30/12.5 for humans.
Reproductive toxicity studies of Zokardis® Plus 30/12.5 conducted in rats and rabbits did not show teratogenic effects of zofenopril or hydrochlorothiazide. However, in pregnant rats and rabbits, the combination significantly increased maternal toxicity compared to zofenopril alone.
Carcinogenicity studies of the zofenopril/hydrochlorothiazide combination have not been conducted.
Carcinogenicity studies of zofenopril monotherapy in mice and rats did not reveal carcinogenic effects.
In standard preclinical safety pharmacology, repeated-dose toxicity, genotoxicity, and carcinogenicity studies, no specific risk of hydrochlorothiazide for humans has been identified.
Clinical characteristics.
Indications.
Essential hypertension of mild to moderate severity.
This combined medicinal product is indicated for patients who have an inadequate response to monotherapy with zofenopril.
Contraindications.
- Pregnancy or planned pregnancy (see sections "Special precautions for use" and "Use in pregnancy or lactation").
- Hypersensitivity to zofenopril or to any other angiotensin-converting enzyme (ACE) inhibitor.
- Hypersensitivity to hydrochlorothiazide or to other sulfonamide derivatives.
- Hypersensitivity to any of the excipients listed in the section "Composition".
- History of angioedema associated with previous treatment with an ACE inhibitor.
- Concomitant use with sacubitril/valsartan. Treatment with Zokardis® Plus 30/12.5 must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see also sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
- Hereditary or idiopathic angioedema.
- Severe hepatic impairment.
- Severe renal impairment (creatinine clearance < 30 mL/min).
- Bilateral renal artery stenosis or stenosis of the renal artery of a single kidney.
- Concomitant use of Zokardis® Plus 30/12.5 with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").
Interaction with other medicinal products and other forms of interaction.
ZOFENOPRIL
Medicinal products increasing the risk of angioedema.
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated, as it increases the risk of angioedema (see sections "Contraindications" and "Special precautions for use").
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus), and vildagliptin may increase the risk of angioedema (see section "Special precautions for use").
Concomitant use is not recommended.
Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other agents that increase serum potassium levels.
Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients treated with zofenopril. Potassium-sparing diuretics such as spironolactone, triamterene, or amiloride, as well as potassium supplements or potassium-containing salt substitutes, may lead to a significant increase in serum potassium levels. Caution should also be exercised when zofenopril is used concomitantly with other agents that increase serum potassium levels, such as trimethoprim or co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of zofenopril with the above-mentioned agents is not recommended. If concomitant use is necessary, these agents should be used with caution and serum potassium levels should be monitored regularly.
ACE inhibitors, angiotensin II receptor blockers, or aliskiren.
Clinical trial data show that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with an increased frequency of adverse events such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to treatment with a single agent acting on the RAAS (see sections "Contraindications", "Special precautions for use", and "Pharmacodynamics").
Concomitant use requiring caution.
Thiazide or loop diuretics.
Prior treatment with high-dose diuretics may lead to dehydration and an increased risk of hypotension during the initial phase of zofenopril therapy (see section "Special precautions for use").
Hypotensive effects may be minimized by discontinuing the diuretic, increasing fluid or salt intake, or by initiating zofenopril at low initial doses.
Anaesthetic agents.
ACE inhibitors may potentiate the hypotensive effect of certain anaesthetic agents.
Narcotics/tricyclic antidepressants/antipsychotics/barbiturates. Orthostatic hypotension may occur.
Other antihypertensive agents (e.g. β-blockers, α-blockers, calcium antagonists).
An additive hypotensive effect or potentiation of drug action may occur. Nitroglycerin, other nitrates, or other vasodilators should be used with caution.
Cimetidine.
Possible increased risk of hypotensive effect.
Cyclosporine.
Hyperkalemia may occur when ACE inhibitors are used concomitantly with cyclosporine.
Serum potassium levels should be monitored.
Heparin.
Hyperkalemia may occur when ACE inhibitors are used concomitantly with heparin.
Serum potassium levels should be monitored.
Allopurinol, procainamide, systemic corticosteroids, cytostatic or immunosuppressive agents.
The risk of hypersensitivity reactions may be increased when used concomitantly with ACE inhibitors. Information from other ACE inhibitors indicates an increased risk of leukopenia with concomitant use.
Antidiabetic agents.
Rarely, ACE inhibitors may potentiate the hypoglycemic effects of insulin and oral antidiabetic agents (e.g. sulfonylureas) in patients with diabetes mellitus. In such cases, dose reduction of the antidiabetic agent may be necessary when used concomitantly with ACE inhibitors.
Hemodialysis with high-flux dialysis membranes.
The risk of anaphylactoid reactions is increased when used concomitantly with ACE inhibitors.
Sympathomimetic agents.
The hypotensive effect of ACE inhibitors may be reduced; careful monitoring is required to ensure the desired therapeutic effect is achieved.
Antacids.
May reduce the bioavailability of ACE inhibitors.
Food.
May reduce the rate, but not the extent, of zofenopril absorption.
Gold compounds.
There have been reports of an increased incidence of nitritoid reactions (vasodilatory symptoms including flushing, nausea, dizziness, hypotension, which may be severe) following injection of gold compounds (e.g. sodium aurothiomalate) in patients receiving ACE inhibitor therapy.
Additional information.
Cytochrome P450 enzyme system. There are no clinical data on direct interaction between zofenopril and other active substances metabolized by cytochrome P450 enzymes. However, in vitro metabolism studies with zofenopril have shown no potential for interaction with substances metabolized by CYP enzymes.
HYDROCHLOROTHIAZIDE
Concomitant use requiring caution.
Cholestyramine and colestipol resins.
Absorption of hydrochlorothiazide is impaired in the presence of anion-exchange resins. After single-dose administration, cholestyramine and colestipol resins bind hydrochlorothiazide and reduce its gastrointestinal absorption by 85% and 43%, respectively.
Sulfonamide-derived diuretics should be taken at least 1 hour before or 4–6 hours after administration of these resins.
Corticosteroids, ACTH, amphotericin B (parenteral form), carbenoxolone, stimulant laxatives.
Concomitant use with hydrochlorothiazide may increase the risk of electrolyte disturbances, particularly hypokalemia.
Calcium salts.
Serum calcium levels may increase when used concomitantly with thiazide diuretics due to reduced calcium excretion.
Cardiac glycosides.
Hypokalemia or hypomagnesemia induced by thiazide diuretics may predispose to cardiac arrhythmias caused by cardiac glycosides.
Medicinal products that may cause torsades de pointes.
Caution should be exercised when hydrochlorothiazide is used concomitantly with agents that may cause torsades de pointes (e.g. certain antiarrhythmics, some neuroleptics, and other drugs capable of inducing torsades de pointes), due to the risk of hypokalemia.
Vasopressor amines (e.g. adrenaline).
The response to vasopressor amines may be reduced, but not to a degree that precludes their use with hydrochlorothiazide.
Non-depolarizing muscle relaxants (e.g. tubocurarine).
The response to muscle relaxants may be enhanced when used concomitantly with hydrochlorothiazide.
Amantadine.
Thiazide diuretics may increase the risk of adverse reactions associated with amantadine.
Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone, allopurinol).
Dosage adjustment of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid levels. Higher doses of probenecid or sulfinpyrazone may be needed. Concomitant use of thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol.
Additional information.
Effect on laboratory test results: due to the effects of thiazide diuretics on calcium metabolism, they may influence parathyroid function tests.
COMBINED MEDICINAL PRODUCT ZOKARDIS® PLUS 30/12.5
(ZOFENOPRIL/HYDROCHLOROTHIAZIDE)
Concomitant use is not recommended.
Lithium preparations.
Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and may potentiate the already elevated risk of lithium toxicity associated with ACE inhibitors. Therefore, Zokardis® Plus 30/12.5 is not recommended to be combined with lithium preparations. If combination therapy is necessary, careful monitoring of serum lithium levels is required.
Biochemical parameters.
Thiazide diuretics may reduce serum protein-bound iodine concentration without evidence of thyroid dysfunction.
Concomitant use requiring caution.
Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid at doses ≥ 3 g per day.
NSAIDs may reduce the antihypertensive effects of ACE inhibitors and diuretics. In addition, NSAIDs and ACE inhibitors have been reported to have an additive effect in increasing serum potassium levels, while renal function may decrease. These effects are generally reversible and occur more frequently in patients with impaired renal function. Acute renal failure may rarely occur, particularly in patients with renal impairment, e.g. due to dehydration, or in elderly patients.
Ethanol.
The antihypertensive effect of ACE inhibitors and hydrochlorothiazide is enhanced.
Trimethoprim.
Concomitant use of ACE inhibitors, thiazide diuretics, and trimethoprim increases the risk of hyperkalemia.
Special precautions for use.
ZOFENOPRIL.
Arterial hypotension.
Like other ACE inhibitors and diuretics, Zokardis® Plus 30/12.5 may cause a significant drop in arterial pressure, especially after the first dose, although symptomatic arterial hypotension is rarely observed in patients with uncomplicated arterial hypertension.
It is more likely to occur in patients with disturbances in water-electrolyte balance due to diuretic therapy, salt-restricted diet, dialysis, diarrhea, or vomiting, as well as in patients with severe renin-dependent arterial hypertension (see sections "Interaction with other medicinal products and other types of interactions" and "Undesirable effects").
Symptomatic arterial hypotension has been observed in patients with heart failure, with or without concomitant renal impairment. The likelihood of its occurrence is higher in patients with more severe degrees of heart failure, associated with the use of high-dose loop diuretics, hyponatremia, or impaired renal function.
In patients at increased risk of symptomatic arterial hypotension, treatment should be initiated under strict medical supervision, preferably in a hospital setting, starting with low doses that are gradually increased. At the beginning of therapy with Zokardis® Plus 30/12.5, diuretic therapy should be temporarily discontinued if possible.
These recommendations also apply to patients with angina pectoris or cerebrovascular disease, in whom excessive reduction in arterial pressure may lead to myocardial infarction or acute cerebrovascular events.
If arterial hypotension develops, the patient should be placed in a supine position. Intravenous administration of 0.9% sodium chloride solution may be required to restore circulating blood volume. A decrease in arterial pressure after the first dose of the drug does not preclude subsequent dose escalation provided hypotension is effectively managed.
Patients with renovascular hypertension.
When ACE inhibitors are used in patients with bilateral renal artery stenosis or stenosis of the renal artery of a single functioning kidney, there is an increased risk of severe arterial hypotension and renal failure; diuretic therapy may be a precipitating factor. Renal failure may be accompanied by only minor changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.
Such patients should start treatment with a low dose, gradually increased, under close medical supervision and with monitoring of renal function.
Patients with renal impairment.
Appropriate careful monitoring of renal function should be performed during therapy. Cases of renal failure have been reported during ACE inhibitor therapy, primarily in patients with severe heart failure or kidney disease, including renal artery stenosis. In some patients without apparent kidney pathology, increases in blood urea and creatinine concentrations have been observed, especially when diuretics are used concomitantly. In such cases, dose reduction of the active substances of the drug may be required. Close monitoring of renal function is recommended during the first few weeks of treatment.
Patients undergoing hemodialysis.
When high-flux polycrylonitrile membranes (e.g., AN 69) are used for hemodialysis, patients taking ACE inhibitors may experience anaphylactoid reactions within the first minutes of the session, such as facial swelling, flushing, arterial hypotension, and dyspnea. Therefore, an alternative membrane or another antihypertensive agent is recommended.
The efficacy and safety of zofenopril in patients with myocardial infarction undergoing hemodialysis have not been established; therefore, it should not be used in such patients.
Patients undergoing low-density lipoprotein (LDL) apheresis.
In patients taking ACE inhibitors who undergo LDL apheresis with dextran sulfate, anaphylactoid reactions similar to those observed in patients undergoing hemodialysis with high-flux membranes (see above) may occur; therefore, such patients are recommended to use an antihypertensive agent from another class.
Anaphylactic reactions during desensitization therapy or after insect bites.
Rarely, life-threatening anaphylactoid reactions have occurred in patients taking ACE inhibitors during desensitization therapy (e.g., with Hymenoptera venom) or after insect bites. These reactions were avoided when ACE inhibitors were temporarily discontinued, but recurred after inadvertent re-administration of the drug. Therefore, caution should be exercised when performing such therapy in patients taking ACE inhibitors.
Renal transplantation.
There is no experience with the use of Zokardis® Plus 30/12.5 in patients who have recently undergone renal transplantation; therefore, it is not recommended for such patients.
Primary hyperaldosteronism.
Patients with primary hyperaldosteronism usually do not respond to antihypertensive agents that inhibit the renin-angiotensin system; therefore, zofenopril is not recommended.
Hypersensitivity/angioedema.
Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis, and/or larynx may occur in patients taking ACE inhibitors, most often during the first weeks of treatment. However, in isolated cases, severe angioedema may occur even after prolonged ACE inhibitor therapy. ACE inhibitor therapy should be immediately discontinued and replaced with an agent from another class of antihypertensive drugs.
Angioedema involving the tongue, glottis, and larynx may be fatal. In such cases, immediate medical assistance is required, including (but not limited to) immediate subcutaneous administration of 1:1000 adrenaline solution (0.3–0.5 mL) or slow intravenous administration of 1 mg/mL adrenaline (which should be diluted according to instructions), under careful ECG and arterial pressure monitoring. The patient should be hospitalized and kept under observation for at least 12–24 hours until all observed symptoms have completely resolved.
Even in cases where only tongue swelling occurs without respiratory distress, the patient may require monitoring, as antihistamines and corticosteroids alone may be insufficient.
Angioedema caused by angiotensin-converting enzyme inhibitors occurs more frequently in patients of African descent than in other patients.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may have an increased risk of developing angioedema when using an ACE inhibitor (see section "Contraindications").
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Treatment with sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of Zokardis® Plus 30/12.5. Treatment with Zokardis® Plus 30/12.5 should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other types of interactions").
Concomitant use of ACE inhibitors with rac-cadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin may increase the risk of angioedema (e.g., swelling of the airways or tongue with or without respiratory distress) (see section "Interaction with other medicinal products and other types of interactions"). Caution should be exercised when initiating rac-cadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in a patient already taking any ACE inhibitor.
Cough.
A dry, non-productive cough that resolves after discontinuation of therapy may occur with the use of ACE inhibitors, which should be considered when performing differential diagnosis of cough.
Hepatic impairment.
Rarely, the use of ACE inhibitors has been associated with a syndrome beginning with cholestatic jaundice followed by fulminant hepatic necrosis and (sometimes) fatal outcome. The mechanism of this syndrome is unclear. Patients who develop jaundice or a significant increase in liver enzymes during ACE inhibitor therapy should discontinue the ACE inhibitor and receive appropriate treatment.
Serum potassium levels.
ACE inhibitors may cause hyperkalemia because they inhibit aldosterone release. In patients with normal renal function, this effect is usually insignificant. However, in patients with impaired renal function and/or patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, heparin, trimethoprim, or co-trimoxazole (also known as trimethoprim/sulfamethoxazole), and especially aldosterone antagonists or angiotensin receptor blockers, hyperkalemia may occur. Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium levels and renal function should be monitored (see section "Interaction with other medicinal products and other types of interactions").
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of the RAAS with concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other types of interactions" and "Pharmacodynamics").
If dual blockade therapy is considered absolutely necessary, it should only be performed under the supervision of a specialist, with frequent and careful monitoring of renal function, electrolyte levels, and arterial pressure.
ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Surgery/anesthesia.
In patients undergoing major surgical procedures or anesthesia, ACE inhibitors may cause arterial hypotension up to shock, as they may block the formation of angiotensin II due to compensatory renin release. If discontinuation of ACE inhibitors is not possible, careful monitoring of circulating blood and plasma volume is required.
Aortic stenosis / mitral valve stenosis / hypertrophic cardiomyopathy.
ACE inhibitors should be used with caution in patients with mitral valve stenosis and impaired outflow from the left ventricle and should be avoided in cases of cardiogenic shock and stenosis causing significant hemodynamic effects.
Neutropenia/agranulocytosis.
Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients taking ACE inhibitors. The risk of neutropenia is related to the dose and type of ACE inhibitor and depends on the patient's clinical condition. It is rarely observed in patients with uncomplicated clinical presentation but may occur with mild renal impairment, especially when associated with vascular collagenosis, e.g., systemic lupus erythematosus, scleroderma, immunosuppressive therapy, allopurinol or procainamide treatment, or a combination of these factors. Some of these patients developed severe infections that were in some cases resistant to intensive antibiotic therapy.
When using zofenopril in such patients, it is recommended to determine the leukocyte count and leukocyte formula before starting treatment, every 2 weeks during the first 3 months of zofenopril treatment, and thereafter as needed. During treatment, all patients should be advised to report any signs of infectious involvement (e.g., sore throat, fever), and a leukocyte formula analysis should be performed. If neutropenia (neutrophil count less than 1000/mm³) is detected or suspected, zofenopril and other concomitant medications (see section "Interaction with other medicinal products and other types of interactions") should be discontinued. After discontinuation of ACE inhibitors, neutrophil count returns to baseline levels.
Psoriasis.
ACE inhibitors should be used with caution in patients with psoriasis.
Proteinuria.
Proteinuria may occur more frequently in patients with existing renal impairment or those taking relatively high doses of ACE inhibitors. In patients with a history of kidney disease, urine protein levels (in the first morning urine sample using test strips) should be determined before starting treatment and regularly during treatment.
Patients with diabetes mellitus.
In patients with diabetes mellitus who are already taking oral antidiabetic agents or insulin, blood glucose levels should be carefully monitored during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other types of interactions").
Lithium preparations.
Combining lithium preparations with Zokardis® Plus 30/12.5 is generally not recommended (see section "Interaction with other medicinal products and other types of interactions").
Ethnic differences.
Like other angiotensin-converting enzyme inhibitors, zofenopril may have less antihypertensive effect in patients of African descent than in other patients.
Angiotensin-converting enzyme inhibitors more frequently cause angioedema in patients of African descent than in patients of other races.
Pregnancy.
Zokardis® Plus 30/12.5 is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with Zokardis® Plus 30/12.5, the drug should be discontinued immediately. If necessary, the drug should be replaced with another medicinal product approved for use during pregnancy (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
HYDROCHLOROTHIAZIDE.
Renal function impairment.
In patients with kidney disease, the use of thiazide diuretics may exacerbate azotemia. Cumulative effects of this active substance may manifest in patients with impaired renal function. If progressive renal function impairment becomes evident (indicated by increased non-protein nitrogen levels), the prescribed treatment should be carefully reviewed and, if necessary, the diuretic discontinued.
Hepatic function impairment.
Thiazide diuretics should be used with caution in patients with impaired liver function or progressive liver disease, as even minor changes in water-electrolyte balance may trigger hepatic coma.
Metabolic and endocrine effects.
Thiazide diuretics may impair glucose tolerance. Adjustment of insulin or oral antidiabetic agent dosage may be required (see section "Interaction with other medicinal products and other types of interactions"). Thiazide diuretic therapy may unmask latent diabetes mellitus, and an increase in cholesterol and triglyceride levels is also possible. Use of these agents may provoke exacerbation of hyperuricemia and/or gout in some patients.
Electrolyte imbalance.
All patients taking diuretics should undergo periodic determination of serum electrolyte levels at appropriate intervals.
Thiazide diuretics, including hydrochlorothiazide, may cause disturbances in water-electrolyte balance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Symptoms indicating water-electrolyte imbalance include dry mouth, thirst, weakness, drowsiness, lethargy, restlessness, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, and gastrointestinal disorders such as nausea and vomiting.
Although hypokalemia may develop with the use of thiazide diuretics, concomitant administration with zofenopril may reduce diuretic-induced hypokalemia. The risk of hypokalemia is highest in patients with hepatic cirrhosis, patients with a sudden increase in diuresis, patients receiving insufficient electrolytes from food, and patients concomitantly taking corticosteroids or ACTH (see section "Interaction with other medicinal products and other types of interactions").
Hyponatremia due to dilution may occur in patients with edema during hot weather. Chloride deficiency is generally mild and usually does not require treatment.
Thiazide diuretics may reduce calcium excretion in urine and cause mild, reversible elevation of serum calcium levels in the absence of known calcium metabolism disorders. Significant hypercalcemia may indicate latent hyperparathyroidism. Thiazide diuretics should be discontinued before testing parathyroid gland function.
Thiazide diuretics may increase magnesium excretion in urine, which may lead to hypomagnesemia.
Systemic lupus erythematosus.
Exacerbation or worsening of systemic lupus erythematosus has been reported with the use of thiazide diuretics.
Non-melanoma skin cancer (NMSC).
In two epidemiological studies based on data from the Danish national cancer registry, increasing cumulative doses of hydrochlorothiazide were associated with an increased risk of NMSC (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)). The photosensitizing effects of hydrochlorothiazide may be a possible mechanism for the development of NMSC.
Patients taking hydrochlorothiazide should be informed about the risk of NMSC and advised to regularly check their skin for any new lesions and immediately report any suspicious skin lesions. To minimize the risk of skin cancer, patients should be advised to take possible preventive measures such as limiting exposure to sunlight and UV radiation and using appropriate protection when such exposure occurs. Suspicious skin lesions should be promptly examined, including histological examination of biopsy samples. In patients who have previously had NMSC, a review of hydrochlorothiazide use may also be necessary (see also section "Undesirable effects").
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma.
Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the drug. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. The primary treatment is to discontinue the drug as quickly as possible. If intraocular pressure remains uncontrolled, surgical, medical, or surgical treatment methods may be necessary. Risk factors for the development of acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.
Acute respiratory toxicity.
Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide use. Pulmonary edema usually develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening lung condition, and hypotension. If ARDS is suspected, use of Zokardis® Plus 30/12.5 should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be used in patients who have previously experienced ARDS after taking hydrochlorothiazide.
Anti-doping test.
Hydrochlorothiazide, included in this medicinal product, may cause false-positive results in anti-doping tests.
Other.
Hypersensitivity reactions are possible in patients with or without a history of allergy or bronchial asthma.
Cases of photosensitivity reactions have been reported with the use of thiazide diuretics (see section "Undesirable effects"). If a photosensitivity reaction occurs during treatment, it is recommended to discontinue treatment. If re-administration of a diuretic is necessary, it is recommended to protect exposed areas of the body from sunlight or ultraviolet radiation.
COMBINED MEDICINAL PRODUCT ZOKARDIS® PLUS 30/12.5.
(ZOFENOPRIL/HYDROCHLOROTHIAZIDE).
In addition to the warnings related to individual components, the following should be considered:
Pregnancy.
Zokardis® Plus 30/12.5 is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with Zokardis® Plus 30/12.5, the drug should be discontinued immediately. If necessary, the drug should be replaced with another medicinal product approved for use during pregnancy (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
Patients with renal impairment.
Considering the effects of zofenopril and hydrochlorothiazide in patients with impaired renal function, Zokardis® Plus 30/12.5 should not be prescribed to patients with moderate to severe renal impairment (creatinine clearance < 45 mL/min).
Hypokalemia risk.
Combination of an ACE inhibitor with a thiazide diuretic does not exclude the occurrence of hypokalemia. Regular monitoring of serum potassium levels is required.
Galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption syndrome.
This medicinal product contains lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome should not take this medicinal product.
Use during pregnancy or breastfeeding.
Pregnancy.
ZOFENOPRIL.
Use of ACE inhibitors is contraindicated in pregnant women or women planning pregnancy (see sections "Contraindications" and "Special precautions for use").
Epidemiological data on the teratogenic risk associated with ACE inhibitor use during the first trimester of pregnancy do not allow definitive conclusions, but a slight increase in risk cannot be excluded. Except in cases where long-term ACE inhibitor therapy is indicated for life-saving reasons, patients planning pregnancy are recommended to switch to alternative antihypertensive agents with a proven safety profile during pregnancy. If pregnancy is diagnosed, ACE inhibitor therapy should be discontinued immediately and alternative therapy initiated if necessary.
ACE inhibitor use during the second and third trimesters of pregnancy may result in fetotoxic effects (reduced renal function, oligohydramnios, delayed ossification of skull bones) and neonatal toxicity (renal failure, hypotension, hyperkalemia) (see preclinical safety data). If ACE inhibitor use begins in the second trimester of pregnancy, ultrasound examination of fetal kidney function and skull condition is recommended. Newborns whose mothers took ACE inhibitors during pregnancy should be closely monitored for arterial hypotension (see sections "Contraindications" and "Special precautions for use").
HYDROCHLOROTHIAZIDE.
Experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Considering the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters may lead to impaired fetoplacental perfusion and affect the fetus and newborn, causing jaundice, electrolyte imbalance, and thrombocytopenia.
Hydrochlorothiazide should not be used to treat gestational edema, hypertensive disorders of pregnancy, or preeclampsia due to the risk of reduced plasma volume and placental hypoperfusion in the absence of positive effects on disease progression.
Hydrochlorothiazide should not be used to treat essential hypertension in pregnant women, except in individual cases where other therapy cannot be administered.
COMBINED MEDICINAL PRODUCT ZOKARDIS® PLUS 30/12.5.
(ZOFENOPRIL/HYDROCHLOROTHIAZIDE).
Considering the effects of individual components of this combined medicinal product on pregnancy, use of Zokardis® Plus 30/12.5 is contraindicated in pregnant women and women planning pregnancy (see sections "Contraindications" and "Special precautions for use").
Breastfeeding.
There is no information on the use of Zokardis® Plus 30/12.5 during breastfeeding; therefore, the drug is not recommended for breastfeeding women. It is advisable to use other drugs with a proven safety profile during breastfeeding, especially when breastfeeding newborns or premature infants.
HYDROCHLOROTHIAZIDE.
Hydrochlorothiazide passes into human breast milk in small amounts. High doses of thiazides causing intense diuresis may suppress milk production. Use of Zokardis® Plus 30/12.5 during breastfeeding is not recommended. If Zokardis® Plus 30/12.5 is used during breastfeeding, the dose should be as low as possible.
Ability to affect reaction speed when driving vehicles or operating machinery.
Studies on the effect on the ability to drive vehicles or operate machinery have not been conducted. When driving vehicles or operating machinery, it should be remembered that drowsiness, dizziness, or fatigue may occasionally occur.
Method of Administration and Dosage.
Dosage.
Adults.
Prior to initiating treatment with the fixed-dose combination, it is recommended to establish the appropriate doses of the individual components (i.e., zofenopril and hydrochlorothiazide).
Direct substitution of monotherapy with the fixed-dose combination product may be considered if appropriate.
For patients without disturbances in water-electrolyte balance, the usual effective dose is 1 tablet once daily.
Zokardis® Plus 30/12.5 is not recommended for patients suspected of having water-electrolyte imbalance.
Elderly patients (aged 65 years and older).
Elderly patients with normal creatinine clearance do not require dose adjustment. Zokardis® Plus 30/12.5 is not recommended for elderly patients with reduced creatinine clearance (less than 45 mL/min).
Creatinine clearance can be calculated based on serum creatinine concentration using the Cockcroft-Gault formula:
CC (mL/min) = [(140 - age) * body weight (kg)]
72 * serum Cr (mg/dL)
The above method is used to calculate creatinine clearance in men. For women, the resulting value should be multiplied by 0.85.
Children.
The use of Zokardis® Plus 30/12.5 in children and adolescents under 18 years of age is not recommended due to lack of data on safety and efficacy.
Patients with renal impairment or undergoing dialysis.
Patients with mild renal impairment and arterial hypertension (creatinine clearance > 45 mL/min) may receive the same dose and dosing regimen of Zokardis® Plus 30/12.5 as patients with normal renal function.
The use of Zokardis® Plus 30/12.5 is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 45 mL/min) (see section "Special precautions").
Zokardis® Plus 30/12.5 is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications").
The use of Zokardis® Plus 30/12.5 is not recommended in hypertensive patients undergoing dialysis.
Patients with hepatic impairment.
For hypertensive patients with mild or moderate hepatic impairment who have previously received zofenopril 30 mg as monotherapy, the same dosing regimen as in patients with normal liver function may be applied.
Zokardis® Plus 30/12.5 is contraindicated in hypertensive patients with severe hepatic impairment.
Method of Administration.
Zokardis® Plus 30/12.5 should be administered once daily, independent of food intake.
To facilitate swallowing, the tablet may be divided into two halves, which should be swallowed one after the other at the prescribed time.
Children.
The use of the drug in children is not recommended due to lack of data on safety and efficacy.
Overdose.
Symptoms of overdose include severe arterial hypotension, shock, stupor, bradycardia, electrolyte disturbances, and renal failure.
Treatment.
Symptomatic and supportive therapy should be administered. In case of overdose, the patient should be closely monitored, preferably in an intensive care unit. Frequent monitoring of serum electrolytes and creatinine levels is required. Therapeutic measures depend on the nature and severity of symptoms. If the drug was recently ingested, measures to prevent absorption should be taken, such as gastric lavage, administration of adsorbents, and sodium sulfate. In case of hypotension, the patient should be placed in shock position and consideration should be given to volume-expanding agents and/or angiotensin II administration. Bradycardia and excessive vagal reactions should be treated with atropine. If necessary, an artificial pacemaker should be used. ACE inhibitors can be removed from the circulation by hemodialysis. The use of high-flux polycrylonitrile membranes should be avoided.
Overdose with hydrochlorothiazide is associated with electrolyte disturbances (hypokalemia, hypochloremia) and dehydration due to excessive diuresis. The most common signs and symptoms of overdose are nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or exacerbation of cardiac arrhythmias caused by concomitant use of digitalis glycosides or certain antiarrhythmic agents.
Adverse reactions.
In controlled clinical studies involving 597 patients who were randomly administered zofenopril and hydrochlorothiazide, no adverse reactions specific to this combination were observed. Only adverse reactions previously established for calcium zofenopril or hydrochlorothiazide were noted. The frequency of adverse reactions was not related to the patient's sex or age.
List of adverse reactions in table format.
All adverse reactions observed during clinical trials, as well as those having at least a possible or probable relationship to treatment with Zokardis® Plus 30/12.5, are listed in Table 1. These reactions are classified by system organ class and frequency of occurrence: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (≤ 1/10,000).
Table 1
| MedDRA System organ class |
Adverse reactions |
Frequency |
| Infections and infestations |
Infectious disease |
Occasional |
| Bronchitis |
Occasional |
|
| Pharyngitis |
Occasional |
|
| Metabolism and nutrition disorders |
Hypercholesterolemia |
Occasional |
| Hypoglycemia |
Occasional |
|
| Hyperlipidemia |
Occasional |
|
| Hypokalemia |
Occasional |
|
| Hyperkalemia |
Occasional |
|
| Hyperuricemia |
Occasional |
|
| Nervous system disorders |
Dizziness |
Common |
| Headache |
Common |
|
| Somnolence |
Occasional |
|
| Syncope |
Occasional |
|
| Hypertension |
Occasional |
|
| Psychiatric disorders |
Insomnia |
Occasional |
| Cardiac disorders |
Angina pectoris |
Occasional |
| Atrial fibrillation |
Occasional |
|
| Myocardial infarction |
Occasional |
|
| Palpitations |
Occasional |
|
| Vascular disorders |
Flushing |
Occasional |
| Arterial hypotension |
Occasional |
|
| Arterial hypertension |
Occasional |
|
| Respiratory, thoracic and mediastinal disorders |
Cough |
Common |
| Dyspnea |
Occasional |
|
| Gastrointestinal disorders |
Nausea |
Occasional |
| Dyspepsia |
Occasional |
|
| Gastritis |
Occasional |
|
| Gingivitis |
Occasional |
|
| Dry mouth |
Occasional |
|
| Abdominal pain |
Occasional |
|
| Skin and subcutaneous tissue disorders |
Angioedema |
Occasional |
| Psoriasis |
Occasional |
|
| Acne |
Occasional |
|
| Skin dryness |
Occasional |
|
| Pruritus |
Occasional |
|
| Urticaria |
Occasional |
|
| Musculoskeletal and connective tissue disorders |
Back pain |
Occasional |
| Renal and urinary disorders |
Polyuria |
Occasional |
| General disorders and administration site conditions |
Asthenia |
Occasional |
| Influenza-like symptoms |
Occasional |
|
| Peripheral edema |
Occasional |
|
| Reproductive system and breast disorders |
Erectile dysfunction |
Occasional |
| Investigations |
Increased creatinine levels |
Occasional |
| Liver function test abnormal |
Occasional |
ADDITIONAL INFORMATION ON INDIVIDUAL COMPONENTS.
Known adverse reactions characteristic of each active substance when used individually may occur during the use of Zokardis® Plus 30/12.5.
ZOFENOPRIL.
The adverse reactions listed in Table 2 below are typical for ACE inhibitors and were observed during clinical studies in patients receiving zofenopril.
Table 2
| MedDRA Organ system class |
Adverse reactions |
Frequency |
| Nervous system disorders |
Dizziness |
Common |
| Headache |
Common |
|
| Respiratory, thoracic and mediastinal disorders |
Cough |
Common |
| Gastrointestinal disorders |
Nausea |
Common |
| Vomiting |
Common |
|
| Skin and subcutaneous tissue disorders |
Rash |
Uncommon |
| Angioedema |
Rare |
|
| Musculoskeletal and connective tissue disorders |
Muscle cramps |
Uncommon |
| General disorders and administration site conditions |
Fatigue |
Common |
| Asthenia |
Uncommon |
Side effects observed during the use of ACE inhibitors.
Disorders of the blood and lymphatic system.
Agranulocytosis and pancytopenia may occur in some patients.
There have been reports of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.
Endocrine disorders.
Frequency unknown: disorders of antidiuretic hormone secretion.
Metabolism and nutrition disorders.
Very rare: hypoglycemia.
Psychiatric disorders.
Rare: depression, mood changes, sleep disturbances, confusion.
Disorders of the nervous system.
Sometimes: paresthesia, dysgeusia, disturbance of equilibrium.
Disorders of the eye.
Rare: blurred vision.
Disorders of the ear and labyrinth.
Rare: tinnitus.
Cardiac disorders.
There have been reports of isolated cases of tachycardia, palpitations, arrhythmias, angina, and myocardial infarction during ACE inhibitor therapy in the presence of arterial hypotension.
Vascular disorders.
Severe arterial hypotension has been observed at the beginning of therapy or when increasing the dose of the drug. It most commonly occurs in certain risk groups (see section "Special precautions"). Arterial hypotension may be accompanied by symptoms such as dizziness, feeling of weakness, visual disturbances, and rarely – loss of consciousness (syncope).
Rarely, skin hyperemia is observed.
Respiratory, thoracic and mediastinal disorders.
Rare: dyspnea, sinusitis, rhinitis, glossitis, bronchitis, bronchospasm have been reported. In a small subgroup of patients, the use of ACE inhibitors was associated with the development of angioedema involving facial and oropharyngeal tissues. In isolated cases, angioedema caused obstruction of the upper airways, leading to fatal outcomes.
Gastrointestinal disorders.
Sometimes: abdominal pain, diarrhea, constipation, and dry mouth may occur.
There have been reports of isolated cases of pancreatitis and intestinal obstruction associated with the use of ACE inhibitors.
Very rarely, angioedema of the small intestine is observed.
Hepatobiliary disorders.
There have been reports of isolated cases of cholestatic jaundice and hepatitis associated with the use of ACE inhibitors.
Skin and subcutaneous tissue disorders.
Allergic and hypersensitivity reactions such as pruritus, urticaria, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriasis-like rashes, alopecia, which may be accompanied by fever, myalgia, arthralgia, eosinophilia, and/or elevated titers of antinuclear antibodies (ANA), may sometimes occur.
Rare: hyperhidrosis.
Musculoskeletal and connective tissue disorders.
Sometimes: myalgia.
Renal and urinary disorders.
Development or worsening of renal failure is possible. There have been reports of acute renal failure (see section "Special precautions").
Rarely, disorders of urination were observed.
Reproductive system and breast disorders.
Rare: erectile dysfunction.
General disorders and administration site conditions.
Very rare: peripheral edema and chest pain.
Additional investigations.
Increased blood urea and creatinine levels may occur, which are reversible upon discontinuation of the drug, particularly in patients with pre-existing renal impairment, severe heart failure, and renovascular hypertension.
In some patients, decreased hemoglobin and hematocrit, reduced platelet and leukocyte counts have been observed. There have been reports of increased liver enzymes and bilirubin levels in serum.
HYDROCHLOROTHIAZIDE.
The following adverse reactions have been observed during the use of hydrochlorothiazide as monotherapy.
Benign, malignant and unspecified neoplasms (including cysts and polyps).
Frequency unknown: non-melanoma skin cancer (NMSC) (basal cell carcinoma and squamous cell carcinoma).
NMSC: Based on available epidemiological data, a link has been established between cumulative hydrochlorothiazide dose and NMSC (see also sections "Special precautions" and "Pharmacodynamics").
Disorders of the blood and lymphatic system.
Leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, bone marrow suppression.
Immune system disorders.
Anaphylactic reactions.
Metabolism and nutrition disorders.
Anorexia, dehydration, gout, diabetes mellitus, metabolic alkalosis, hyperuricemia, hyperglycemia, hyperamylasemia, electrolyte disturbances (hyponatremia, hypokalemia, hypomagnesemia, hypochloremia, hypercalcemia, including).
Psychiatric disorders.
Apathy, confusion, depression, increased excitability, restlessness, sleep disturbances.
Disorders of the nervous system.
Convulsions, clouding of consciousness, coma, headache, dizziness, paresthesia, paresis.
Disorders of the eye.
Frequency unknown: choroidal effusion, acute myopia, acute angle-closure glaucoma.
Xanthopsia, blurred vision, myopia (exacerbation), decreased lacrimation.
Disorders of the ear and labyrinth.
Vertigo.
Cardiac disorders.
Cardiac arrhythmias, palpitations.
Vascular disorders.
Orthostatic hypotension, thrombosis, embolism, shock.
Respiratory, thoracic and mediastinal disorders.
Pneumonia, interstitial lung diseases, pulmonary edema.
Frequency "very rare": acute respiratory distress syndrome (ARDS) (see section "Special precautions").
Gastrointestinal disorders.
Dry mouth, nausea, vomiting, gastric discomfort, diarrhea, constipation, abdominal pain, paralytic ileus, flatulence, sialadenitis, pancreatitis.
Hepatobiliary disorders.
Cholestatic jaundice, cholecystitis.
Skin and subcutaneous tissue disorders.
Pruritus, purpura, urticaria, photosensitivity reactions, rash, cutaneous form of systemic lupus erythematosus, necrotizing vasculitis, toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders.
Muscle cramps, myalgia.
Renal and urinary disorders.
Renal function impairment, acute renal failure, interstitial nephritis, glucosuria.
Reproductive system and breast disorders.
Erectile dysfunction.
General disorders and administration site conditions.
Asthenia, fever, fatigue, thirst.
Additional investigations.
Changes in electrocardiogram, increased blood cholesterol and triglyceride levels.
Reporting suspected adverse reactions.
Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals should report any suspected adverse reactions.
Shelf life. 3 years.
Do not use the medicinal product after the expiry date stated on the packaging.
Storage conditions.
Store at temperatures not exceeding 30 °C. Keep out of the reach of children.
Packaging.
Blister packs of 14 film-coated tablets; 1 or 2 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
Menarini - von Heyden GmbH.
A. Menarini Manufacturing Logistics and Services S.r.l.
Manufacturer's address and location of operations.
Leipziger Strasse 7-13, 01097 Dresden, Germany.
Via Campo di Pile, 67100 L'Aquila (AQ), Italy.
Marketing Authorization Holder.
Menarini International Operations Luxembourg S.A.
Address of the Marketing Authorization Holder.
1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.