Zokardis® 7.5 mg
UkraineTable of Contents
I N S T R U C T I O N for medical use of the medicinal product ZOCARDISâ 7.5 MG
Composition:
Active substance: 1 film-coated tablet contains 7.5 mg of zofenopril calcium, equivalent to 7.2 mg of zofenopril;
Excipients:
Core: microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, magnesium stearate, colloidal anhydrous silicon dioxide;
Film coating: hypromellose, titanium dioxide (E 171), polyethylene glycol 400, polyethylene glycol 6000.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: white-colored, round, biconvex film-coated tablets.
Pharmacotherapeutic group.
Angiotensin-converting enzyme (ACE) inhibitors, single-component preparations.
ATC code C09A A15.
Pharmacological Properties
Pharmacodynamics
The mechanism of action of the medicinal product Zokardis® in hypertension and acute myocardial infarction is primarily due to inhibition of the plasma renin-angiotensin-aldosterone system. Inhibition of ACE (Ki 0.4 nM in rabbit lungs for the arginine salt of zofenoprilat) leads to a reduction in angiotensin II levels in plasma, resulting in decreased vasoconstrictive activity and aldosterone secretion. Concurrently, even a slight reduction in aldosterone may lead to a modest increase in serum potassium concentration, accompanied by sodium and fluid loss. Due to inhibition of angiotensin II's effect on renin secretion, plasma renin activity increases. ACE activity in plasma decreases by 53.4% 24 hours after a single oral dose of 30 mg zofenopril calcium.
Inhibition of ACE leads to increased activity of the circulating and local kallikrein-kinin system, which influences peripheral vasodilation via activation of the prostaglandin system. This mechanism may contribute to the antihypertensive effect of zofenopril calcium and is likely responsible for certain adverse effects. In patients with arterial hypertension, administration of Zokardis® results in comparable reductions in blood pressure in both supine and standing positions without compensatory increases in heart rate. After administration of Zokardis®, mean systemic vascular resistance tends to decrease. For some patients, optimal reduction in arterial pressure may require several weeks of therapy. The antihypertensive effect is maintained during long-term treatment. Rapid rebound hypertension does not occur upon abrupt discontinuation of therapy. Currently, there are no data on the effect of Zokardis® on morbidity and mortality in patients with arterial hypertension. Although antihypertensive efficacy has been demonstrated across all racial groups, the average response to monotherapy with an ACE inhibitor is lower in black patients (typically from a hypertensive population with low renin levels) compared to other patients. This difference disappears when a diuretic is added. The clinical benefit of early administration of Zokardis® after myocardial infarction may be related to several factors, such as reduction in plasma angiotensin II levels (thereby limiting ventricular remodeling, which may negatively affect survival prognosis in post-infarction patients) and increased concentration of vasodilatory substances in plasma/tissues (prostaglandin-kinin system).
A randomized, placebo-controlled clinical trial of zofenopril was conducted in 1556 patients with prior myocardial infarction who did not receive thrombolytic therapy. Treatment was initiated within 24 hours and continued for 6 weeks. In the group treated with zofenopril, the incidence of major combined endpoints (severe heart failure and/or death within 6 weeks) was reduced: zofenopril – 7.1%, placebo – 10.6%. Survival rates at one year were higher in the Zokardis® treatment group.
Other Information
Two large randomized controlled trials (ONTARGET [Ongoing Telmisartan Monotherapy and Telmisartan and Ramipril Combination Therapy, Global Endpoint Trial] and VA NEPHRON-D [Diabetic Nephropathy]) evaluated the use of combined ACE inhibitors with angiotensin receptor blockers (ARBs).
ONTARGET was a study conducted in patients with cardiovascular and cerebrovascular diseases or type 2 diabetes mellitus with evidence of target organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes and diabetic nephropathy. These studies did not demonstrate a significant beneficial effect on renal function and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Due to similar pharmacodynamic properties, these findings are also relevant for other ACE inhibitors and angiotensin II receptor blockers.
ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) was a study evaluating 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 prematurely terminated due to an increased risk of adverse outcomes. The number of deaths due to cardiovascular causes and strokes was higher in the aliskiren group than in the placebo group, and serious adverse reactions (hyperkalemia, hypotension, and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.
Pharmacokinetics
Zofenopril calcium is a prodrug, as the active inhibitor is the sulfhydryl-containing zofenoprilat, formed by thioester hydrolysis.
Absorption
Zofenopril calcium is rapidly and completely absorbed after oral administration and is almost entirely converted to zofenoprilat, which reaches peak plasma concentration within 1.5 hours after oral administration of Zokardis®. The kinetics of a single dose are linear within the dose range of 10–80 mg zofenopril calcium, and no accumulation occurs after administration of 15–60 mg zofenopril calcium over 3 weeks. Food in the gastrointestinal tract reduces the rate of absorption but not the extent of absorption, and AUC values of zofenoprilat are practically identical after administration with or without food.
Distribution
After administration of radiolabeled zofenopril calcium, approximately 88% of circulating radioactivity was ex vivo protein-bound, and the volume of distribution at steady state was 96 L.
Metabolism
After administration of radiolabeled zofenopril calcium, eight metabolites were identified in human urine, accounting for 76% of 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%). After oral administration of zofenopril calcium, the elimination half-life of zofenoprilat is 5.5 hours, and total body clearance is 1300 mL/min.
Excretion
Radiolabeled zofenoprilat administered intravenously is excreted in urine (76%) and feces (16%). After oral administration of radiolabeled zofenopril calcium, 69% and 26% of radioactivity are excreted in urine and feces, respectively, indicating dual elimination pathways (renal and hepatic).
Pharmacokinetics in Specific Patient Populations
Elderly Patients
Dose adjustment is not required in elderly patients if renal function is normal.
Renal Impairment
Based on comparison of key pharmacokinetic parameters of zofenopril after oral administration of radiolabeled zofenopril calcium, elimination of zofenopril in patients with renal impairment (creatinine clearance >45 and <90 mL/min) occurs at the same rate 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 rate is reduced by 50% compared to normal. This indicates that such patients should receive half the usual starting dose of Zokardis®.
In patients with end-stage renal disease undergoing hemodialysis or peritoneal dialysis, elimination rate is reduced to 25% of normal. This indicates that such patients should receive one-quarter of the usual initial dose of Zokardis®.
Hepatic Impairment
In patients with mild to moderate hepatic impairment receiving single doses of radiolabeled zofenopril calcium, Cmax and Tmax values of zofenoprilat were similar to those in patients without hepatic dysfunction. However, AUC values in patients with cirrhosis were nearly twice those in patients with normal liver function. This indicates that patients with mild to moderate hepatic impairment should receive half the usual starting dose of Zokardis® used in patients with normal liver function.
There are no pharmacokinetic data available for zofenopril and zofenoprilat in patients with severe hepatic impairment; therefore, zofenopril is contraindicated in such patients.
Clinical characteristics.
Indications.
Arterial hypertension
Treatment of mild to moderate essential hypertension.
Acute myocardial infarction
Treatment of acute myocardial infarction (within the first 24 hours) with signs and symptoms (or without symptoms) of heart failure and stable hemodynamics, provided thrombolytic therapy has not been administered.
Contraindications.
Hypersensitivity to zofenopril calcium or to any other angiotensin-converting enzyme (ACE) inhibitor, or to any of the excipients contained in the medicinal product.
History of angioedema associated with previous ACE inhibitor therapy.
Concomitant use with sacubitril/valsartan. Treatment with Zocardis® must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
Hereditary or idiopathic angioedema.
Severe hepatic impairment.
Bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.
Pregnancy or planned pregnancy (see section "Use during pregnancy or breastfeeding").
The medicinal product is contraindicated in women of childbearing potential who are not using effective contraception.
Concomitant use of Zocardis® with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²).
Interaction with other medicinal products and other forms of interaction.
Medicinal products that increase the risk of angioedema
Concomitant use of ACE inhibitors and sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections "Contraindications" and "Special precautions for use").
Concomitant use of ACE inhibitors with racécadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin may increase the risk of angioedema (see section "Special precautions for use").
Concomitant use with the following medicinal products is not recommended.
Potassium-sparing diuretics, potassium-containing supplements, potassium-containing salt substitutes, and other medicinal products that increase potassium levels
Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients treated with zofenopril. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium-containing 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 and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic, similar to amiloride. Therefore, combination of zofenopril with the above-mentioned medicinal products is not recommended. If such combination is necessary, it should be used with caution and serum potassium levels should be monitored frequently.
ACE inhibitors, angiotensin II receptor blockers, or aliskiren
Clinical studies have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with an increased risk of adverse reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single RAAS-active agent (see sections "Contraindications", "Special precautions for use", "Pharmacodynamics").
Concomitant use with the following medicinal products requires special caution.
Diuretics (thiazides or loop diuretics). Prior use of high doses of diuretics may lead to dehydration and risk of developing arterial hypotension at the beginning of zofenopril therapy. The likelihood of hypotensive effects can be reduced by discontinuing the diuretic, increasing fluid and salt intake, or initiating therapy with low doses of zofenopril.
Lithium. Cases of reversible increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of ACE inhibitors. Concomitant use of thiazide diuretics with lithium-containing products may increase the risk of lithium intoxication, which may be further increased when ACE inhibitors are used concomitantly. Therefore, concomitant use of zofenopril with lithium-containing products is not recommended, and if such combination is necessary, serum lithium levels should be closely monitored.
Gold. Cases have been reported of increased incidence of nitritoid reactions (vasodilatory symptoms including flushing, nausea, dizziness, hypotension) of potentially severe nature in patients receiving ACE inhibitors and parenteral gold therapy (e.g., sodium aurothiomalate).
Anesthetic agents. ACE inhibitors may potentiate the hypotensive effect of anesthetic agents.
Narcotics/tricyclic antidepressants/antipsychotics/barbiturates. Orthostatic hypotension may occur.
Other antihypertensive agents (beta-blockers, alpha-blockers, calcium antagonists). Additive hypotensive effects or enhanced drug effects are possible. Nitroglycerin, other nitrates, and vasodilators should be used with caution.
Cimetidine. Increased risk of arterial hypotension.
Cyclosporine. Hyperkalemia may occur with concomitant use of ACE inhibitors and cyclosporine. Monitoring of serum potassium levels is recommended.
Heparin. Hyperkalemia may occur with concomitant use of ACE inhibitors and heparin. Monitoring of serum potassium levels is recommended.
Allopurinol, cytostatic agents, immunosuppressants, systemic corticosteroids, and procainamide. Concomitant use with ACE inhibitors increases the risk of hypersensitivity reactions. Concomitant use with ACE inhibitors may also increase the risk of leukopenia.
Antidiabetic agents. Rarely, ACE inhibitors may enhance the hypoglycemic effect of insulin and oral antidiabetic agents, such as sulfonylureas, in patients with diabetes mellitus. Therefore, when used concomitantly with ACE inhibitors, a reduction in the dose of antidiabetic agents may be necessary.
Hemodialysis using high-flux dialysis membranes. Risk of anaphylactoid reactions is increased when used concomitantly with ACE inhibitors.
Considerations for concomitant use.
Nonsteroidal anti-inflammatory drugs (including acetylsalicylic acid at doses ≥ 3 g/day). The antihypertensive effect of ACE inhibitors may be reduced. Furthermore, NSAIDs and ACE inhibitors may additionally increase serum potassium levels, while renal function may deteriorate. These effects are reversible and occur more frequently in patients with impaired renal function. Acute renal failure may rarely occur, particularly in patients with renal impairment, especially elderly or dehydrated patients.
Antacids reduce the bioavailability of ACE inhibitors.
Sympathomimetic agents may reduce the antihypertensive effect of ACE inhibitors. Close monitoring of such patients is necessary to ensure the desired therapeutic effect is achieved.
Food. The rate, but not the extent, of absorption of zofenopril calcium may be reduced.
Additional information. There are no direct clinical data available on interactions between zofenopril and other drugs metabolized by CYP enzymes. However, in vitro metabolism studies of zofenopril demonstrate no potential for interaction with drugs metabolized by CYP enzymes.
Special precautions for use.
Hypotension
Like other ACE inhibitors, Zokardis® may cause a significant drop in blood pressure, particularly after the first dose, although symptomatic hypotension is rarely observed in patients with uncomplicated arterial hypertension. It is more likely to occur in patients with fluid and electrolyte disturbances due to diuretic therapy, dietary salt restriction, diarrhea, or vomiting, or in those with severe renin-dependent hypertension.
Symptomatic hypotension may occur in patients with heart failure, whether or not associated with renal impairment. It is more likely in patients with more severe heart failure, particularly those receiving high doses of loop diuretics, hyponatremia, or impaired renal function. Treatment of patients at increased risk of symptomatic hypotension should be initiated under strict medical supervision, preferably in a hospital setting, using low doses and careful dose titration.
If possible, diuretic therapy should be temporarily discontinued at the start of Zokardis® treatment.
The same approach applies to patients with angina or cerebrovascular disease, in whom excessive hypotension may lead to myocardial infarction or cerebrovascular events.
In case of hypotension, the patient should be placed in a supine position. Intravenous administration of physiological saline may be necessary to restore fluid volume. The occurrence of hypotension after the initial dose does not preclude subsequent careful dose titration once adequate control is achieved.
In some patients with heart failure and normal or low blood pressure, additional reduction in systemic arterial pressure may occur during Zokardis® therapy. This is an expected effect and usually not a reason to discontinue treatment. However, if hypotension becomes symptomatic, dose reduction or discontinuation of Zokardis® therapy may be required.
Hypotension in acute myocardial infarction
Zokardis® treatment should not be initiated in patients with acute myocardial infarction if there is a risk of additional severe hemodynamic depression following vasodilator therapy. This applies to patients with systolic blood pressure < 100 mm Hg or in cases of cardiogenic shock. Zokardis® treatment in patients with acute myocardial infarction may lead to severe hypotension. If prolonged hypotension occurs (systolic blood pressure < 90 mm Hg for more than 1 hour), Zokardis® should be discontinued. Zokardis® should only be used in patients with severe heart failure after acute myocardial infarction if the patient has a stable hemodynamic status.
Patients with acute myocardial infarction and hepatic impairment
The efficacy and safety of Zokardis® in patients with hepatic impairment who develop myocardial infarction have not been established. Therefore, Zokardis® should not be used in these patient groups.
Elderly patients
Zokardis® should be used with caution in elderly patients (aged 75 years and older) with myocardial infarction.
Patients with renovascular hypertension
There is an increased risk of severe hypotension and renal failure in patients with renovascular hypertension and pre-existing bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney when treated with ACE inhibitors. Additional risk factors include diuretic therapy. In patients with unilateral renal artery stenosis, loss of renal function may occur even with minor changes in serum creatinine levels. If Zokardis® treatment is considered absolutely necessary, it should be initiated in a hospital setting under strict medical supervision, starting with low doses and careful dose titration. Diuretic therapy should be temporarily discontinued at the start of Zokardis® treatment, and renal function should be monitored during the first few weeks of therapy.
Patients with renal impairment
Zokardis® should be used cautiously in patients with renal impairment, as they require lower dosing. Careful monitoring of renal function is essential during therapy. Cases of renal failure have been reported with ACE inhibitors, particularly in patients with severe heart failure or pre-existing renal disease, including renal artery stenosis. In some patients with mild pre-existing renal disease, blood urea and creatinine concentrations may increase, especially when used concomitantly with diuretics. Dose reduction of the ACE inhibitor and/or discontinuation of the diuretic may be required. Monitoring of renal function is recommended during the first few weeks of therapy.
The efficacy and safety of Zokardis® in patients with renal impairment who develop myocardial infarction have not been established. Therefore, Zokardis® should not be used in patients with renal impairment (serum creatinine ≥ 2.1 mg/dL and proteinuria ≥ 500 mg/day) and myocardial infarction.
Patients undergoing dialysis
In patients undergoing dialysis with high-flux polyacrylonitrile membranes (e.g., AN 69), angioedema-like reactions such as facial swelling, flushing, hypotension, and dyspnea may occur within the first minutes of hemodialysis when receiving ACE inhibitors. An alternative membrane or antihypertensive agent is recommended.
The efficacy and safety of Zokardis® in patients with myocardial infarction undergoing hemodialysis have not been established. Therefore, Zokardis® should not be used in these patients.
Patients undergoing LDL apheresis
In patients receiving ACE inhibitors and undergoing LDL apheresis with dextran sulfate, anaphylactoid reactions similar to those observed during dialysis with high-flux polyacrylonitrile membranes (see above) may occur. For such patients, antihypertensive agents from another class are recommended.
Anaphylactic reactions during desensitization or after insect bites
Rarely, life-threatening anaphylactic reactions may occur in patients receiving ACE inhibitors during desensitization therapy (e.g., for hymenoptera venom) or after insect bites. Attempts to avoid such reactions by temporarily discontinuing ACE inhibitors have failed, as reactions recurred upon re-administration. Therefore, special caution is required for patients receiving ACE inhibitors undergoing such desensitization procedures.
Renal transplantation
Experience with the use of Zokardis® in patients with recent kidney transplantation is lacking.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism generally do not respond to antihypertensive agents acting via suppression of the renin-angiotensin system. Therefore, use of this drug is not recommended.
Hypersensitivity/angioedema
Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis, and/or larynx may occur in patients, most commonly during the first weeks of ACE inhibitor therapy. However, severe angioedema may rarely develop after prolonged ACE inhibitor treatment. In such cases, ACE inhibitors should be promptly discontinued and replaced with agents from another class for continued therapy.
Angioedema of the tongue, glottis, or larynx may be fatal. Immediate treatment is required, which may include subcutaneous injection of 1:1000 adrenaline solution (0.3–0.5 mL) or slow intravenous administration of 1 mg/mL adrenaline (diluted according to instructions) with strict ECG and blood pressure monitoring. The patient should be hospitalized and monitored for at least 12–24 hours and not discharged until symptoms have completely resolved.
Even in cases of isolated tongue swelling without respiratory distress, observation may be necessary, as treatment with antihistamines and corticosteroids may be insufficient.
ACE inhibitors cause a higher incidence of angioedema in patients of Black race compared to other racial groups.
The risk of angioedema may be increased in patients with a history of angioedema not related to ACE inhibitor therapy (see section "Contraindications").
Concomitant use of ACE inhibitors and sacubitril/valsartan is contraindicated due to increased risk of angioedema. Sacubitril/valsartan therapy should not be initiated earlier than 36 hours after the last dose of Zokardis®. Zokardis® therapy 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 forms of interaction").
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin may increase the risk of angioedema (e.g., airway swelling or tongue swelling with or without breathing difficulties) (see section "Interaction with other medicinal products and other forms of interaction"). Special caution is required when initiating therapy with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving ACE inhibitors.
Cough
A dry, non-productive cough may occur during Zokardis® therapy, which resolves after discontinuation of the drug. Cough caused by ACE inhibitors should be considered in the differential diagnosis of cough.
Hepatic impairment
Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes fatal. The mechanism of this syndrome is not established. Patients receiving ACE inhibitors who develop jaundice or marked elevation of liver enzymes should discontinue ACE inhibitors and receive appropriate medical care.
Serum potassium
ACE inhibitors may cause hyperkalemia due to inhibition of aldosterone release. In patients with normal renal function, this effect is usually mild. However, hyperkalemia may occur in patients with impaired renal function and/or those taking potassium supplements (including salt substitutes), potassium-sparing diuretics, heparin, trimethoprim, co-trimoxazole (trimethoprim/sulfamethoxazole), and especially aldosterone antagonists or angiotensin receptor blockers. Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients taking ACE inhibitors, and serum potassium levels and renal function should be monitored (see section "Interaction with other medicinal products and other forms of interaction").
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and renal impairment (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").
If dual blockade is considered absolutely necessary, it should be performed only under specialist supervision with frequent and careful monitoring of renal function, electrolytes, and blood pressure.
ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Surgery/anesthesia
ACE inhibitors may cause arterial hypotension or even shock in patients undergoing major surgery or during anesthesia, as they may block angiotensin II formation, leading to compensatory renin release. If discontinuation of the ACE inhibitor is not possible, intravascular and plasma volume should be carefully monitored.
Aortic or mitral stenosis or hypertrophic cardiomyopathy. ACE inhibitors should be used with caution in patients with mitral stenosis or left ventricular outflow tract obstruction.
Neutropenia/agranulocytosis
Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. The risk of neutropenia is considered dose- and ACE inhibitor type-dependent and related to the patient's clinical status. Neutropenia rarely occurs in patients with uncomplicated clinical conditions. It may develop in patients with mild renal impairment and particularly in those with vascular pathology as a manifestation of collagenosis (e.g., systemic lupus erythematosus, scleroderma), during immunosuppressive therapy, allopurinol, procainamide, or combinations of these risk factors. Some of these patients may develop severe infections that may not respond to intensive antibiotic therapy.
In patients receiving zofenopril, white blood cell count and differential should be determined before treatment, every 2 weeks during the first 3 months of therapy, and periodically thereafter. Patients should be advised to report any signs of infection (e.g., sore throat, fever), and white blood cell differential counts should be performed. If neutropenia (neutrophil count < 1000/mm³) is confirmed or suspected, zofenopril and other concomitant medications should be discontinued.
This syndrome is reversible upon discontinuation of the ACE inhibitor.
Psoriasis
ACE inhibitors should be used with caution in patients with psoriasis.
Proteinuria
Proteinuria may occur, particularly in patients with pre-existing renal dysfunction or those receiving relatively high doses of ACE inhibitors. In patients with a history of renal disease, urine protein content (test strip on first morning urine sample) should be determined before treatment and periodically thereafter.
Diabetic patients
In patients with diabetes mellitus already receiving antidiabetic agents or insulin, blood glucose levels should be closely monitored during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").
Lithium
The combination of lithium and Zokardis® is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Ethnic differences
Like other ACE inhibitors, zofenopril may be less effective in reducing blood pressure in patients of Black race compared to other racial groups.
The risk of angioedema due to ACE inhibitor use is higher in patients of Black race.
Pregnancy
Zokardis® is contraindicated in pregnant women and women planning pregnancy. If pregnancy is confirmed during Zokardis® therapy, treatment must be immediately discontinued and replaced with another medicinal product approved for use during pregnancy.
Other
This medicinal product contains lactose and therefore should not be used in patients with rare hereditary conditions associated with galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding.
Pregnancy
ACE inhibitors are contraindicated in pregnant women and women planning pregnancy (see section "Contraindications"). Epidemiological data on teratogenic risk associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive, although a slight increase in risk cannot be excluded. For women planning pregnancy who require long-term ACE inhibitor therapy, alternative antihypertensive treatment with established safety should be considered. If pregnancy is confirmed during treatment with this medicinal product, therapy must be immediately discontinued and replaced with another medicinal product approved for use during pregnancy. Use of ACE inhibitors during the second and third trimesters of pregnancy may result in fetotoxic effects (impaired renal function, oligohydramnios, delayed skull ossification), and in newborns, renal failure, arterial hypotension, and hyperkalemia. If fetotoxic effects occur during ACE inhibitor therapy in the second or third trimester, ultrasound examination is indicated to assess renal function and skull ossification. Newborns whose mothers received ACE inhibitors during pregnancy should be closely monitored for arterial hypotension.
Breastfeeding
Since information on the use of zofenopril during breastfeeding is lacking, its use is not recommended in breastfeeding women. During breastfeeding, particularly of newborns or preterm infants, alternative, safer medicinal products are preferred.
Ability to influence reaction speed when driving or operating machinery.
No studies on the effect of zofenopril on the ability to drive or operate machinery have been conducted. Drowsiness, dizziness, or fatigue may occur during treatment; therefore, patients should take this into account and carefully assess their ability to drive or operate machinery.
Method of administration and dosage.
Doses
Arterial hypertension
Adults
The dose of the drug is individually adjusted depending on the level of arterial pressure before taking the next dose. Dose escalation is performed with an interval of 4 weeks.
Patients without fluid and electrolyte depletion
Treatment is initiated at a dose of 15 mg once daily, which is then increased to achieve optimal arterial pressure. The usual effective dose is 30 mg per day. The maximum dose is 60 mg per day, which can be taken once daily or divided into two doses. If necessary, additional antihypertensive agents, e.g., diuretics, may be prescribed (see sections "Contraindications", "Special precautions", "Interaction with other medicinal products and other forms of interactions", "Pharmacodynamics").
Patients with suspected fluid or electrolyte depletion
In patients at high risk of such conditions, arterial hypotension may occur after administration of the first dose (see section "Special precautions"). The initial dose is 15 mg once daily, provided that salt and/or fluid deficits have been corrected and long-term diuretic therapy has been discontinued 2–3 days prior to initiating angiotensin-converting enzyme (ACE) inhibitors. If this is not possible, the initial dose should be 7.5 mg once daily.
Patients at high risk of severe acute arterial hypotension require strict monitoring, preferably in a hospital setting, until maximal effect after the first dose is achieved and with each dose increase of the ACE inhibitor and/or diuretic. This also applies to patients with angina pectoris or cerebrovascular disease, in whom excessive hypotension may lead to myocardial infarction or cerebrovascular accident.
Renal impairment and dialysis
For patients with arterial hypertension and mild renal impairment (creatinine clearance > 45 mL/min), the same doses of Zokardis® should be prescribed as for patients with normal renal function. For patients with moderate to severe renal impairment (creatinine clearance < 45 mL/min), Zokardis® should be prescribed at half the therapeutic dose once daily. The initial dose and dosing regimen of Zokardis® for patients with arterial hypertension undergoing dialysis should be ¼ of the dose established for patients with normal renal function.
Recent clinical trials have demonstrated a high incidence of anaphylactoid-like reactions in patients taking ACE inhibitors during hemodialysis with high-flux membranes or during LDL apheresis.
Elderly patients (aged 65 years and older)
For elderly patients with normal creatinine clearance, there is no need to adjust the dose.
For elderly patients with reduced creatinine clearance (< 45 mL/min), half the daily dose is recommended.
Creatinine clearance can be calculated using the following formula:
| Creatinine clearance (mL/min) = |
[(140 - age) × body weight (kg)] |
| 72 × serum creatinine (mg/dL) |
The formula provided allows the calculation of creatinine clearance for men. For women, the resulting value should be multiplied by 0.85.
Hepatic impairment
For patients with mild or moderate hepatic impairment, the initial dose of Zocardis® should be half the dose administered to patients with normal liver function. Zocardis® is contraindicated in patients with severe hepatic impairment.
Acute myocardial infarction
Adults
Treatment with Zocardis® should be initiated within 24 hours of the onset of first symptoms of myocardial infarction and continued for 6 weeks. The following dosing regimen should be used:
Days 1 and 2: 7.5 mg every 12 hours;
Days 3 and 4: 15 mg every 12 hours;
From day 5 onwards: 30 mg every 12 hours.
If systolic blood pressure is low (≤ 120 mm Hg) at the start of treatment and during the first three days following myocardial infarction, the daily dose should not be increased. In case of arterial hypotension (≤ 100 mm Hg), treatment should continue using the previously prescribed dose. In case of severe hypotension (≤ 90 mm Hg on two consecutive blood pressure measurements taken at least 1 hour apart), Zocardis® should be discontinued. After 6 weeks of treatment, therapy should be discontinued in patients without signs of left ventricular dysfunction or heart failure, following assessment of the patient's condition. If such signs persist, treatment may be continued for a prolonged period. Appropriate standard therapy, such as nitrates, acetylsalicylic acid, or β-blockers, should also be used.
Elderly patients (over 65 years of age)
Zocardis® should be used with caution in patients aged 75 years and older with myocardial infarction.
Renal impairment and dialysis
The efficacy and safety of Zocardis® in the treatment of patients with myocardial infarction and renal impairment or those undergoing hemodialysis have not been established; therefore, Zocardis® should not be administered to such patients.
Hepatic impairment
The efficacy and safety of Zocardis® in the treatment of patients with myocardial infarction and hepatic impairment have not been established; therefore, Zocardis® should not be administered to such patients.
Method of administration
Zocardis® may be administered independently of food intake. Dosage should be adjusted according to the patient's therapeutic response.
Children
The safety and efficacy of Zocardis® in children and adolescents (under 18 years of age) have not been established. Therefore, the use of Zocardis® in pediatric patients is not recommended.
Overdose
Symptoms of overdose include severe arterial hypotension, shock, stupor, bradycardia, electrolyte disturbances, and renal failure. After an overdose, the patient should be under close medical supervision, preferably in an intensive care unit. Serum electrolytes and creatinine levels should be monitored frequently. Therapeutic measures depend on the nature and severity of symptoms. If overdose occurred recently, gastric lavage, activated charcoal, and sodium sulfate should be administered. In case of signs of arterial hypotension, the patient should be placed in a horizontal position with elevated legs. Consideration should be given to administration of plasma volume expanders and/or angiotensin II. In case of bradycardia and significant vagal reactions, atropine should be administered; if necessary, a cardiac pacemaker may be used. ACE inhibitors may be removed from circulation by hemodialysis. Polycrylonitrile membranes with high permeability should not be used.
Adverse reactions.
Table of adverse reactions
Below is a list of all adverse reactions reported in clinical practice for patients treated with Zocardis®. They are presented by organ systems and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), and very rare (≤ 1/10,000).
| System organ classes according to MedDRA dictionary |
Adverse reactions |
Frequency |
| Nervous system disorders |
Dizziness |
Common |
| Headache |
Common |
|
| Cardiac disorders |
Palpitations |
Uncommon |
| Vascular disorders |
Hypotension (see section "Special precautions") |
Uncommon |
| Syncope |
Uncommon |
|
| Respiratory, thoracic and mediastinal disorders |
Cough |
Common |
| Gastrointestinal disorders |
Nausea |
Common |
| Vomiting |
Common |
|
| Skin and subcutaneous tissue disorders |
Rash |
Uncommon |
| Angioedema |
Uncommon |
|
| Pruritus |
Uncommon |
|
| Urticaria |
Uncommon |
|
| Musculoskeletal and connective tissue disorders |
Muscle cramps |
Uncommon |
| General disorders |
Increased fatigue |
Common |
| Asthenia |
Uncommon |
|
| Metabolism and nutrition disorders |
Hyperkalaemia |
Uncommon |
The following adverse reactions have been observed during therapy with ACE inhibitors.
Blood and lymphatic system disorders
Agranulocytosis and pancytopenia may occur in some patients.
Hemolytic anemia has been reported in patients with glucose-6-phosphate dehydrogenase deficiency.
Metabolism and nutrition disorders
Very rare: hypoglycemia.
Endocrine system disorders
Frequency unknown: disturbance in antidiuretic hormone secretion.
Psychiatric disorders
Rare: depression, mood alterations, sleep disturbances, disorientation.
Nervous system disorders
Rare: taste disturbances, paresthesia, balance disorders.
Eye disorders
Rare: blurred vision.
Ear and labyrinth disorders
Rare: tinnitus.
Cardiac disorders
In isolated cases, tachycardia, arrhythmia, angina pectoris, and myocardial infarction have been reported after administration of ACE inhibitors in the presence of hypotension.
Vascular disorders
Severe hypotension may occur at the beginning of treatment or after dose escalation, particularly in patients belonging to specific risk groups (see section "Special precautions"). In the presence of hypotension, symptoms such as dizziness, weakness, and visual disturbances may occur. Flushing may also occur occasionally.
Respiratory system disorders
Rarely, dyspnea, sinusitis, rhinitis, glossitis, bronchitis, and bronchospasm have been reported. In a small number of patients, ACE inhibitors have caused angioedema affecting the face and oropharyngeal tissues. In isolated cases, angioedema of the upper airways has led to fatal obstruction.
Gastrointestinal disorders
Abdominal pain, diarrhea, constipation, and dry mouth may occur occasionally.
Pancreatitis and intestinal obstruction have been described in isolated cases after administration of ACE inhibitors.
Very rare: angioedema of the small intestine.
Hepatobiliary disorders
In isolated cases, cholestatic jaundice and hepatitis have been reported after administration of ACE inhibitors.
Skin and subcutaneous tissue disorders
Allergic reactions and hypersensitivity reactions such as polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriasiform eruptions, and alopecia may occur occasionally.
These may be accompanied by fever, myalgia, arthralgia, eosinophilia, and/or increased titers of antinuclear antibodies.
Rarely, hyperhidrosis may occur.
Musculoskeletal and connective tissue disorders
Myalgia may occur occasionally.
Renal and urinary disorders
Renal impairment may occur or worsen. Acute renal failure has been reported (see section "Special precautions").
Urinary disorders occur rarely.
Reproductive system and breast disorders
Rare: erectile dysfunction.
General disorders
Very rare: peripheral edema and chest pain.
Laboratory tests
Increased blood urea and creatinine levels may occur, reversible upon discontinuation of the drug, particularly in patients with renal impairment, severe heart failure, or renovascular hypertension.
Decreased hemoglobin, hematocrit, platelet count, and white blood cell count have been reported in some patients.
Elevated serum liver enzymes and bilirubin levels have also been reported.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, and patients or their legal representatives should report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions.
No special storage conditions required. Keep out of reach and sight of children.
Packaging.
7 film-coated tablets per blister, 1 blister per cardboard box;
14 film-coated tablets per blister, 1 or 2 blisters per cardboard box.
Prescription status.
Prescription only.
Manufacturer.
A. Menarini Manufacturing Logistics and Services S.r.l. / Menarini - von Heyden GmbH.
Manufacturer's address.
Via Campo di Pile, 67100 L’Aquila (AQ), Italy / Leipziger Strasse 7-13, 01097 Dresden, Germany.
Marketing authorization holder.
Menarini International Operations Luxembourg S.A.
Address of the marketing authorization holder and/or its representative.
1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.