Hiten

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HİTEN (HITEN)

Composition:

Active substance: perindopril tert-butylamine;

1 tablet contains 4 mg or 8 mg of perindopril tert-butylamine;

Excipients: anhydrous lactose, anhydrous colloidal silicon dioxide, microcrystalline cellulose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

4 mg tablets: white or almost white tablets, capsule-shaped, uncoated, with embossing "D" on one side and "5", "8" and a line between them on the other side;

8 mg tablets: white or almost white tablets, round, biconvex, uncoated, with embossing "D" on one side and "5", "9" and a line between them on the other side.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors, single-component. Perindopril. ATC code C09A A04.

Pharmacological Properties.

Pharmacodynamics.

Perindopril is an inhibitor of the enzyme converting angiotensin I into angiotensin II (angiotensin-converting enzyme, ACE). ACE, also known as kininase, is an exopeptidase that enables the conversion of angiotensin I into the vasoconstrictor angiotensin II, and also causes the breakdown of the vasodilator bradykinin into inactive heptapeptide. Inhibition of ACE leads to a decrease in angiotensin II concentration in plasma, resulting in increased plasma renin activity (due to inhibition of negative feedback on renin release) and reduced aldosterone secretion. Since ACE inactivates bradykinin, inhibition of ACE also leads to increased activity of circulating and local kallikrein-kinin system (and thus to activation of the prostaglandin system). This mechanism underlies the antihypertensive effect of ACE inhibitors and partially accounts for certain adverse effects (e.g., cough).

The pharmacological activity of the drug is due to the active metabolite of perindopril, perindoprilat. Other metabolites have not shown in vitro inhibition of ACE activity.

Arterial Hypertension.

Perindopril is effective in all stages of arterial hypertension (mild, moderate, and severe); it reduces systolic and diastolic blood pressure in both supine and standing positions. It decreases peripheral vascular resistance, resulting in reduced arterial pressure. As a consequence, peripheral blood flow increases without affecting heart rate. Renal blood flow usually increases, while glomerular filtration rate typically remains unchanged.

The maximum antihypertensive effect develops within 4–6 hours after a single dose and persists for at least 24 hours: the residual effect is approximately 87–100% of the maximum effect.

Blood pressure reduction occurs rapidly. In patients who respond to treatment, normalization of blood pressure occurs within one month and is maintained without development of tachyphylaxis.

Discontinuation of treatment does not lead to rebound effect. Perindopril reduces left ventricular hypertrophy.

It has been confirmed that perindopril exerts vasodilatory properties in humans. This improves the elasticity of large arteries and reduces the wall-to-lumen ratio in small arteries.

Additional therapy with a thiazide diuretic results in additive synergy. Combination of ACE inhibitors with thiazide diuretics also reduces the risk of diuretic-induced hypokalemia.

Perindopril reduces cardiac workload by decreasing preload and afterload.

Studies in patients with heart failure have shown:

• reduction in filling pressure of the left and right ventricles;
• reduction in systemic peripheral resistance;
• increase in cardiac index and improvement in cardiac output.

In comparative studies with placebo and other ACE inhibitors, initiation of treatment with a 2 mg dose of perindopril in patients with mild to moderate heart failure did not result in any significant reduction in blood pressure compared to placebo.

Patients with a history of cerebrovascular disease.

The multicenter, international, double-blind, randomized, placebo-controlled PROGRESS study demonstrated the benefits of 4-year treatment with perindopril (as monotherapy or in combination with indapamide) in preventing recurrent stroke in patients with a history of cerebrovascular disease.

The primary endpoint was stroke.

After a 2-week initial period of treatment with perindopril tert-butylamine 2 mg (equivalent to perindopril arginine 2.5 mg) once daily, followed by 2 weeks of treatment with 4 mg (equivalent to perindopril arginine 5 mg) once daily, 6,105 patients were randomized into two groups: one group received placebo (n = 3,054), and the other received perindopril tert-butylamine 4 mg (equivalent to perindopril arginine 5 mg) as monotherapy or in combination with indapamide (n = 3,051). Indapamide was added to patients who had indications for diuretic use and no contraindications to its administration.

This therapy was administered in addition to standard treatment for stroke and/or arterial hypertension or any other pathological conditions.

All patients enrolled in the study had a history of cerebrovascular disease (stroke or transient ischemic attack) within the previous 5 years. Blood pressure was not an inclusion criterion: 2,916 patients had arterial hypertension, and 3,189 patients had normal blood pressure.

After a mean follow-up of 3.9 years, systolic/diastolic blood pressure decreased on average by 9.0/4.0 mm Hg, and the risk of recurrent stroke (both ischemic and hemorrhagic) was significantly reduced by 28% (95% CI [17; 38], p < 0.0001) compared to the placebo group (10.1% vs. 13.8%).

Significant reductions were also observed in the risk of:

• fatal or disabling stroke (4% vs. 5.9%, corresponding to a 33% risk reduction);
• major cardiovascular events, namely cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (15% vs. 19.8%, corresponding to a 26% risk reduction);
• stroke-related dementia (1.4% vs. 2.1%, corresponding to a 34% risk reduction), and severe post-stroke cognitive impairment (1.6% vs. 2.8%, corresponding to a 45% risk reduction);
• major coronary events, including non-fatal myocardial infarction or fatal outcome of ischemic heart disease (3.8% vs. 5%, corresponding to a 26% risk reduction).

These therapeutic benefits were observed in patients regardless of the presence or absence of arterial hypertension, age, sex, stroke type, or presence of diabetes. The results of the PROGRESS study showed that one stroke could be prevented for every 23 patients treated over 5 years, and one major cardiovascular complication could be prevented for every 18 patients.

Patients with stable IHD.

An international, multicenter, randomized, double-blind, placebo-controlled clinical trial lasting 4 years included 12,218 patients aged 18 years and older, randomized into two groups: 6,110 patients received 8 mg of perindopril tert-butylamine and 6,108 patients received placebo. Patients enrolled had confirmed ischemic heart disease (IHD) and no clinical symptoms of heart failure. Overall, 90% of patients had a history of myocardial infarction and/or revascularization surgery. Most patients in the study received perindopril in addition to standard therapy: antiplatelet agents, lipid-lowering drugs, and beta-blockers.

The primary efficacy endpoint was a composite measure of cardiovascular mortality, non-fatal myocardial infarction, and/or cardiac arrest with successful resuscitation. Treatment with perindopril 8 mg (equivalent to perindopril arginine 10 mg) once daily resulted in a significant absolute reduction of the primary endpoint by 1.9% (relative risk reduction of 20%, 95% CI [9.4; 28.6], p < 0.001).

In patients with a history of myocardial infarction and/or revascularization, an absolute reduction of 2.2% in the primary endpoint was observed, corresponding to a relative risk reduction of 22.4% (95% CI [12.0; 31.6], p < 0.001) compared to placebo.

Use in children.

The safety and efficacy of perindopril in children and adolescents under 18 years of age have not been established.

In an open-label, non-comparative clinical study, 62 children aged 2 to 15 years with glomerular filtration rate > 30 mL/min/1.73 m² received perindopril at a mean dose of 0.07 mg/kg. The dose was individually adjusted, increasing up to a maximum of 0.135 mg/kg/day depending on patient profile and blood pressure response to treatment. 59 patients participated in the study for 3 months, and 36 patients continued treatment for at least 24 months (mean study duration: 44 months). Systolic and diastolic blood pressure remained stable (from study entry to last visit) in patients previously treated with other antihypertensive agents, and decreased in those not previously treated. More than 75% of children had systolic and diastolic blood pressure below the 95th percentile at their last study visit. The safety profile in children was consistent with the known safety profile of perindopril.

Pharmacokinetics.

Absorption. After oral administration, perindopril is rapidly absorbed, with peak plasma concentration reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour. Bioavailability ranges from 65% to 70%. Perindopril is a prodrug. Approximately 27% of the total absorbed perindopril is converted into perindoprilat, the active metabolite. In addition to the active perindoprilat, perindopril forms five inactive metabolites. Peak plasma concentration of perindoprilat is reached within 3–4 hours. Since food intake slows the conversion of perindopril into perindoprilat, thereby reducing bioavailability, perindopril should be taken orally once daily in the morning before meals. A linear relationship exists between perindopril dose and its plasma concentration.

Distribution. The volume of distribution is approximately 0.2 L/kg for unbound perindoprilat. Binding of perindoprilat to plasma proteins, primarily to angiotensin-converting enzyme, is 20%, but this value is dose-dependent.

Elimination. Perindoprilat is excreted in urine. The terminal elimination half-life of the unbound fraction is approximately 17 hours. Steady-state plasma concentration is achieved within 4 days of starting treatment.

Special patient populations. Elimination of perindoprilat is slowed in elderly patients and in patients with cardiac or renal insufficiency. For patients with renal impairment, dose adjustment is recommended based on the degree of impairment (creatinine clearance). Dialysis clearance of perindoprilat is 70 mL/min.

Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of the parent molecule is reduced by half. However, the amount of perindoprilat formed is not reduced. Therefore, dose adjustment is not required for such patients.

Clinical characteristics.

Indications.

• Arterial hypertension.
• Heart failure (only for 4 mg tablets).
• Prevention of recurrent stroke in patients with cerebrovascular disease.
• Prevention of cardiovascular complications in patients with documented stable ischemic heart disease. Long-term treatment reduces the risk of myocardial infarction and heart failure (based on the EUROPA trial results).

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients, or to any other ACE inhibitor;
• history of angioedema associated with previous ACE inhibitor therapy (see section "Special precautions");
• idiopathic or hereditary angioedema;
• concomitant use of medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction");
• concomitant use with sacubitril/valsartan. The use of the medicinal product Xiten must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction");
• pregnancy or planned pregnancy (see section "Use during pregnancy or breastfeeding");
• extracorporeal treatments leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction");
• significant bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Clinical data indicate 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 a higher incidence of adverse reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to treatment with a single RAAS-acting agent (see sections "Contraindications" and "Special precautions").

Medicinal products increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications", "Special precautions"). Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Perindopril therapy should be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions").

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) increases the risk of angioedema (see section "Special precautions").

Medicinal products causing hyperkalemia.

Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients receiving the medicinal product Xiten. Certain medicinal products or therapeutic classes may cause hyperkalemia, including: aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Concomitant use of these agents increases the risk of hyperkalemia. Therefore, concomitant use of Xiten with the above-mentioned agents is not recommended. If concomitant use is necessary, it should be done with caution and close monitoring of serum potassium levels.

Concomitant use is contraindicated (see section "Contraindications").

Aliskiren: concomitant use increases the risk of hyperkalemia, worsening renal function, cardiovascular complications, and fatal outcomes. Therefore, concomitant use of Xiten and aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function.

Extracorporeal treatments involving blood contact with negatively charged surfaces, such as high-flux dialysis or hemofiltration membranes (e.g., polyacrylonitrile membranes) or low-density lipoprotein apheresis with dextran sulfate, may increase the risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using different types of dialysis membranes or alternative classes of antihypertensive agents.

Concomitant use not recommended (see section "Special precautions").

Aliskiren: concomitant use increases the risk of hyperkalemia, worsening renal function, cardiovascular complications, and fatal outcomes. Therefore, concomitant use of Xiten and aliskiren is generally not recommended.

Concomitant use of ACE inhibitors and angiotensin receptor blockers. Clinical data show that in patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with RAAS-acting agents. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in individual cases under strict monitoring of renal function, potassium levels, and blood pressure.

Estramustine. Increases the risk of adverse reactions such as angioedema.

Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium salts. Hyperkalemia (including fatal cases) may occur, especially in patients with renal impairment (additive hyperkalemic effect). These agents are not recommended for concomitant use with perindopril (see section "Special precautions"). However, if concomitant use is necessary, it should be done with caution and frequent monitoring of plasma potassium levels.

For use of spironolactone in heart failure, see "Concomitant use requiring special attention".

Lithium. Concomitant use of ACE inhibitors with lithium preparations may lead to reversible increases in plasma lithium concentrations and, consequently, increased risk of lithium toxicity. Concomitant use of perindopril with lithium is not recommended. If such combination is clinically necessary, plasma lithium levels must be closely monitored (see section "Special precautions").

Racecadotril. Treatment with ACE inhibitors (e.g., perindopril) may induce angioedema. This risk may be increased when used concomitantly with racecadotril (a medicinal product used to treat acute diarrhea).

mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus). Patients receiving mTOR inhibitors may belong to a high-risk group for developing angioedema (see section "Special precautions").

Concomitant use requiring special attention.

Antidiabetic agents (insulin, oral hypoglycemic agents). Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the hypoglycemic effect, increasing the risk of hypoglycemia. This phenomenon is most likely to occur during the first weeks of combination therapy and in patients with renal impairment.

Baclofen. Enhances the antihypertensive effect. Blood pressure should be monitored and antihypertensive doses adjusted if necessary.

Diuretics. In patients receiving diuretics, especially those with disturbed water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The risk of hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume, or increasing salt intake prior to starting perindopril tert-butylamine. Treatment should be initiated at low doses with gradual dose escalation.

In arterial hypertension, if a previously prescribed diuretic may have caused water/electrolyte depletion, it should be discontinued before starting ACE inhibitor therapy (diuretic therapy may be resumed later) or the ACE inhibitor should be initiated at a low dose with gradual dose escalation.

In congestive heart failure on diuretic therapy, initiation of ACE inhibitor therapy should start at the lowest dose, possibly after reducing the diuretic dose.

In all cases, renal function (creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone (12.5–50 mg daily) is used concomitantly with low doses of ACE inhibitors, the following should be considered:

• Failure to follow prescribing recommendations for this combination may result in hyperkalemia (possibly fatal) in patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with an ACE inhibitor and a loop diuretic;
• absence of hyperkalemia and renal impairment should be confirmed before initiating this combination;
• close monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g/day. The antihypertensive effect of ACE inhibitors may be attenuated when used concomitantly with NSAIDs such as anti-inflammatory doses of acetylsalicylic acid, COX-2 inhibitors, or nonselective NSAIDs. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including acute renal failure, and elevated plasma potassium levels, particularly in patients with a history of renal impairment. Such combinations should be used cautiously, especially in elderly patients. Patients should be adequately hydrated, and renal function should be monitored closely upon initiation of combination therapy and periodically thereafter.

Concomitant use requiring attention.

Antihypertensive agents and vasodilators. Concomitant use of antihypertensive agents may enhance the hypotensive effect of perindopril tert-butylamine. Concomitant use with nitroglycerin and other nitrates, or with other vasodilators, may lead to additional blood pressure reduction.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin). In patients receiving a combination of a gliptin and an ACE inhibitor, the risk of angioedema may increase due to the gliptin's inhibition of dipeptidyl peptidase-IV (DPP-IV) activity.

Concomitant use of certain anesthetics, tricyclic antidepressants, or antipsychotics with ACE inhibitors may lead to further blood pressure reduction (see section "Special precautions").

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Gold. Nitrate-like reactions (symptoms: facial flushing, nausea, vomiting, and arterial hypotension) rarely occur in patients receiving ACE inhibitors, including perindopril, concomitantly with injectable gold preparations (sodium aurothiomalate).

Special precautions for use.

Stable ischemic heart disease.

If an episode of unstable angina (of any severity) occurred during the first month of perindopril treatment, the risk/benefit ratio should be carefully evaluated before deciding on continuing therapy.

Arterial hypotension.

ACE inhibitors may cause a reduction in blood pressure. Symptomatic arterial hypotension is less common in patients with uncomplicated arterial hypertension and is more likely to occur in patients with hypovolemia, in those taking diuretics, on a low-salt diet, in patients undergoing dialysis, in patients with diarrhea or vomiting, or in patients with severe renin-dependent arterial hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects"). Symptomatic arterial hypotension is more likely in patients with symptomatic heart failure, with or without concomitant renal impairment. The occurrence of symptomatic arterial hypotension is most likely in patients with more severe degrees of heart failure who are taking high doses of loop diuretics, have hyponatremia, or functional renal impairment. To reduce the risk of symptomatic arterial hypotension, patients should be under close medical supervision at the beginning of therapy and during dose titration (see sections "Dosage and administration" and "Undesirable effects"). The same precautions apply to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

In the event of arterial hypotension, the patient should be placed in a supine position and, if necessary, receive intravenous 0.9% (9 mg/mL) sodium chloride solution. Transient hypotension is not a contraindication for further use of the drug, which can usually be continued without difficulty after restoration of blood volume and blood pressure elevation.

In some patients with congestive heart failure and normal or low blood pressure, perindopril tert-butylamine may cause additional reduction in systemic arterial pressure. This effect is predictable and usually does not require discontinuation of the drug. If hypotension becomes symptomatic, dose reduction or discontinuation of the drug may become necessary.

Stenosis of aortic and mitral valves/hypertrophic cardiomyopathy.

As with other ACE inhibitors, perindopril tert-butylamine should be administered with caution in patients with mitral valve stenosis or left ventricular outflow tract obstruction (aortic stenosis or hypertrophic cardiomyopathy).

Renal impairment.

In patients with renal impairment (creatinine clearance < 60 mL/min), the initial dose of perindopril should be adjusted according to the patient's creatinine clearance (see section "Dosage and administration"), and subsequently based on the patient's response to treatment. Monitoring of potassium and creatinine levels is standard practice for such patients (see section "Undesirable effects").

In patients with symptomatic heart failure, arterial hypotension occurring at the initiation of ACE inhibitor therapy may lead to deterioration in renal function, and in some cases, to acute renal failure, which is usually reversible.

In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, treatment with ACE inhibitors has been associated with increases in blood urea and serum creatinine levels, which usually return to normal after discontinuation of therapy. This is particularly relevant in patients with pre-existing renal impairment. In patients with concomitant renovascular hypertension, the risk of severe arterial hypotension and renal failure is increased. Treatment of such patients should be initiated under close medical supervision, starting with low doses and cautious dose titration. In this context, diuretic therapy may predispose to arterial hypotension; therefore, diuretics should be discontinued and renal function should be monitored during the first weeks of treatment with perindopril tert-butylamine.

In some patients with arterial hypertension who had no evidence of renovascular disease prior to treatment, increases in blood urea and serum creatinine have developed, usually mild and transient, especially when perindopril tert-butylamine was administered concomitantly with a diuretic. However, this is more common in patients with pre-existing renal impairment. Dose reduction and/or discontinuation of the diuretic and/or perindopril tert-butylamine may become necessary.

Patients undergoing hemodialysis.

Anaphylactoid reactions have been reported in patients undergoing hemodialysis with high-flux polyacrylonitrile membranes while receiving concomitant ACE inhibitor therapy. Therefore, for such patients, a decision should be made regarding the use of an alternative type of dialysis membrane or an alternative class of antihypertensive agents.

Patients after kidney transplantation.

Experience with the use of perindopril tert-butylamine in patients after recent kidney transplantation is lacking.

Renovascular hypertension.

The use of ACE inhibitors in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney increases the risk of hypotension and renal failure (see section "Contraindications"). Diuretic therapy may be a predisposing factor. Loss of renal function may manifest as minimal changes in serum creatinine levels even in patients with stenosis of one renal artery.

Hypersensitivity/angioedema.

Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis, and/or larynx have been reported in patients receiving ACE inhibitors, including perindopril tert-butylamine (see section "Undesirable effects"). This may occur at any time during treatment. In such cases, the drug must be discontinued immediately and appropriate monitoring of the patient should be instituted until symptoms completely resolve. In isolated cases where swelling is limited to the face and lips, the patient's condition usually improves without treatment. Administration of antihistamines may be helpful in reducing symptoms.

Angioedema involving laryngeal swelling may be fatal. In cases where swelling involves the tongue, glottis, or larynx, causing airway obstruction, emergency treatment is required, which may include administration of adrenaline and/or securing airway patency. Patients should remain under close medical supervision until symptoms have completely resolved and the condition is stabilized.

Patients with a history of angioedema unrelated to ACE inhibitor use are at increased risk of developing angioedema during ACE inhibitor therapy (see section "Contraindications").

Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, there was no prior history of facial angioedema and C1 esterase levels were normal. The diagnosis of intestinal angioedema was confirmed by abdominal computed tomography, ultrasound, or during surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be excluded in the differential diagnosis of abdominal pain in patients taking ACE inhibitors.

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see section "Contraindications"). Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril 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 neutral endopeptidase (NEP) inhibitors (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) increases the risk of angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction"). Caution should be exercised when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.

Anaphylactoid reactions during LDL apheresis.

Rarely, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulfate. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.

Anaphylactoid reactions during desensitization therapy.

Anaphylactoid reactions may occur in patients receiving ACE inhibitors during desensitization therapy with bee venom-containing products. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy, but may recur if provocation tests are performed carelessly.

Hepatic impairment.

Rare cases of a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes fatal, have been reported during ACE inhibitor therapy. The mechanism of this syndrome is unknown. Patients who develop jaundice or marked elevations in liver enzymes during ACE inhibitor therapy should discontinue the drug and undergo appropriate medical evaluation and treatment (see section "Undesirable effects").

Neutropenia/agranulocytosis/thrombocytopenia/anemia.

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors. Perindopril should be used with extreme caution in patients with collagen vascular diseases, those receiving immunosuppressants, allopurinol, or procainamide, or in the presence of a combination of these risk factors, especially with pre-existing renal impairment. Serious infections, occasionally unresponsive to intensive antibiotic therapy, may develop in such patients. If perindopril is prescribed to these patients, periodic monitoring of white blood cell counts is recommended, and patients should be informed to report any signs of infection (e.g., sore throat, fever).

Racial factor.

ACE inhibitors are more likely to cause angioedema in patients of Black race than in those of other races. As with other ACE inhibitors, perindopril is less effective in reducing blood pressure in patients of Black race compared to patients of other races. This may be explained by the lower plasma renin levels in African-American patients with arterial hypertension.

Cough.

Cough has been reported during ACE inhibitor therapy. The cough is typically non-productive and persistent, and resolves after discontinuation of the drug. Cough induced by ACE inhibitors should be considered in the differential diagnosis of cough.

Surgery/anesthesia.

ACE inhibitors may block the secondary formation of angiotensin II in response to compensatory renin release during surgery or anesthesia with hypotensive agents. The drug should be discontinued one day before surgery. If arterial hypotension occurs and is considered to be due to this mechanism, the patient's condition can be normalized by increasing circulating blood volume.

Hyperkalemia.

Increased serum potassium concentration has been observed in some patients receiving ACE inhibitors, including perindopril. ACE inhibitors can cause hyperkalemia due to suppression of aldosterone release. This effect is usually mild in patients with normal renal function. Risk factors for hyperkalemia include renal impairment, worsening renal function, age (>70 years), diabetes mellitus, intercurrent conditions such as dehydration, acute heart decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, potassium-containing salt substitutes, or other drugs that increase serum potassium (e.g., heparin). Use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to significant increases in serum potassium. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. Potassium-sparing diuretics and angiotensin receptor blockers should be prescribed with caution in patients receiving ACE inhibitors, and careful monitoring of serum potassium and renal function is required. If concomitant use of perindopril and any of the above-mentioned substances is considered necessary, they should be used with caution and with frequent monitoring of serum potassium levels (see section "Interaction with other medicinal products and other forms of interaction").

Patients with diabetes mellitus.

Patients with diabetes mellitus receiving oral antidiabetic agents or insulin should have their blood glucose levels closely monitored during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

Lithium.

Concomitant use of lithium and perindopril is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Potassium-sparing agents, potassium-containing dietary supplements, or potassium-containing salt substitutes.

Concomitant use of perindopril with potassium-sparing agents or potassium-containing dietary supplements is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Data indicate 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 concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If dual blockade therapy is considered absolutely necessary, it should be administered only under specialist supervision with frequent and careful monitoring of renal function, electrolyte levels, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) should not receive aliskiren concomitantly (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Primary hyperaldosteronism. Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, use of this medicinal product is not recommended.

Excipients.

The drug contains lactose; therefore, perindopril tert-butylamine is not recommended for patients with rare hereditary intolerance to galactose, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency.

Use during pregnancy or breastfeeding.

Pregnancy. Use of ACE inhibitors is contraindicated during pregnancy (see section "Contraindications"). The drug should not be used in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment, the drug must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

Epidemiological data on the risk of teratogenic effects associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive, so a small increase in risk cannot be excluded. It is well established that ACE inhibitor use during the second and third trimesters of pregnancy causes fetotoxicity and neonatal toxicity.

If a woman took an ACE inhibitor during the second trimester of pregnancy, ultrasound evaluation of fetal renal function and skull ossification is recommended. Newborns whose mothers received ACE inhibitors during pregnancy should be closely monitored for possible development of arterial hypotension.

Breastfeeding. Use of perindopril tert-butylamine during breastfeeding is not recommended due to lack of data on its passage into breast milk. During breastfeeding, it is preferable to prescribe an alternative treatment with a better-studied safety profile, especially when nursing a newborn or premature infant.

Fertility. No effect on reproductive capacity or fertility has been observed.

Ability to affect reaction speed when driving vehicles or operating machinery.

Perindopril tert-butylamine does not have a direct effect on the ability to drive vehicles or operate machinery. However, some patients may experience individual reactions related to reduced blood pressure, especially at the beginning of treatment or when used concomitantly with other antihypertensive drugs. As a result, the ability to drive vehicles or operate machinery may be reduced.

Dosage and Administration

Hiten is recommended to be taken orally once daily, with a sufficient amount of liquid (e.g., water), in the morning before a meal.

The dosage should be individually adjusted according to the patient's individual characteristics and blood pressure levels.

Arterial hypertension. Perindopril can be used as monotherapy or in combination with other pharmacological classes of antihypertensive agents.

Initial dose. The recommended initial dose is 4 mg once daily in the morning. In patients with a highly active renin-angiotensin-aldosterone system (particularly those with renovascular hypertension, sodium depletion and/or dehydration, cardiac decompensation, severe arterial hypertension, or elderly patients), an excessive reduction in arterial pressure may occur after the first dose. Therefore, treatment initiation in such patients should be conducted under close medical supervision, and the recommended initial dose is 2 mg (1/2 tablet of Hiten 4 mg).

Maintenance dose. After 1 month of treatment, the dose may be increased to 8 mg daily.

At the beginning of perindopril therapy, arterial hypotension may develop. This is most likely in patients concurrently receiving diuretics. Since dehydration and/or excessive sodium chloride loss may occur in these patients, perindopril should be administered with caution. If possible, diuretic therapy should be discontinued 2–3 days prior to starting perindopril. In hypertensive patients who cannot discontinue diuretics, treatment with Hiten should be initiated at a dose of 2 mg. Renal function and serum potassium levels should be monitored. Subsequent dosage adjustments of perindopril should be based on blood pressure response. Diuretic therapy may be reintroduced if necessary.

For elderly patients, treatment should be initiated at a dose of 2 mg, which may be gradually increased after 1 month to 4 mg, and subsequently to 8 mg, depending on renal function (see table).

Heart failure (for 4 mg tablets). Treatment with perindopril in combination with non-potassium-sparing diuretics and/or digoxin and/or beta-blockers should be initiated under close medical supervision. The initial dose is 2 mg in the morning. After 2 weeks, if well tolerated, the dose may be increased to 4 mg daily. Dose adjustments should be made based on the individual clinical response of each patient.

Patients with severe heart failure and those at high risk (patients with impaired renal function and predisposition to electrolyte imbalance, or those receiving diuretics and/or vasodilators) should initiate treatment under close medical supervision.

Whenever possible, correction of the aforementioned conditions (e.g., salt depletion with or without hyponatremia, hypovolemia, or intensive diuretic therapy) should be performed prior to initiating perindopril in patients at high risk of symptomatic hypotension. Blood pressure, renal function, and serum potassium levels should be carefully monitored both before and during perindopril treatment.

Prevention of recurrent stroke in patients with cerebrovascular disease. The recommended initial dose is 2 mg (½ tablet of Hiten 4 mg). After 2 weeks of treatment, the dose should be increased to 4 mg. If additional blood pressure control is required after 2 weeks of treatment with 4 mg, indapamide 1 tablet may be added. Treatment may be initiated anytime from 2 weeks to several years after the initial stroke.

Prevention of cardiovascular complications in patients with documented stable ischemic heart disease. Initiate Hiten at a dose of 4 mg, then after 2 weeks, provided the dose is well tolerated and considering renal function, increase to 8 mg.

For elderly patients, initiate treatment with an initial dose of 2 mg daily for 1 week, followed by 4 mg once daily for the next week, and subsequently increase to 8 mg once daily depending on renal function (see table). Dose escalation should only occur if the lower dose is well tolerated.

Patients with impaired renal function. Dosage for patients with impaired renal function depends on creatinine clearance (see Table 1).

Table 1

Dose adjustment in renal impairment

* - Perindoprilat clearance during dialysis is 70 mL/min. Patients undergoing hemodialysis should take the dose after completion of dialysis.

Patients with hepatic impairment. Dose adjustment is not required in patients with hepatic dysfunction.

Children.

The efficacy and safety of use in children under 18 years of age have not been established. Available information is provided in the section «Pharmacodynamics», but adequate dosing recommendations cannot be given. Therefore, perindopril is not recommended for use in children.

Overdose.

There is insufficient information regarding perindopril overdose. Symptoms associated with angiotensin-converting enzyme (ACE) inhibitors overdose may include arterial hypotension, circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough, etc.

In case of overdose, intravenous administration of 0.9% sodium chloride solution (9 mg/mL) is recommended. If arterial hypotension occurs, the patient should be placed in a supine position with low head elevation. If possible, angiotensin II and/or intravenous catecholamines should be administered. Perindopril can be removed from systemic circulation by hemodialysis (see section «Special instructions»). In case of treatment-resistant bradycardia, temporary cardiac pacing is indicated. Continuous monitoring of vital signs, serum electrolytes, and creatinine levels is required.

Adverse reactions.

The safety profile of perindopril is consistent with the safety profile of ACE inhibitors.

The most commonly reported adverse reactions observed during clinical studies with perindopril are: dizziness, headache, paresthesia, vertigo, visual disturbances, tinnitus, arterial hypotension, cough, dyspnea, abdominal pain, constipation, diarrhea, taste disturbances (dysgeusia), dyspepsia, nausea, vomiting, pruritus, rash, maculopapular rash, muscle cramps, asthenia.

Adverse effects listed below have been reported during clinical studies and the post-marketing period with perindopril use, with the following frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Table 2.

*Frequency was calculated from clinical trial data for adverse reactions identified from spontaneous reports

Clinical Trials

In an international, multicenter, randomized, double-blind, placebo-controlled clinical study lasting 4 years, involving 12,218 patients aged 18 years and older, information was systematically collected only on serious adverse reactions. A small number of patients experienced serious adverse reactions: 16 (0.3%) out of 6,122 patients in the perindopril group and 12 (0.2%) out of 6,107 patients in the placebo group. Among patients receiving perindopril, hypotension was observed in 6 patients, angioneurotic edema in 3 patients, and sudden cardiac arrest in 1 patient. Patients who discontinued the study due to adverse events included 6.0% (n=366) reporting cough, arterial hypotension, or any other intolerance to perindopril, compared to 2.1% (n=129) of patients receiving placebo.

Reporting of suspected adverse reactions. It is important to report suspected adverse reactions after marketing authorization. This enables continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life.

2 years.

After opening the aluminum pouch, the shelf life is 60 days.

Storage conditions.

Keep out of reach and sight of children. Store at temperatures not exceeding 25 °C.

Blister packs must be kept in the aluminum pouch and in the cardboard box.

Packaging.

Tablets of 4 mg, 10 tablets per blister. Three blisters together with 1 silica gel sachet are packaged in a triple-layer aluminum pouch. One pouch per cardboard box.

Tablets of 8 mg, 10 tablets per blister. Three blisters together with 1 silica gel sachet are packaged in a triple-layer aluminum pouch. One pouch per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Aurobindo Pharma Limited (Unit III)/Aurobindo Pharma Limited (Unit III).

Manufacturer's address.

Survey No 313, 314, Block I, II, III, IV, Bachupally Village, Quthubullapur Mandal, Ranga Reddy District (A.P), India.