Perindoprila arginin-Tad (Tablets) Instructions for Use

Marketing Authorization Holder

TAD PHARMA GmbH (Germany)

Manufactured By

Krka d.d., Novo mesto (Slovenia)

ATC Code

C09AA04 (Perindopril)

Active Substance

Perindopril (Rec.INN registered by WHO)

Dosage Forms

	Perindoprila arginin-Tad	Tablets 5 mg
		Tablets 10 mg

Dosage Form, Packaging, and Composition

Tablets

10 pcs. – blisters (3 pcs.) – cardboard packs (30 pcs.) – By prescription
10 pcs. – blisters (6 pcs.) – cardboard packs (60 pcs.) – By prescription
10 pcs. – blisters (9 pcs.) – cardboard packs (90 pcs.) – By prescription

Tablets

10 pcs. – blisters (3 pcs.) – cardboard packs (30 pcs.) – By prescription
10 pcs. – blisters (6 pcs.) – cardboard packs (60 pcs.) – By prescription
10 pcs. – blisters (9 pcs.) – cardboard packs (90 pcs.) – By prescription

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin-converting enzyme (ACE) inhibitors

Pharmacological Action

ACE inhibitor. It is a prodrug from which the active metabolite perindoprilat is formed in the body. It is believed that the mechanism of antihypertensive action is associated with competitive inhibition of ACE activity, which leads to a decrease in the rate of conversion of angiotensin I to angiotensin II, a potent vasoconstrictor substance.

As a result of the decrease in angiotensin II concentration, a secondary increase in plasma renin activity occurs due to the elimination of negative feedback during renin release and a direct decrease in aldosterone secretion. Due to its vasodilatory action, it reduces total peripheral vascular resistance (afterload), pulmonary capillary wedge pressure (preload), and resistance in the pulmonary vessels; increases cardiac output and exercise tolerance.

The antihypertensive effect develops within the first hour after taking perindopril, reaches a maximum after 4-8 hours, and lasts for 24 hours.

Clinical studies with perindopril (monotherapy or in combination with a diuretic) have shown a significant reduction in the risk of recurrent stroke (both ischemic and hemorrhagic), as well as the risk of fatal or disabling strokes; major cardiovascular complications, including myocardial infarction, including fatal ones; dementia associated with stroke; serious cognitive impairments.

These therapeutic benefits were noted in both patients with arterial hypertension and those with normal blood pressure, regardless of age, gender, presence or absence of diabetes, and type of stroke.

It has been shown that with the use of perindopril tert-butylamine at a dose of 8 mg/day (equivalent to 10 mg of perindopril arginine) in patients with stable coronary artery disease, there is a significant reduction in the absolute risk of complications included in the primary efficacy criterion (mortality from cardiovascular diseases, frequency of non-fatal myocardial infarction and/or cardiac arrest with subsequent successful resuscitation) by 1.9%.

In patients who had previously had a myocardial infarction or a coronary revascularization procedure, the absolute risk reduction was 2.2% compared to the placebo group.

Perindopril is used both as monotherapy and in fixed combinations with indapamide, with amlodipine.

Pharmacokinetics

After oral administration, Perindopril is rapidly absorbed from the gastrointestinal tract. C_max is reached after 1 hour. Bioavailability is 65-70%.

During metabolism, Perindopril is biotransformed to form an active metabolite – perindoprilat (about 20%) and 5 inactive compounds. C_max of perindoprilat in plasma is reached between 3 and 5 hours after administration.

The binding of perindoprilat to plasma proteins is insignificant (less than 30%) and depends on the concentration of the active substance. V_d of free perindoprilat is close to 0.2 l/kg.

Does not accumulate. Repeated administration does not lead to accumulation and T_1/2 corresponds to its period of activity.

When taken with food, the metabolism of perindopril slows down.

T_1/2 of perindopril is 1 hour.

Perindoprilat is excreted from the body by the kidneys; T_1/2 of its free fraction is 3-5 hours.

In elderly patients, as well as in renal and heart failure, the excretion of perindoprilat is slowed.

Indications

Arterial hypertension.

Chronic heart failure.

Prevention of recurrent stroke (combination therapy with indapamide) in patients who have had a stroke or transient ischemic attack.

Stable coronary artery disease: reduction of the risk of cardiovascular complications in patients with stable coronary artery disease.

ICD codes

Dosage Regimen

Take the tablet once daily in the morning, before a meal.

For arterial hypertension, initiate therapy at 5 mg once daily. Adjust the dose to 10 mg once daily after at least one month based on blood pressure response. The maximum daily dose is 10 mg.

For chronic heart failure, start with 2.5 mg once daily under close medical supervision. Increase the dose to 5 mg once daily after two weeks, provided it is well tolerated.

For secondary stroke prevention, initiate with perindopril arginine 5 mg and indapamide 2.5 mg once daily. After two weeks, increase the perindopril arginine dose to 10 mg once daily.

For stable coronary artery disease, the recommended maintenance dose is 10 mg once daily. Begin therapy with 5 mg once daily for two weeks, then increase to 10 mg.

In elderly patients, start treatment at 2.5 mg once daily. Titrate the dose gradually, monitoring renal function and serum potassium.

Adjust the dosage in patients with renal impairment. For creatinine clearance 30-60 mL/min, the maximum dose is 5 mg daily. For creatinine clearance 15-30 mL/min, the maximum dose is 2.5 mg daily. Treatment is not recommended when creatinine clearance is below 15 mL/min.

In patients with liver cirrhosis, dose adjustment is not typically required. Monitor patients closely, as hepatic impairment may affect drug metabolism.

Do not abruptly discontinue therapy. Regularly monitor blood pressure, renal function, and serum electrolyte levels during treatment.

Adverse Reactions

From the hematopoietic system eosinophilia, decrease in hemoglobin and hematocrit, thrombocytopenia, leukopenia/neutropenia, agranulocytosis, pancytopenia, hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency.

From the metabolism hypoglycemia, hyperkalemia, reversible after drug withdrawal, hyponatremia.

From the nervous system paresthesia, headache, dizziness, vertigo, sleep disorders, mood lability, drowsiness, fainting, confusion.

From the sensory organs visual disturbances, tinnitus.

From the cardiovascular system excessive decrease in blood pressure and associated symptoms, vasculitis, tachycardia, palpitations, cardiac arrhythmias, angina pectoris, myocardial infarction and stroke, possibly due to excessive blood pressure reduction in high-risk patients.

From the respiratory system cough, shortness of breath, bronchospasm, eosinophilic pneumonia, rhinitis.

From the digestive system constipation, nausea, vomiting, abdominal pain, taste disturbance, dyspepsia, diarrhea, dryness of the oral mucosa, pancreatitis, hepatitis (cholestatic or cytolytic).

From the skin and subcutaneous tissue skin itching, rash, photosensitivity, pemphigus, increased sweating.

Allergic reactions angioedema, urticaria, erythema multiforme.

From the musculoskeletal system muscle cramps, arthralgia, myalgia.

From the urinary system renal failure, acute renal failure.

From the reproductive system erectile dysfunction.

General reactions asthenia, chest pain, peripheral edema, weakness, fever, falls.

From laboratory parameters increased activity of liver transaminases and bilirubin in blood serum, increased concentration of urea and creatinine in blood plasma.

Contraindications

History of angioedema, simultaneous use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus or impaired renal function (GFR <60 ml/min/1.73 m²), pregnancy, lactation, children and adolescents under 18 years of age, hypersensitivity to perindopril, hypersensitivity to other ACE inhibitors.

Use in Pregnancy and Lactation

Perindopril is contraindicated for use during pregnancy and during lactation (breastfeeding).

Use in Renal Impairment

In case of impaired renal function, adjustment of the dosage regimen is required depending on the creatinine clearance values.

Pediatric Use

Contraindicated in children.

Special Precautions

With caution, Perindopril should be used in bilateral renal artery stenosis or stenosis of the artery of a single kidney; renal failure; systemic connective tissue diseases; therapy with immunosuppressants, allopurinol, procainamide (risk of developing neutropenia, agranulocytosis); reduced circulating blood volume (taking diuretics, salt-restricted diet, vomiting, diarrhea); angina pectoris; cerebrovascular diseases; renovascular hypertension; diabetes mellitus; chronic heart failure of functional class IV according to the NYHA classification; simultaneously with potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes, with lithium preparations; with hyperkalemia; surgical intervention/general anesthesia; hemodialysis using high-flux membranes; desensitizing therapy; LDL apheresis; condition after kidney transplantation; aortic stenosis/mitral stenosis/hypertrophic obstructive cardiomyopathy; in patients of the Black race.

Cases of arterial hypotension, fainting, stroke, hyperkalemia and impaired renal function (including acute renal failure) have been reported in predisposed patients, especially with the simultaneous use of drugs that affect the renin-angiotensin-aldosterone system (RAAS). Therefore, dual blockade of the RAAS as a result of combining an ACE inhibitor with an angiotensin II receptor antagonist or aliskiren is not recommended.

Before starting treatment with perindopril, all patients are recommended to have their kidney function examined.

During treatment with perindopril, kidney function, the activity of liver enzymes in the blood should be regularly monitored, and peripheral blood tests should be performed (especially in patients with diffuse connective tissue diseases, in patients receiving immunosuppressive agents, allopurinol). Patients with sodium and fluid deficiency should have their water and electrolyte disturbances corrected before starting treatment.

Drug Interactions

The risk of developing hyperkalemia increases with the simultaneous use of perindopril with other drugs that can cause hyperkalemia: aliskiren and aliskiren-containing drugs, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparin, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim.

When used simultaneously with aliskiren in patients with diabetes mellitus or impaired renal function (GFR <60 ml/min), the risk of hyperkalemia, deterioration of renal function and increased frequency of cardiovascular morbidity and mortality increases (in patients of these groups, this combination is contraindicated).

Simultaneous use with aliskiren is not recommended in patients without diabetes mellitus or impaired renal function, as it may increase the risk of hyperkalemia, deterioration of renal function and increased frequency of cardiovascular morbidity and mortality.

The literature has reported that in patients with established atherosclerotic disease, heart failure, or diabetes with target organ damage, simultaneous therapy with an ACE inhibitor and an angiotensin II receptor antagonist is associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared with the use of only one drug affecting the RAAS. Dual blockade (for example, when combining an ACE inhibitor with an angiotensin II receptor antagonist) should be limited to individual cases with careful monitoring of renal function, potassium levels and blood pressure.

Simultaneous use with estramustine may lead to an increased risk of side effects such as angioedema.

With simultaneous use of lithium preparations and perindopril, a reversible increase in the concentration of lithium in the blood serum and associated toxic effects is possible (this combination is not recommended).

Simultaneous use with hypoglycemic drugs (insulin, oral hypoglycemic agents) requires special caution, since ACE inhibitors, including Perindopril, may enhance the hypoglycemic effect of these drugs up to the development of hypoglycemia. This is usually observed in the first weeks of simultaneous therapy and in patients with impaired renal function.

Baclofen enhances the antihypertensive effect of perindopril; when used simultaneously, dose adjustment of the latter may be required.

In patients receiving diuretics, especially those that remove fluid and/or salts, an excessive decrease in blood pressure may be observed at the beginning of therapy with perindopril, the risk of which can be reduced by discontinuing the diuretic, replenishing fluid or salt loss before starting therapy with perindopril, and also by using perindopril in a low initial dose with its subsequent gradual increase.

In chronic heart failure, when using diuretics, Perindopril should be used in a low dose, possibly after reducing the dose of the simultaneously used potassium-sparing diuretic. In all cases, renal function (creatinine concentration) should be monitored in the first weeks of using ACE inhibitors.

Use of eplerenone or spironolactone in doses from 12.5 mg to 50 mg/day and ACE inhibitors (including perindopril) in low doses: when treating heart failure of functional class II-IV according to the NYHA classification with left ventricular ejection fraction <40% and previously used ACE inhibitors and “loop” diuretics, there is a risk of developing hyperkalemia (with possible fatal outcome), especially if the recommendations regarding this combination are not followed. Before using this combination, it is necessary to ensure the absence of hyperkalemia and impaired renal function. It is recommended to regularly monitor the concentration of creatinine and potassium in the blood – weekly in the first month of treatment and monthly thereafter.

Simultaneous use of perindopril with NSAIDs (acetylsalicylic acid in a dose that has an anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) may lead to a decrease in the antihypertensive effect of ACE inhibitors. Simultaneous use of ACE inhibitors and NSAIDs may lead to deterioration of renal function, including the development of acute renal failure, and an increase in serum potassium levels, especially in patients with reduced renal function. Use this combination with caution in elderly patients. Patients should receive adequate amounts of fluid; it is recommended to carefully monitor renal function, both at the beginning and during treatment.

The hypotensive effect of perindopril may be enhanced when used simultaneously with other antihypertensive drugs, vasodilators, including short- and long-acting nitrates.

Simultaneous use of gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin) with ACE inhibitors (including perindopril) may increase the risk of angioedema due to suppression of dipeptidyl peptidase IV activity by the gliptin.

Simultaneous use of perindopril with tricyclic antidepressants, antipsychotic drugs and general anesthetics may lead to an enhancement of the antihypertensive effect.

Sympathomimetics may weaken the antihypertensive effect of perindopril.

When using ACE inhibitors, including perindopril, in patients receiving intravenous gold preparations (sodium aurothiomalate), a symptom complex was described in which facial skin flushing, nausea, vomiting, and arterial hypotension were observed.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.