Prenessa (Tablets) Instructions for Use

Marketing Authorization Holder

Krka-Rus, LLC (Russia)

ATC Code

C09AA04 (Perindopril)

Active Substance

Perindopril (Rec.INN registered by WHO)

Dosage Form

Prenessa

Tablets 8 mg: 10, 14, 30, 60, 90, pcs.

Dosage Form, Packaging, and Composition

14 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.
15 pcs. – blister packs (2) – cardboard packs.
15 pcs. – blister packs (4) – cardboard packs.
15 pcs. – blister packs (6) – cardboard packs.
30 pcs. – blister packs (1) – cardboard packs.
30 pcs. – blister packs (2) – cardboard packs.
30 pcs. – blister packs (3) – cardboard packs.
7 pcs. – blister packs (2) – cardboard packs.

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

ACE blocker

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 the antihypertensive action is associated with the competitive inhibition of ACE activity, which leads to a decrease in the rate of conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor substance.

As a result of the decrease in the concentration of angiotensin II, 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 vasodilating 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 hypotensive effect develops within the first hour after taking perindopril, reaches a maximum after 4-8 hours and lasts for 24 hours.

In clinical studies with the use of perindopril (monotherapy or in combination with a diuretic), 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 deterioration of cognitive functions was shown.

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

It has been shown that against the background of 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 provided for by the main efficacy criterion (mortality from cardiovascular diseases, the 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 as 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 the period of its 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 down.

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, preferably in the morning before a meal.

For arterial hypertension, initiate therapy at 2 mg once daily. Titrate to a maintenance dose of 4 mg once daily after at least one week. The maximum dose is 8 mg once daily.

For chronic heart failure, start with 2 mg once daily under close medical supervision. Increase the dose to 4 mg once daily after two weeks, provided the initial dose is well-tolerated.

For secondary stroke prevention, use perindopril in a fixed-dose combination with indapamide. The recommended dose is perindopril arginine 5 mg (equivalent to perindopril erbumine 4 mg) plus indapamide 1.25 mg once daily. Begin therapy between two weeks and several years after the stroke event.

For stable coronary artery disease, the maintenance dose is 4 mg once daily. If necessary, reduce the initial dose to 2 mg once daily for two weeks before increasing to 4 mg.

In patients with renal impairment, adjust the dose based on creatinine clearance (Clcr). For Clcr 30-60 ml/min, the maximum dose is 4 mg daily. For Clcr 15-30 ml/min, the maximum dose is 2 mg daily. For Clcr below 15 ml/min (dialysis patients), the initial dose is 2 mg on dialysis days.

For elderly patients, initiate therapy at 2 mg once daily. Titrate to 4 mg and then to 8 mg once daily if necessary and well-tolerated, after assessing renal function.

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 senses 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 decrease in blood pressure 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 the period of lactation (breastfeeding).

Use in Renal Impairment

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

Pediatric Use

Contraindicated in children.

Special Precautions

With caution, Perindopril should be used for 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 Negroid 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 RAAS. Therefore, dual blockade of the RAAS as a result of the combination of an ACE inhibitor with an angiotensin II receptor antagonist or aliskiren is not recommended.

Before starting treatment with perindopril, all patients are recommended to examine renal function.

During treatment with perindopril, renal 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 who receive immunosuppressive agents, allopurinol). Patients with sodium and fluid deficiency should correct water and electrolyte disorders 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.

With simultaneous use with aliskiren in patients with diabetes mellitus or impaired renal function (GFR <60 ml/min), the risk of hyperkalemia, deterioration of renal function and an increase in the 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, because an increase in the risk of hyperkalemia, deterioration of renal function and an increase in the frequency of cardiovascular morbidity and mortality is possible.

The literature has reported that in patients with established atherosclerotic disease, heart failure, or diabetes mellitus with target organ damage, simultaneous therapy with an ACE inhibitor and an angiotensin II receptor antagonist is associated with a higher incidence of hypotension, fainting, hyperkalemia and deterioration of 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, because ACE inhibitors, including Perindopril, can enhance the hypoglycemic effect of these drugs up to the development of hypoglycemia. As a rule, this is observed in the first weeks of simultaneous therapy and in patients with impaired renal function.

Baclofen enhances the antihypertensive effect of perindopril; with simultaneous use, dose adjustment of the latter may be required.

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

In chronic heart failure, in case of 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: in the therapy of 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 in case of non-compliance with the recommendations regarding this combination. Before using this combination, it is necessary to make sure that there is no 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 can 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 by simultaneous use 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 developing angioedema due to the 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 increase in the antihypertensive effect.

Sympathomimetics may weaken the antihypertensive effect of perindopril.

When using ACE inhibitors, including perindopril, in patients receiving intravenous gold preparation (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.