Parnavel (Capsules) Instructions for Use

Marketing Authorization Holder

Atoll LLC (Russia)

Manufactured By

Ozon, LLC (Russia)

ATC Code

C09AA04 (Perindopril)

Active Substance

Perindopril (Rec.INN registered by WHO)

Dosage Forms

	Parnavel	Capsules 2 mg: 7, 10, 14, 20, 21, 28, 30, 35, 40, 42, 49, 50, 56, 60, 63, 70, 80, 90, 100, 120, 150, 180, 210, 240, 270 or 300 pcs.
		Capsules 4 mg: 7, 10, 14, 20, 21, 28, 30, 35, 40, 42, 49, 50, 56, 60, 63, 70, 80, 90, 100, 120, 150, 180, 210, 240, 270 or 300 pcs.
		Capsules 8 mg: 7, 10, 14, 20, 21, 28, 30, 35, 40, 42, 49, 50, 56, 60, 63, 70, 80, 90, 100, 120, 150, 180, 210, 240, 270 or 300 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 2, with a dark blue body and a grey-lilac cap; capsule contents – powder or a mixture of powder and granules, white or white with a creamy tint; compaction of the capsule contents is allowed, which disintegrates upon pressure.

Excipients: microcrystalline cellulose (MCC-112) – 106 mg, potato starch – 3 mg, magnesium stearate – 1 mg.

Capsule body composition: Brilliant Black dye – 0.1401%, Iron Oxide Black dye – 0.6367%, Titanium Dioxide – 0.9006%, Gelatin – up to 100%.
Capsule cap composition: Azorubine dye – 0.0199%, Brilliant Blue dye – 0.011%, Titanium Dioxide – 2.2075%, Gelatin – up to 100%.

7 pcs. – blister packs (1) – cardboard packs.
7 pcs. – blister packs (2) – cardboard packs.
7 pcs. – blister packs (3) – cardboard packs.
7 pcs. – blister packs (4) – cardboard packs.
7 pcs. – blister packs (5) – cardboard packs.
7 pcs. – blister packs (6) – cardboard packs.
7 pcs. – blister packs (7) – cardboard packs.
7 pcs. – blister packs (8) – cardboard packs.
7 pcs. – blister packs (9) – cardboard packs.
7 pcs. – blister packs (10) – cardboard packs.
10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (2) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (4) – cardboard packs.
10 pcs. – blister packs (5) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (7) – cardboard packs.
10 pcs. – blister packs (8) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.
10 pcs. – blister packs (10) – cardboard packs.
30 pcs. – blister packs (1) – cardboard packs.
30 pcs. – blister packs (2) – cardboard packs.
30 pcs. – blister packs (3) – cardboard packs.
30 pcs. – blister packs (4) – cardboard packs.
30 pcs. – blister packs (5) – cardboard packs.
30 pcs. – blister packs (6) – cardboard packs.
30 pcs. – blister packs (7) – cardboard packs.
30 pcs. – blister packs (8) – cardboard packs.
30 pcs. – blister packs (9) – cardboard packs.
30 pcs. – blister packs (10) – cardboard packs.

Capsules hard gelatin, size No. 2, with a dark blue body and a blue cap; capsule contents – powder or a mixture of powder and granules, white or white with a creamy tint; compaction of the capsule contents is allowed, which disintegrates upon pressure.

Excipients: microcrystalline cellulose (MCC-112) – 104 mg, potato starch – 3 mg, magnesium stearate – 1 mg.

Capsule body composition: Brilliant Black dye – 0.1401%, Iron Oxide Black dye – 0.6367%, Titanium Dioxide – 0.9006%, Gelatin – up to 100%.
Capsule cap composition: Azorubine dye – 0.038%, Patent Blue dye – 0.0697%, Titanium Dioxide – 1.6367%, Gelatin – up to 100%.

7 pcs. – blister packs (1) – cardboard packs.
7 pcs. – blister packs (2) – cardboard packs.
7 pcs. – blister packs (3) – cardboard packs.
7 pcs. – blister packs (4) – cardboard packs.
7 pcs. – blister packs (5) – cardboard packs.
7 pcs. – blister packs (6) – cardboard packs.
7 pcs. – blister packs (7) – cardboard packs.
7 pcs. – blister packs (8) – cardboard packs.
7 pcs. – blister packs (9) – cardboard packs.
7 pcs. – blister packs (10) – cardboard packs.
10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (2) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (4) – cardboard packs.
10 pcs. – blister packs (5) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (7) – cardboard packs.
10 pcs. – blister packs (8) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.
10 pcs. – blister packs (10) – cardboard packs.
30 pcs. – blister packs (1) – cardboard packs.
30 pcs. – blister packs (2) – cardboard packs.
30 pcs. – blister packs (3) – cardboard packs.
30 pcs. – blister packs (4) – cardboard packs.
30 pcs. – blister packs (5) – cardboard packs.
30 pcs. – blister packs (6) – cardboard packs.
30 pcs. – blister packs (7) – cardboard packs.
30 pcs. – blister packs (8) – cardboard packs.
30 pcs. – blister packs (9) – cardboard packs.
30 pcs. – blister packs (10) – cardboard packs.

Capsules hard gelatin, size No. 2, with a dark blue body and a lilac cap; capsule contents – powder or a mixture of powder and granules, white or white with a creamy tint; compaction of the capsule contents is allowed, which disintegrates upon pressure.

Excipients: microcrystalline cellulose (MCC-112) – 100 mg, potato starch – 3 mg, magnesium stearate – 1 mg.

Capsule body composition: Brilliant Black dye – 0.1401%, Iron Oxide Black dye – 0.6367%, Titanium Dioxide – 0.9006%, Gelatin – up to 100%.
Capsule cap composition: Azorubine dye – 0.023%, Patent Blue dye – 0.006%, Titanium Dioxide – 1%, Gelatin – up to 100%.

7 pcs. – blister packs (1) – cardboard packs.
7 pcs. – blister packs (2) – cardboard packs.
7 pcs. – blister packs (3) – cardboard packs.
7 pcs. – blister packs (4) – cardboard packs.
7 pcs. – blister packs (5) – cardboard packs.
7 pcs. – blister packs (6) – cardboard packs.
7 pcs. – blister packs (7) – cardboard packs.
7 pcs. – blister packs (8) – cardboard packs.
7 pcs. – blister packs (9) – cardboard packs.
7 pcs. – blister packs (10) – cardboard packs.
10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (2) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (4) – cardboard packs.
10 pcs. – blister packs (5) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (7) – cardboard packs.
10 pcs. – blister packs (8) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.
10 pcs. – blister packs (10) – cardboard packs.
30 pcs. – blister packs (1) – cardboard packs.
30 pcs. – blister packs (2) – cardboard packs.
30 pcs. – blister packs (3) – cardboard packs.
30 pcs. – blister packs (4) – cardboard packs.
30 pcs. – blister packs (5) – cardboard packs.
30 pcs. – blister packs (6) – cardboard packs.
30 pcs. – blister packs (7) – cardboard packs.
30 pcs. – blister packs (8) – cardboard packs.
30 pcs. – blister packs (9) – cardboard packs.
30 pcs. – blister packs (10) – 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. 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 vasodilating action, it reduces total peripheral vascular resistance (afterload), pulmonary capillary wedge pressure (preload) and resistance in pulmonary vessels; increases cardiac output and exercise tolerance.

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

In clinical studies, the use of perindopril (monotherapy or in combination with a diuretic) showed 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. 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 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, the incidence 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 in 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. 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 is slowed 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 capsule once daily in the morning, preferably 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 month. The maximum daily dose is 8 mg.

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

For secondary stroke prevention, initiate perindopril at 2 mg once daily for the first two weeks before starting concomitant indapamide. Increase the perindopril dose to 4 mg once daily.

For stable coronary artery disease, the recommended maintenance dose is 4 mg once daily. After one month, consider increasing the dose to 8 mg once daily based on renal function.

In elderly patients, start treatment at 2 mg once daily. Titrate to 4 mg and then 8 mg if necessary, after assessing renal function and tolerability.

Adjust the dose in patients with renal impairment. For creatinine clearance (CrCl) ≥60 mL/min, the maximum dose is 8 mg daily. For CrCl 30-60 mL/min, the maximum dose is 4 mg daily. For CrCl 15-30 mL/min, the maximum dose is 2 mg daily. For CrCl <15 mL/min (including patients on dialysis), the recommended dose is 2 mg on dialysis days.

Monitor blood pressure and renal function, especially after initiation or dose titration. Correct any dehydration or salt depletion prior to initiation to minimize the risk of symptomatic hypotension.

Adverse Reactions

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

From 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, dry 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, dose adjustment is required depending on the creatinine clearance values.

Pediatric Use

Contraindicated in children.

Special Precautions

Use with caution 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 simultaneous use with drugs that affect the renin-angiotensin-aldosterone system. Therefore, dual blockade of the renin-angiotensin-aldosterone system as a result of combining an ACE inhibitor with an angiotensin II receptor antagonist or aliskiren is not recommended.

Before starting treatment with perindopril, it is recommended to examine renal function in all patients.

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 receiving immunosuppressive agents, allopurinol). Patients with sodium and fluid deficiency should correct water and electrolyte imbalances before starting treatment.

Drug Interactions

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

Concomitant use with aliskiren is not recommended in patients without diabetes mellitus or impaired renal function, as an increase in the risk of hyperkalemia, worsening of renal function, and increased frequency of cardiovascular morbidity and mortality is possible.

Literature has reported that in patients with established atherosclerotic disease, heart failure, or diabetes mellitus with target organ damage, concomitant therapy with an ACE inhibitor and an angiotensin II receptor antagonist is associated with a higher frequency of hypotension, syncope, hyperkalemia, and worsening of renal function (including acute renal failure) compared to 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.

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

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

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

Baclofen enhances the antihypertensive effect of perindopril; dose adjustment of the latter may be required during concomitant use.

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

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

Use of eplerenone or spironolactone in doses from 12.5 mg to 50 mg/day and ACE inhibitors (including perindopril) in low doses: during therapy for heart failure of NYHA functional class II-IV with left ventricular ejection fraction <40% and previously used ACE inhibitors and loop diuretics, there is a risk of 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 serum creatinine and potassium levels – weekly during the first month of treatment and monthly thereafter.

Concomitant use of perindopril with NSAIDs (acetylsalicylic acid at a dose exerting an anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) may lead to a reduction in the antihypertensive effect of ACE inhibitors. Concomitant use of ACE inhibitors and NSAIDs may lead to worsening of renal function, including the development of acute renal failure, and an increase in serum potassium, 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 concomitant use with other antihypertensive drugs, vasodilators, including short- and long-acting nitrates.

Concomitant 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.

Concomitant use of perindopril with tricyclic antidepressants, antipsychotic drugs, and agents for general anesthesia may lead to an enhancement of the antihypertensive effect.

Sympathomimetics may reduce the antihypertensive effect of perindopril.

When using ACE inhibitors, including perindopril, in patients receiving intravenous gold preparations (sodium aurothiomalate), a symptom complex has been described, characterized by facial flushing, nausea, vomiting, and arterial hypotension.

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.