Parnavel, tablets 4 mg, 30 pcs.

Parnavel – hypotensive, helps to restore the elasticity of large arterial vessels, reduces the severity of myocardial hypertrophy of the left ventricle, normalizes heart function.

Pharmacodynamics

The ACE inhibitor. ACE suppression leads to a decrease in plasma angiotensin II, resulting in a decrease in aldosterone secretion.

Perindopril acts through its active metabolite perindoprilat. It eliminates the vasoconstrictor effect of angiotensin II, increases the concentration of bradykinin and vasodilator prostaglandins (ACE converts inactive angiotensin I into angiotensin II, which has a vasoconstrictor effect, and also causes degradation of bradykinin and prostaglandin, which have vasodilator activity); reduces the production and release of aldosterone, suppresses the release of norepinephrine from the sympathetic nerve fiber endings and the formation of endothelin in the vascular wall. Decrease of angiotensin II formation is accompanied by increase of blood plasma renin activity (due to inhibition of negative feedback).

The suppression of ACE is accompanied by increased activity of both circulating and tissue kallikrein-kinin system, and the prostaglandin system is also activated.

It promotes restoration of elasticity of large arterial vessels (decrease of formation of excessive amount of subendothelial collagen), reduces pressure in pulmonary capillaries, with long-term prescription it reduces expression of left ventricular myocardial hypertrophy and interstitial fibrosis, normalizes myosin isoenzyme profile; it normalizes heart function.
Decreases preload and postload (decreases systolic and diastolic blood pressure (BP) in “lying” and “standing” position), filling pressure of the left and right ventricles, total peripheral resistance of vessels; increases minute volume of circulation and cardiac index without changing heart rate (in patients with chronic heart failure), in therapeutic doses does not increase heart rate, increases regional blood flow in muscles.

increases the concentration of high-density lipoproteins, in patients with hyperuricemia reduces the concentration of uric acid. Increases renal blood flow, does not change glomerular filtration rate.

In patients with chronic heart failure causes significant reduction of clinical signs of heart failure, increases exercise tolerance (by ergometer test). After oral administration of an average single dose, the maximum hypotensive effect is achieved in 4-6 hours and is maintained for 24 hours. Stabilization of the hypotensive effect is observed after 1 month of therapy and is maintained for a long time. Discontinuation of treatment is not accompanied by development of “withdrawal” syndrome.

Pharmacokinetics

Absorption – 25%, bioavailability – 65-70%.

The time to reach maximum plasma concentration is 1 h, perindoprilat – 3-4 h. During metabolism 20% is transformed into active metabolite – perindoprilat (taking perindopril after meals reduces the proportion of perindoprilat formed – significant clinical significance); the remaining amount – into 5 inactive compounds. T½ (half-life) of perindopril-1h. Binding of perindoprilat with blood plasma proteins is insignificant, with ACE – less than 30% (depends on concentration). Distribution volume of free perindoprilat is 0.2 l/kg.

Perindoprilat is excreted by the kidneys, T½ of the free metabolite fraction is 3-5 hours. Dissociation of perindoprilat bound to ACE is slow. As a consequence, the “effective” T½ is 25 h. Repeated administration of perindopril does not result in its cumulation, and the T½ of perindoprilat when repeatedly administered corresponds to its period of activity.

The excretion of perindoprilat is slower in elderly patients as well as in patients with chronic heart failure and chronic renal failure (in the latter the dose should be adjusted according to creatinine clearance). Dialysis clearance of perindopril is 70 ml/min.

In patients with cirrhosis hepatic clearance of perindopril is decreased by half, while the total amount of perindoprilate produced does not change and dosing regimen adjustment is not required.

Indications

Arterial hypertension, chronic heart failure.

Active ingredient

Composition

Active ingredient:

perindopril erbumin 4 mg.

Associated substances:

Lactose (milk sugar);

Microcrystalline cellulose;

corn starch;

povidone (polyvinylpolypyrrolidone);

magnesium stearate.

How to take, the dosage

Internal, in the morning, before meals.

The initial dose for treatment of arterial hypertension is 4 mg per day if necessary (after 1 month), the dose may be increased to 8 mg per day in a single dose. While prescribing ACE inhibitors in patients receiving diuretics therapy the sharp drop of BP may be noted. To prevent this we recommend to stop diuretics 2-3 days before the supposed therapy with Parnavel or to prescribe the preparation in lower dose – 2 mg once per day.
In patients with renovascular hypertension the initial dose is 2 mg once per day. If necessary, the dose can be increased later.

In elderly patients, therapy should be started with a dose of 2 mg daily and then, if necessary, gradually increased up to a maximum dose of 8 mg daily.

The treatment of patients with chronic heart failure in combination with a potassium-saving diuretic and/or digoxin, it is recommended to start under close medical supervision, Parnavel be prescribed in an initial dose of 2 mg once daily, in the morning.
Later, after 1-2 weeks of therapy, the drug dose may be increased to 4 mg once daily.

In patients with impaired renal function the preparation’s dose should be adjusted taking into account the degree of renal failure: depending on creatinine clearance. If creatinine clearance is 30-60 ml/min. – 2 mg once a day; with a creatinine clearance of 1530 ml/min. – 2 mg every other day; in patients on hemodialysis (creatinine clearance less than 15 ml/min) – 2 mg per day of dialysis. If creatinine clearance is more than 60 ml/min. – 4 mg per day. Patients with impaired liver function do not require dose changes.

Interaction

Increases the severity of hypoglycemic effect of insulin and sulfonylurea derivatives.

Baclofen, tricyclic antidepressants, antipsychotics (neuroleptics), saluretics increase the hypotensive effect and increase the risk of orthostatic hypotension (additive effect), antacids decrease the bioavailability of ACE inhibitors.

Glucocorticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase 2 (COX-2) inhibitors, acetylsalicylic acid (more than 3 g/day) reduce the severity of hypotensive effect (fluid and electrolyte retention).

Allopurinol, immunosuppressants, including cytostatics and systemic glucocorticosteroids, procainamide – when combined with ACE inhibitors – risk of leukopenia.

Potassium-saving diuretics (spironolacgon, triamterene, amiloride), potassium preparations increase the risk of hyperkalemia.
The simultaneous use of drugs that can cause hyperkalemia and ACE inhibitors is not recommended, except in cases of severe hypokalemia (serum potassium control).

In concomitant use with lithium preparations, its excretion from the body may be delayed (regular monitoring of lithium in the blood is necessary). Diuretics, drugs for general anesthesia and muscle relaxants, ethanol increase the risk of excessive BP decrease. The risk of clinically significant arterial hypotension may be reduced by discontinuing diuretics several days prior to treatment with perindopril.

Perindopril may be administered together with acetylsalicylic acid (as an antiplatelet agent), thrombolytics, beta-adrenoblockers and/or nitrates. Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors. When prescribing such a combination, the effectiveness of ACE inhibitors should be evaluated.

When concomitant use with the preparation of gold (sodium aurothiomalate) in injectable form the adverse events were observed in patients: “flushes” of blood to the face, nausea, vomiting, hypotension (hypotension is regarded as increase of ACE inhibitors effect under the influence of gold preparation).

Special Instructions

The risk of arterial hypotension and/or renal insufficiency against the background of taking the drug increases with significant loss of sodium and water (strict salt-free diet, and/or taking diuretics, diarrhea, vomiting) or renal artery stenosis (blockade of the renin-angiotensin system in these situations may lead, especially during the first drug administration and during the first 2 weeks of treatment, to a sudden decrease of blood pressure and development of chronic renal failure). It is recommended to determine creatinine, electrolyte and urea concentrations before and during therapy (within 1 month).
In patients with arterial hypertension who are already receiving diuretics therapy, it is necessary to stop their administration (3 days before the start of Parnavel) and to add them again if necessary in future.

In patients with chronic heart failure receiving diuretic therapy, if possible, their dose should be reduced several days before starting Parnavel.

In patients at risk, especially those with decompensated chronic heart failure, elderly patients, as well as patients with baseline low BP, impaired renal function, or those receiving high doses of diuretics, initiation of the drug should be controlled. In patients on hemodialysis, the use of polyacrylonitrile membranes should be avoided (possible development of anaphylactoid reactions). It is necessary to stop taking before the upcoming surgical intervention one day in advance and warn the anesthesiologist about taking the drug.

The administration of ACE inhibitors is sometimes associated with a syndrome beginning with the development of cholestatic jaundice that progresses to fulminant liver necrosis and (sometimes) is fatal. The mechanism of this syndrome is not clear. If symptoms of jaundice or elevated liver enzyme activity occur in patients taking ACE inhibitors, therapy with the drug should be discontinued and appropriate evaluation should be performed.

In normal renal function and in the absence of other complications, neutropenia is rare. ACE inhibitors are indicated only in emergency cases in the presence of systemic vasculitis, immunosuppressive therapy, administration of allopurinol or procainamide, and also in the combination of all these factors, especially against a background of previous renal failure. There is a risk of severe infectious diseases resistant to intensive antibiotic therapy. During therapy with perindopril in patients with the above factors it is necessary to regularly monitor the white blood cell count and warn the patient to inform the doctor about the appearance of any symptoms of infection.
During the procedure of low-density lipoprotein apheresis with dextran-sulfate absorption, when administering ACE inhibitors patients may develop anaphylactic reactions.

Impact on the ability to drive a car and perform activities requiring increased attention

In view of the risk of arterial hypotension and dizziness, ACE inhibitors should be prescribed with caution in persons driving motor vehicles and engaged in activities requiring increased attention and rapid motor reaction.

Contraindications

Hypersensitivity to perindopril and other components of the drug or other ACE inhibitors, history of angioedema during therapy with ACE inhibitors, hereditary or idiopathic angioedema, pregnancy, lactation, age under 18 years, hereditary lactose intolerance, lactase deficiency or glucose and galactose malabsorption.

Side effects

Cardiovascular system disorders: often – excessive BP decrease and related sympathy, rarely – arrhythmia, angina pectoris, myocardial infarction and stroke.

Urinary system disorders: decreased renal function and acute renal failure.

Respiratory system disorders: often – “dry” cough, difficulty in breathing; rare bronchospasm, rhinorrhea, eosinophilic pneumonia.

Digestive system disorders: frequently – nausea, vomiting, abdominal pain, change in taste, diarrhea or constipation, dry mouth, decreased appetite, cholestatic or cytolytic jaundice, pancreatitis, intestinal edema.

The central nervous system: often – headache, asthenia, fatigue, dizziness, tinnitus, visual disturbances, muscle cramps, paresthesias; rarely – decreased mood, insomnia; extremely rare – confusion.

Allergic reactions: common – skin rash, itching, rarely – urticaria, angioedema; very rare – erythema multiforme.

Laboratory indices: frequent – hypercreatininemia, proteinuria, hyperkalemia; hyperuricemia; rare (with prolonged use in high doses) – neutropenia, leukopenia, hypogemoglobinemia, thrombocytopenia, reduced hematocrit; Very rarely – agranulocytosis, pancytopenia, increased “liver” enzymes activity, hyperbilirubinemia, hemolytic anemia (with glucose-6-phosphate dehydrogenase deficiency).

Others: increased sweating, impaired sexual function.

Overdose

Symptoms: marked BP decrease, shock, stupor, bradycardia, tachycardia, restlessness and cough, dizziness, electrolyte disorders (hyperkalemia, hyponatremia), renal failure.

Treatment: gastric lavage, restoration of water-electrolyte balance, intravenous administration of 0.9% sodium chloride solution. If BP is significantly decreased, the patient should be placed horizontally with legs elevated; the volume of circulating blood should be restored.

If bradycardia develops – atropine, an artificial pacer may be required. Monitoring of serum electrolytes and CK.

Perindopril may be removed from systemic blood flow by hemodialysis. High-flow polyacrylonitrile membranes should be avoided.

Similarities