Instructions for use of PERINDOPRIL-LF (PERINDOPRIL-LF)
Dual blockade of the RAAS is associated with an increased risk of hypotension, hyperkalemia and renal dysfunction (including acute renal failure) compared with monotherapy. Dual blockade of the RAAS using ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended, especially in patients with diabetic nephropathy.
In some cases, when the combined use of ACE inhibitors and angiotensin II receptor blockers is absolutely indicated, careful medical supervision and mandatory monitoring of renal function, water and electrolyte balance, and blood pressure are necessary. This applies to the use of candesartan or valsartan as adjunctive therapy to ACE inhibitors in patients with chronic heart failure. Carrying out double blockade of the RAAS under the careful supervision of a specialist and mandatory monitoring of renal function, water-electrolyte balance and blood pressure is possible in patients with chronic heart failure with intolerance to aldosterone antagonists (spironolactone), who have persistence of symptoms of chronic heart failure, despite other adequate therapy.
Stable ischemic heart disease
If an episode of unstable angina (severe or not) develops during the first month of treatment with perindopril, the balance between benefit and risk should be carefully assessed before continuing treatment.
Arterial hypotension
ACE inhibitors can cause a decrease in blood pressure. In patients with uncomplicated hypertension, severe hypotension rarely occurs; more often it is observed in patients with hypovolemia - while taking diuretics, limiting salt intake from food, in patients on hemodialysis, with diarrhea or vomiting; in patients with severe renin-dependent hypertension. In patients with clinically significant heart failure with or without concomitant renal failure, clinically significant arterial hypotension was recorded. The risk of its development increases in patients with more severe heart failure, while taking loop diuretics in high doses, with hyponatremia or functional kidney damage. Patients at increased risk of developing clinically significant hypotension require careful monitoring during initiation of therapy and dose adjustment. Similar requirements apply to patients with coronary artery disease or cerebrovascular disease, in whom an excessive decrease in blood pressure can lead to the development of myocardial infarction or acute cerebrovascular accident.
If arterial hypotension develops, the patient should be placed in a horizontal position and, if necessary, given intravenous saline. Transient arterial hypotension is not a contraindication to continued treatment, which can usually be restored without complications after an increase in blood pressure due to an increase in blood volume.
In some patients with congestive heart failure and normal or low blood pressure, treatment with perindopril may lead to an additional decrease in systemic blood pressure. This effect is expected and is not a reason to stop treatment. In case of clinically significant arterial hypotension, dose reduction or discontinuation of treatment with perindopril may be required.
Aortic and mitral valve stenosis/hypertrophic cardiomyopathy
As with other ACE inhibitors, perindopril should be used cautiously in patients with mitral valve stenosis and left ventricular outflow tract stenosis, in particular with aortic stenosis or hypertrophic cardiomyopathy.
Renal dysfunction
In case of impaired renal function (creatinine clearance <60 ml/min), the initial dose of perindopril should be adjusted in accordance with the clinical clearance and depending on the clinical response to treatment. Potassium and creatinine levels are usually monitored routinely in these patients.
In patients with clinically significant heart failure, the development of arterial hypotension after initiation of treatment with ACE inhibitors may lead to some deterioration in renal function. In a similar situation, acute renal failure has been described, which is usually irreversible.
In some patients with bilateral renal artery stenosis or solitary renal artery stenosis treated with ACE inhibitors, increases in serum urea and creatinine levels were detected, which were usually mild and reversible after discontinuation of treatment. This is especially likely in patients with impaired renal function. In the case of renovascular hypertension, there is an increased risk of severe hypotension and renal failure. In such patients, treatment should begin under close medical supervision with a low dose, followed by careful dose titration. Since treatment with diuretics may be a predisposing factor in the development of the above conditions, diuretics should be discontinued during the first weeks of treatment with perindopril, while monitoring renal function.
In some patients with arterial hypertension and no obvious signs of previous vascular damage to the kidneys, increases in serum urea and creatinine levels developed, which were usually mild and transient, especially when perindopril was used concomitantly with diuretics. These manifestations are more likely to develop in patients with pre-existing kidney damage. In such cases, dose reduction and/or discontinuation of diuretic and/or perindopril treatment may be necessary.
Patients on hemodialysis
In patients receiving dialysis using high-flow membranes and concomitant treatment with ACE inhibitors, the development of anaphylactic reactions has been observed. In such cases, consideration should be given to using a different type of dialysate membrane or a different class of antihypertensive drug.
Kidney transplant
There is no experience with the use of perindopril in patients with recent kidney transplantation.
Hypersensitivity/angioedema
Rarely, patients receiving treatment with ACE inhibitors, including perindopril, may develop angioedema of the face, extremities, lips, mucous membranes, tongue, vocal folds and/or larynx. This phenomenon can develop at any time during treatment. In such cases, treatment with perindopril should be stopped immediately and appropriate monitoring of the condition should be initiated until symptoms cease completely. In cases where swelling of only the face or lips was observed, it usually resolved without treatment, although antihistamines were used to relieve symptoms.
Angioedema in combination with laryngeal edema can lead to death. In case of swelling of the tongue, vocal folds and larynx with a high probability of airway obstruction, emergency treatment should be prescribed immediately. This may include administering epinephrine (adrenaline) and/or maintaining a patent airway. The patient should be under close medical supervision until symptoms disappear completely and permanently.
Patients with a history of angioedema not associated with ACE inhibitors may be at increased risk of such edema when treated with ACE inhibitors. In rare cases, life-threatening anaphylactoid reactions have developed in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. Such reactions can be avoided by temporarily suspending ACE inhibitor treatment before each apheresis procedure.
Anaphylactic reactions during desensitization
Patients receiving ACE inhibitors during desensitization (for example, to the venom of Hymenoptera - wasps, bees and other insects) developed anaphylactoid reactions. Such reactions can be avoided by temporarily withdrawing ACE inhibitors, but if accidentally reintroduced, these reactions reappear.
Liver failure
In rare cases, treatment with ACE inhibitors is accompanied by a syndrome that begins with cholestatic jaundice and progresses with the development of fulminant liver necrosis, sometimes death. The mechanism of development of this syndrome is unknown. If jaundice develops or liver enzyme levels increase significantly during treatment with ACE inhibitors, the ACE inhibitor should be discontinued and appropriate medical supervision should be provided in the future.
Neutropenia/agranulocytosis/thrombocytopenia/anemia
In patients receiving ACE inhibitors, the development of neutropenia/agranulocytosis, thrombocytopenia and anemia is observed. In patients with normal renal function and without other complicating factors, neutropenia rarely develops. Perindopril should be used very cautiously in patients with collagen diseases, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially in the case of pre-existing renal impairment. Some of these groups of patients develop serious infections, which in many cases do not respond to active antibiotic therapy. When prescribing perindopril to such patients, periodic monitoring of leukocyte levels is recommended. Patients should be informed to report any signs of infection to their physician.
Race
ACE inhibitors are more likely to cause angioedema in blacks compared to patients of other races.
Similar to other ACE inhibitors, perindopril is less effective in lowering blood pressure in blacks compared to patients of other races; a possible explanation is the widespread prevalence of arterial hypertension with low renin levels among representatives of the black race.
Cough
When treated with ACE inhibitors, a cough may develop. Characterized by a non-productive persistent cough, which stops after discontinuation of treatment. Cough caused by an ACE inhibitor should be considered in the differential diagnosis of cough.
Surgery/anesthesia
During major surgery or during anesthesia with drugs that cause hypotension, perindopril may block the formation of angiotensin II due to compensatory release of renin. Treatment should be stopped the day before surgery. If arterial hypotension associated with this mechanism develops, it can be corrected with fluid therapy.
Hyperkalemia
Increases in potassium levels have been observed in some patients during treatment with ACE inhibitors, including perindopril. Patients at risk of developing hyperkalemia include those with renal failure, uncontrolled diabetes mellitus, those taking potassium-sparing diuretics, potassium supplements or salt substitutes containing potassium, and other drugs that increase potassium levels (eg, heparin). If concomitant use of these drugs is necessary, regular monitoring of potassium levels is recommended.
Patients with diabetes mellitus
In patients with diabetes mellitus taking oral hypoglycemic agents or insulin, glycemic levels should be carefully monitored during the first month of treatment with an ACE inhibitor.
Lithium preparations
The combination of lithium and perindopril is generally not recommended.
Potassium-sparing diuretics, potassium supplements and potassium-containing salt substitutes
In general, combinations of perindopril and potassium-sparing diuretics, potassium supplements and potassium-containing salt substitutes are not recommended.
Excipients
The drug contains lactose, so it should not be prescribed to patients with rare hereditary diseases:
- congenital galactosemia, lactase deficiency, glucose/galactose malabsorption syndrome.
Use in pediatrics
It is not recommended to prescribe the drug to children and adolescents under the age of 18 years,
because There are no data on the effectiveness and safety of perindopril tertbutylamine in this category of patients.
Impact on the ability to drive vehicles and operate machinery
No studies have been conducted on the effect on the ability to drive and operate machines.
If it is necessary to drive vehicles or operate machinery while using the drug, the possibility of dizziness or fatigue should be taken into account.
Pharmacological properties of the drug Perindopril
ACE inhibitor. It prevents the enzymatic conversion of angiotensin I to angiotensin II, a powerful vasopressor agent, as well as the transformation of bradykinin, which has a depressor effect, into an inactive heptapeptide. In the body, perindopril undergoes hydrolysis to form an active metabolite - perindoprilate, which is directly associated with pharmacological effects. Perindopril for hypertension (arterial hypertension) has a pronounced hypotensive effect, causes peripheral vasodilation and reduces peripheral vascular resistance, restores the elasticity of the arterial wall, and with systematic use leads to regression of left ventricular hypertrophy. Combination with diuretics enhances the antihypertensive effect of perindopril. In case of heart failure, it reduces myocardial hypertrophy, prevents the development of dystrophic changes, restores the isoenzymatic profile of myosin, normalizes the filling pressure of the right and left ventricles, and increases cardiac output; in case of coronary artery disease, it reduces the frequency of arrhythmias during myocardial reperfusion. Reduces heart work by reducing pre- and afterload. When taken orally, perindopril is rapidly absorbed; the maximum concentration in blood plasma is observed 1 hour after administration. Bioavailability - 65–70%. About 20% of perindopril in the body is transformed into an active metabolite - perindoprilat, the maximum concentration of which in the blood plasma is observed 3-4 hours after administration. The half-life is 1 hour. Food intake reduces the bioavailability of perindopril and the rate of its transformation into perindoprilat. The volume of distribution of free perindoprilate is approximately 0.2 l/kg. Less than 30% binds to plasma proteins. In addition to perindoprilate, 5 more inactive metabolites of perindopril are formed in the body. Perindoprilat is excreted in the urine, the half-life of its free fraction is 3–5 hours. Due to the gradual dissociation of perindoprilat from connection with ACE, its “effective” half-life is about 25 hours. During a course of treatment it does not accumulate in the body; the equilibrium state is achieved 4 days after the start of therapy. Elimination of perindoprilate is slowed down in the elderly, with heart and renal failure.
