Perindopril PLUS, tablets 2.5mg+8 mg 30 pcs

Kidney function impairment

The therapy is contraindicated in patients with moderate to severe renal impairment (CKI less than 60 ml/min). In some patients with arterial hypertension without previous obvious impairment of renal function during the therapy, laboratory signs of functional renal insufficiency may appear. In this case, the treatment should be discontinued. Subsequently, combination therapy may be resumed with a low-dose combination of indapamide and perindopril, or only one of the drugs may be used.

Such patients require regular monitoring of potassium and serum creatinine concentration – two weeks after the start of therapy and every 2 months thereafter. Renal insufficiency occurs more frequently in patients with severe chronic heart failure or initial renal dysfunction, including renal artery stenosis. The drug Perindopril PLUS is not recommended in cases of bilateral renal artery stenosis or artery stenosis of the only functioning kidney.

Arterial hypotension and water-electrolyte imbalance

In cases of initial hyponatremia, there is a risk of sudden development of arterial hypotension, especially in patients with renal artery stenosis. Therefore, during dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and decreased plasma electrolyte content, e.g., after diarrhea or vomiting. These patients require regular monitoring of plasma electrolytes.

In case of severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for continuation of therapy. After recovery of circulating blood volume and BP, therapy may be resumed using lower doses of the drugs, or only one of the drugs may be used.

Potassium content

The combined use of perindopril and indapamide does not prevent hypokalemia, especially in patients with diabetes or renal insufficiency. As with any hypotensive drug and diuretic, regular monitoring of plasma potassium is necessary.

Auxiliary substances

Please note that the excipients of the drug include lactose monohydrate. Perindopril PLUS should not be used in patients with hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Lithium preparations

The concomitant use of Perindopril PLUS with lithium preparations is not recommended.

Perindopril PLUS should not be used in children and adolescents less than 18 years of age because of lack of data about the effectiveness and safety of indapamide and perindopril, either alone or together, in this age group of patients.

Perindopril

Double blockade of the angiotensin-aldosterone system (RAAS)

. There is evidence for an increased risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure) when ACE inhibitors are used concomitantly with ARA II or aliskiren. Therefore, dual blockade of the RAAS by combining an ACE inhibitor with ARA II or aliskiren is not recommended.

If dual blockade is absolutely necessary, it should be performed under close professional supervision with regular monitoring of renal function, plasma electrolytes and BP.

The use of ACE inhibitors in combination with ARA II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Potassium-saving diuretics, potassium preparations, potassium salt substitutes, and dietary supplements

Perindopril should not be used with potassium-saving diuretics or with potassium preparations, potassium salt substitutes, or dietary supplements.

Neutropenia / agranulocytosis / thrombocytopenia

There have been reports of neutropenia/ agranulocytosis, thrombocytopenia and anemia with ACE inhibitors. Neutropenia is rare in patients with normal renal function and without concomitant risk factors. Perindopril should be used with extreme caution during systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), as well as during taking immunosuppressants, allopurinol or procainamide, or in combination of these factors, especially in patients with initially impaired renal function.

Some patients had severe infectious diseases, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the number of leukocytes in the blood. Patients should inform the physician of any signs of infectious diseases (e.g., sore throat, fever).

Anemia may develop in patients after kidney transplantation or in those on hemodialysis. The greater the decrease in hemoglobin, the greater the initial hemoglobin decrease. This effect does not seem to be dose-dependent, but may be related to the mechanism of action of ACE inhibitors.

A slight decrease in hemoglobin occurs during the first 6 months, then it remains stable and completely recovers after discontinuation of the drug. Treatment may continue in these patients, but hematologic tests should be performed regularly.

Hypersensitivity / angioedema

In rare cases, angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx may occur when taking ACE inhibitors, including perindopril. This may occur during any period of therapy. If symptoms occur, administration of Perindopril PLUS should be stopped immediately and the patient should be observed until the signs of edema disappear completely. If the swelling only affects the face and lips, it usually resolves on its own, although antihistamines may be used as symptomatic therapy. A higher risk of angioedema has been reported in patients of non-highland race.

In patients with a history of angioedema not associated with ACE inhibitors, there may be an increased risk of developing it when taking this group of drugs.

In rare cases, angioedema of the intestine has developed during therapy with ACE inhibitors. Patients reported abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding angioedema of the face and with normal C-1 esterase levels. The diagnosis was established by abdominal computed tomography, ultrasound, or at the time of surgery. Symptoms went away after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, the possibility of angioedema of the bowel should be considered in the differential diagnosis.

Inhibitors of mTOR (mammalian target of rapamycin) (e.g. sirolimus, everolimus, temsirolimus)

In patients receiving concomitant therapy with mTOR inhibitors may increase the risk of angioedema (including airway or tongue edema with/without respiratory dysfunction).

Anaphylactoid reactions during desensitization

There have been isolated reports of long-term, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitization therapy with venom from hymenopteran insects (bees, wasps). ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. Prescription of ACE inhibitor should be avoided in patients receiving immunotherapy with venom of hymenopterous insects. However, an anaphylactoid reaction can be avoided by temporarily withdrawing the ACE inhibitor at least 24 hours before the desensitization procedure.

Anaphylactoid reactions during LDL apheresis

In rare cases, life-threatening anaphylactoid reactions have developed in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. To prevent anaphylactoid reactions, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.

Hemodialysis

In patients receiving ACE inhibitors, anaphylactoid reactions have been reported when hemodialysis is performed using high-flow membranes (e.g., AN69®). Therefore, it is advisable to use a different type of membrane or to use a hypotensive agent from a different pharmacotherapeutic group.

Cough

Dry, persistent cough may occur with ACE inhibitor therapy and disappear after discontinuation of the drugs of this group. If a patient has a dry cough, you should be aware of the possible iatrogenic nature of this symptom. If the attending physician considers that therapy with ACE inhibitor is necessary for the patient, continuation of therapy with ACE inhibitor is possible.

The risk of arterial hypotension and/or renal failure (in patients with heart failure, electrolyte balance disorders, etc.

In some pathological states there may be significant activation of the RAAS, especially with significant hypovolemia and decrease of plasma electrolyte content (due to salt-free diet or long-term use of diuretics), in patients with baseline low blood pressure, renal artery stenosis, chronic heart failure or cirrhosis with edemas and ascites.

The use of ACE inhibitors causes RAAS blockade and therefore may be accompanied by a sharp decrease in BP and/or increase in plasma creatinine concentration indicating the development of functional renal failure. These phenomena are more often observed when taking the first dose of the drug and during the first two weeks of therapy. In rare cases, these conditions develop acutely and in other terms of therapy. In such cases, it is recommended to resume therapy at a lower dose and then gradually increase the dose.

Elderly age

Before starting perindopril therapy, renal functional activity and plasma content of potassium ions should be assessed. At the start of therapy, the dose of the drug should be adjusted to the degree of BP decrease, especially in cases of dehydration and electrolyte loss. Such measures allow to avoid a sharp decrease in BP.

Atherosclerosis

The risk of arterial hypotension exists in all patients, but special caution should be exercised when using the drug in patients with ischemic heart disease and cerebrovascular insufficiency. In such patients, treatment should be started with low doses of the drug.

Renovascular hypertension

The method of treatment of renovascular hypertension is revascularization. However, the use of ACE inhibitors may be beneficial in this category of patients both awaiting surgery and when surgery is not feasible.

Perindopril PLUS is not indicated in patients with diagnosed or suspected renal artery stenosis, because therapy should be initiated in the hospital setting with lower doses of the combination of indapamide and perindopril.

Heart failure/severe heart failure

In patients with chronic heart failure (NYHA functional class IV), treatment should be initiated with lower doses of indapamide and perindopril combination and under close medical supervision.

Patients with arterial hypertension and coronary heart disease should not discontinue beta-adrenoblocker therapy: the ACE inhibitor should be added to beta-adrenoblocker therapy.

Diabetes mellitus

Patients with type 1 diabetes may have spontaneous increase of potassium in blood. The treatment with Perindopril PLUS is not indicated in these patients, since it should be started with minimal doses and under constant medical monitoring.

In the first month of therapy with ACE inhibitors, plasma glucose concentrations should be monitored closely in patients with diabetes mellitus treated with oral hypoglycemic agents or insulin.

Ethnic differences

Perindopril, like other ACE inhibitors, has a markedly less pronounced antihypertensive effect in patients of the Negro race compared with other races. It is possible that this difference is due to the fact that patients with arterial hypertension of the non-human race are more likely to have low renin activity.

Surgery/general anesthesia

The administration of general anesthesia with ACE inhibitors may result in a significant decrease in BP, especially with the use of general anesthesia agents that have antihypertensive effects.

The use of long-acting ACE inhibitors, including perindopril, should be discontinued if possible a day before surgery. The anesthesiologist should be advised that the patient is taking ACE inhibitors.

Aortic or mitral stenosis/Hypertrophic obstructive cardiomyopathy

The ACE inhibitors should be prescribed with caution in patients with left ventricular outflow tract obstruction.

Hepatic failure

In rare cases, cholestatic jaundice occurs with ACE inhibitors. If this syndrome progresses, fulminant liver necrosis develops, sometimes with a fatal outcome. The mechanism of this syndrome is unclear. If jaundice or significant increase in liver enzymes activity occurs with ACE inhibitor therapy, the patient should discontinue ACE inhibitor therapy and consult a physician.

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia include renal insufficiency, impaired renal function, age older than 70 years, diabetes mellitus, certain concomitant conditions (dehydration, acute decompensation of cardiac activity, metabolic acidosis), concomitant use of potassium-saving diuretics (such as spironolactone and its derivatives eplerenone, triamterene, amiloride) as well as potassium preparations or potassium-containing meal salt substitutes, as well as the use of other drugs that contribute to increased plasma potassium levels (e.g., heparins, ACE inhibitors, angiotensin II receptor antagonists, acetylsalicylic acid at a dose of 3 g/day or more, cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim).

The use of potassium preparations, potassium-saving diuretics, and potassium-containing salt substitutes may lead to a significant increase in blood potassium content, especially in patients with reduced renal function.

Hyperkalemia can lead to serious, sometimes fatal heart rhythm disturbances. If concomitant administration of the above drugs is necessary, treatment should be undertaken with caution with regular monitoring of serum potassium.

Indapamide

Hepatic encephalopathy

The use of thiazide and thiazide-like diuretics may lead to hepatic encephalopathy if liver function is impaired. In this situation, the diuretic should be stopped immediately.

Water-electrolyte balance

The content of sodium ions in blood plasma

The content of sodium ions in blood plasma should be determined before starting treatment, and then regularly monitored against the background of the drug.

Hyponatremia initially may not be accompanied by clinical symptoms, therefore regular laboratory monitoring is necessary. More frequent monitoring of sodium ions is indicated in patients with cirrhosis and elderly patients. Treatment with any diuretics can cause hyponatremia, sometimes with very serious consequences. Hyponatremia accompanied by hypovolemia can lead to dehydration and orthostatic hypotension.

The simultaneous reduction of chlorine ions may lead to the development of secondary compensatory metabolic alkalosis: the frequency of its occurrence and the degree of manifestation are small.

Potassium ion content in plasma

The therapy with thiazide and thiazide-like diuretics is associated with risk of hypokalemia. Hypokalemia (less than 3.4 mmol/l) should be avoided in the following high-risk patients: elderly patients, malnourished patients (both receiving and not receiving combined drug therapy), patients with cirrhosis (with edema and ascites), coronary heart disease, heart failure. Hypokalemia in these patients increases the toxic effect of cardiac glycosides and increases the risk of arrhythmias.

Patients with prolonged QT interval, both congenital and drug-induced, are also at increased risk.

Hypokalemia, like bradycardia, contributes to severe cardiac arrhythmias, especially pirouette arrhythmias, which can be fatal. In all cases described above, more frequent monitoring of plasma potassium ions is necessary. The first measurement of potassium ions should be performed within the first week after the therapy start.

If hypokalemia is detected, appropriate correction should be performed.

Plasma calcium ion content

Thiazide and thiazide-like diuretics may decrease renal excretion of calcium ions, resulting in a slight and temporary increase in plasma calcium content. Severe hypercalcemia may result from previously undiagnosed hyperparathyroidism. Diuretics should be discontinued prior to parathyroid function study.

Plasma glucose concentrations

Blood glucose concentrations in patients with diabetes mellitus should be monitored, especially in the presence of hypokalemia.

Uric acid

The incidence of gout attacks may increase with increasing plasma uric acid concentrations during therapy.

Diuretics and renal function

The thiazide and thiazide-like diuretics are only fully effective in patients with normal or mildly impaired renal function (creatinine plasma concentrations in adults below 25 mg/l or 220 µmol/L).

In elderly patients, plasma creatinine levels should be assessed taking into account age, weight and sex, according to the Cockroft formula:

Creatinine clearance (CK)=(140 – age) x weight/0.814 x plasma creatinine concentration

where: age in years, weight in kg, plasma creatinine concentration in μmol/L.

The formula is appropriate for older men; for older women multiply the result by 0.85.

At the beginning of diuretic treatment, patients may experience a temporary decrease in glomerular filtration rate and an increase in plasma urea and creatinine concentrations due to hypovolemia (due to water and sodium ion excretion). This transient functional renal failure is not dangerous in patients with baseline normal renal function, but in patients with renal insufficiency, its severity may worsen.

Photosensitivity

Photosensitivity reactions have been reported with thiazide and thiazide-like diuretics. If photosensitivity reactions occur with the drug administration, treatment should be discontinued. If continuation of therapy with diuretics is necessary, it is recommended to protect the skin from exposure to sunlight or artificial ultraviolet rays.

Athletes

Indapamide may react positively in doping controls.

Acute myopia and secondary closed angle glaucoma

Sulfonamides and their derivatives may cause idiosyncratic reactions leading to temporary (transient) myopia and acute closed angle glaucoma. Without proper therapy, acute angle closure glaucoma can lead to vision loss. The first step is to stop taking the medication as soon as possible. If intraocular pressure continues to be high, immediate therapeutic or surgical treatment may be necessary. Risk factors that may lead to the development of acute closed angle glaucoma include a history of allergy to sulfonamides or penicillin.

Caution should be exercised when driving motor vehicles and other technical devices that require increased attention and rapid psychomotor reactions.

Systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma); immunosuppressant therapy (risk of neutropenia, agranulocytosis); co-administration with lithium drugs, gold drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), baclofen, corticosteroids, drugs that may cause QT interval prolongation, drugs that may cause polymorphic ventricular tachycardia of the “pirouette” type, except non antiarrhythmic drugs inhibition of bone marrow hematopoiesis; reduced circulating blood volume (taking diuretics, salt-free diet, vomiting, diarrhea); coronary heart disease; cerebrovascular disease; hepatic and renal disorders; renovascular hypertension; diabetes mellitus; chronic heart failure (NYHA functional class IV); hyperuricemia (especially accompanied with gout and urate nephrolithiasis); labile BP; advanced age; hemodialysis with high-flow membranes (e.g., AN69®) or desensitization, LDL apheresis; conditions after kidney transplantation; planned anesthesia aortic valve stenosis/hypertrophic obstructive cardiomyopathy; atherosclerosis; members of the Negro race (less pronounced effect of use); athletes (possible positive reaction in doping control), bilateral renal artery stenosis or presence of only one functioning kidney, concomitant therapy with potassium-saving diuretics, potassium drugs or in patients with high plasma potassium levels.