Index of drugs

Table. 2 / 0,625; Table. 4 / 1.25. Treatment of essential hypertension in patients in whom monotherapy with Perindopril does not allow to obtain normal blood pressure.Table. 8 / 2.5. Treatment of primary hypertension in patients in whom combination therapy with perindopril and Indapamide, at the same doses, allowed to control blood pressure.

1 tabl contains 2 mg, 4 mg or 8 mg perindopril with tert-butylamine and 0.625 mg, 1.25 mg or 2.5 mg indapamide, respectively; tablets contain lactose.

Antihypertensive preparation - combination of an ACE inhibitor (perindopril) with a diuretic (indapamide). The preparation is characterized by the additive synergism of the antihypertensive effect of both its components. Perindopril is converted into the active metabolite - Perindopril, which is an inhibitor of ACE (an enzyme that catalyzes the conversion of angiotensin I to angiotensin II, as well as the breakdown of bradykinin). Suppression of ACE activity leads to: reduction of aldosterone secretion, increase in plasma renin activity, reduction of total peripheral resistance during long-term treatment, the most severe effect in muscle and kidney vascular beds, and is not accompanied by retention of sodium and water or reflex tachycardia. The maximum antihypertensive effect occurs after 4-6 h after a single dose and persisted for at least 24 h. Indapamide is a sulphonamide derivative with pharmacological properties similar to thiazide diuretics. It inhibits sodium resorption in secondary kidney tubules. It increases the excretion of sodium and chloride in the urine and (to a lesser extent) excretion of potassium and Magnesium, thus increasing the production of urine and exerting antihypertensive effects. A combined preparation is bioequivalent to the simultaneous administration of separate components of the drug. After oral administration, perindopril is rapidly absorbed from the gastrointestinal tract and reaches C_max after 1 h. Approximately 27% of the perindopril dose is converted to perindoprilat, the active metabolite. The maximum concentration of perindoprilat in the blood is reached within 3-4 h. Food reduces the bioavailability of perindoprilat. Perindoprilat binds to 20% of plasma proteins. It is excreted in the urine. T_0,5 the free fraction is about 17 h. When repeatedly administered, steady state is achieved within 4 days. Indapamide is rapidly and completely absorbed from the gastrointestinal tract, reaching C_max during one hour. In 79% it is bound to plasma proteins. T_0,5 is 14-24 h. It is excreted in the urine (70%) and faeces (22%) in the form of inactive metabolites.

Hypersensitivity to perindopril or other ACE inhibitors, indapamide or other sulfonamides and other components of the preparation. History of angioneurotic edema (Quincke's edema) associated with previous treatment with ACE inhibitors. Hereditary or idiopathic angioneurotic edema. Hepatic encephalopathy. Severe liver dysfunction. Renal dysfunction (creatinine clearance <30 ml / min - table 2 / 0.625 mg, 4 / 1.25 mg, creatinine clearance <60 ml / min - table 8 / 2.5 mg). Patients on dialysis. Hypokalemia. Untreated, decompensated heart failure. Co-administration with aliskiren in patients with diabetes or renal impairment (GFR <60 ml / min / 1.73 m²). Combination therapy with non-antiarrhythmic drugs that induce ventricular tachycardia is not recommendedtorsade de pointes. II and III trimester of pregnancy. Breastfeeding period.

During the treatment, the concentration of electrolytes in the blood (sodium, potassium), renal function (creatinine) and haematological parameters should be monitored more frequently in patients at risk. Anemia can occur in kidney transplant patients or hemodialyzed patients. A slight decrease in hemoglobin concentration occurs during the first 6 months of treatment with an ACE inhibitor, then the concentration stabilizes and returns to normal after discontinuation of therapy. Individual cases of haemolytic anemia have been reported in patients with congenital G6-PD deficiency.Due to the risk of hypotension, syncope, hyperkalemia and renal dysfunction (including acute renal failure), dual RAA blocking is not recommended (eg, through the combined use of an ACE inhibitor with an angiotensin II receptor antagonist or aliskiren); if the use of the RAA double block is absolutely necessary, it should only be carried out under the supervision of a specialist. At the same time, ACE inhibitors and angiotensin II receptor antagonists should not be used in patients with diabetic nephropathy. The drug should be used with particular caution in patients with highly stimulated renin-angiotensin-aldosterone system, due to the risk of significant hypotension and renal impairment (it is necessary to monitor the kidneys, including renal function, and treatment should be started with a low dose, very low cautiously increased or adjusted doses of individual active substances) - this applies to patients: electrolyte deficiency and hypovolaemia (eg due to the use of diuretics, low sodium diet, diarrhea, vomiting); with low blood pressure values ​​initially; with renal artery stenosis (use is not recommended in patients with bilateral renal artery stenosis or renal artery stenosis of the sole active kidney); with congestive heart failure, with advanced heart failure (NYHA grade IV); with cirrhosis of the liver with edema and ascites. Similar recommendations should be used in patients with ischemic heart disease or cerebrovascular disorders in which a significant reduction in blood pressure can lead to a heart attack or stroke. Caution should also be exercised in patients undergoing major surgery or under general anesthesia with hypotensive agents (it is recommended to stop taking the product 1-2 days before surgery). Particularly cautiously used in patients with: aortic stenosis and hypertrophic cardiomyopathy with a small stroke volume (narrowing of the outflow path from the left ventricle); with concomitant connective tissue diseases (eg systemic lupus erythematosus or scleroderma), in patients using immunosuppressants, Allopurinol or procainamide or with multiple risk factors, especially if a previous renal dysfunction (risk of neutropenia), periodic leukocyte count control is recommended, and patients should be informed about the need to report any signs of infection, i.e. sore throat, fever); with the risk of hyperkalemia (including patients with renal failure, elderly, with diabetes, with metabolic acidosis, with acute heart failure, taking potassium sparing diuretics at the same time, potassium supplements or salt substitutes containing potassium or other drugs increasing the concentration of potassium in the blood, usually not recommended for use with drugs causing hyperkalemia); with the risk of hypokalemia (among others, elderly patients, malnourished persons, with cirrhosis with ascites and peripheral edema, with coronary heart disease, with heart failure) and in patients in whom hypokalemia is a particular threat (patients with long QT syndrome, congenital or iatrogenic, receiving digitalis glycosides); in the elderly. If hypotension persists during treatment, if necessary, it should be given by intravenous infusion of NaCl; mild hypotension usually does not require discontinuation of treatment - after equalization of blood volume and blood pressure, treatment can be restarted with a lower dose of the preparation or just one of the ingredients. In hypertensive patients without prior overt renal function impairment in which renal function tests have demonstrated functional renal failure, therapy should be discontinued and therapy should be restarted with a lower dose or only one component - potassium and creatinine levels should be frequently assessed weeks and then every 2 months during the entire treatment. In patients with hypertension and in patients with coronary insufficiency (ischemic heart disease) starting treatment with ACE inhibitors, it is not necessary to discontinue beta blocking drugs. In diabetic patients treated with oral antidiabetic agents or insulin, glycemic control should be closely monitored (especially during the first month of treatment with the preparation).Indapamide may reduce the excretion of Calcium in the urine and lead to a transient, mild increase in the level of calcium in the blood; significantly elevated calcium levels may indicate unrecognized hyperparathyroidism - in these patients treatment should be stopped and parathyroid function assessed. In patients with elevated uric acid levels, indapamide may increase the incidence of gout attacks. ACE inhibitors may be less effective in lowering blood pressure in black patients than in non-black patients. ACE inhibitors are more likely to cause angioneurotic edema in black patients than in non-black patients. History of angioneurotic edema of a different etiology (not related to ACE inhibitors) potentially increases the risk of this reaction after the use of drugs from this group. In the event of symptoms of angioedema of the face, limbs, lips, mucous membranes, tongue, glottis and / or larynx, the treatment should be discontinued immediately and the patient should be left under observation (with the implementation of appropriate treatment, if necessary) until complete resolution of symptoms . Angioedema of the gut should be considered in the differential diagnosis of abdominal pain in patients receiving ACE inhibitors. Anaphylactoid reactions may occur in patients receiving ACE inhibitors and simultaneously receiving dialysis using high-flow membranes - high flux (use a different type of membrane or antihypertensive drug from another group), during LDL apheresis with dextran sulphate (ACE inhibitor treatment should be discontinued 24 h before each apheresis) or patients undergoing venom allergy therapy (ACE inhibitor should be discontinued) at least 24 hours before desensitization). If cough occurs, iatrogenic etiology should be considered; if the ACE inhibitor is still indicated, continuation of treatment may be considered. If jaundice or significant elevations in liver enzymes occur during treatment, ACE inhibitors should be discontinued immediately. In hepatic impairment, indapamide may cause hepatic encephalopathy - in these cases, the diuretic should be stopped immediately. If hypersensitivity reactions occur, treatment should be discontinued; if re-administration of the diuretic proves necessary, it is recommended to protect the skin against sun and artificial UVA radiation. The efficacy and tolerance of perindopril in children and adolescents has not been established either as monotherapy or in combination therapy - do not use. Due to the lactose content, do not use the preparation in patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

The use of the preparation in the first trimester of pregnancy is not recommended (there is a risk of teratogenic effect). Use in the second and third trimester of pregnancy is contraindicated. Perindopril used in the second and third trimester of pregnancy is toxic to fetal development (deterioration of renal function, oligohydramnios, delayed ossification of the skull) and newborn (renal failure, hypotension, hyperkalemia) - when exposure to the drug occurred from the second trimester of pregnancy, it is recommended an ultrasound examination of the fetus skull and kidneys; children whose mothers took the drug during pregnancy should be closely monitored for hypotension. Prolonged exposure to thiazide during the third trimester of pregnancy may reduce maternal plasma volume as well as utero-placental flow, which may cause placental ischemia and fetal developmental delay; moreover, rare cases of hypoglycaemia and thrombocytopenia have been reported in newborns who have been exposed to the thiazide drug during the perinatal period. The use of the preparation during breast-feeding is contraindicated. Indapamide may reduce or even inhibit the secretion of milk; moreover, it is excreted in human milk, and in the infant may cause hypersensitivity reactions, hypokalaemia, and jaundice of the basal ganglia.

Common: headache, asthenia, dizziness (also of labyrinthine origin), variability of mood and / or sleep disorders, paresthesia, dry cough, shortness of breath, constipation, dry mouth, nausea, epigastric pain, anorexia, vomiting, abdominal pain, taste disorders, dyspepsia, diarrhea, rash, pruritus, maculopapular eruptions,hypotension (orthostatic or not related to the position of the body), muscle cramps. Uncommon: confusion, bronchospasm, angioedema of the face, limbs, lips, mucous membranes, tongue, glottis and / or larynx, urticaria, hypersensitivity reactions (mainly cutaneous, in people prone to allergic and asthmatic reactions), purpura, exacerbation symptoms of existing systemic lupus erythematosus, renal failure, increased sweating, impotence. Rare: hypercalcemia. Very rare: thrombocytopenia, leukopenia / neutropenia, agranulocytosis, aplastic and haemolytic anemia, anemia (more frequently in patients treated with hemodialysis and kidney transplant patients), eosinophilic pneumonia, rhinitis, pancreatitis, cytolytic hepatitis or cholestatic, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, hypersensitivity to light, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), angina pectoris, myocardial infarction (probably secondary to excessive hypotension in high-grade patients risk), severe renal failure. Not known: increased uric acid in the blood, increased blood Glucose, increased liver enzymes, increased urea and creatinine in the blood (more common in patients with renal artery stenosis, treated with diuretics, with renal insufficiency, reversible after discontinuation of treatment) , syncope, hepatic encephalopathy (in patients with hepatic insufficiency), prolongation of the QT interval in ECG,torsades de pointes (potentially fatal), potassium loss with particularly dangerous reductions in potassium in at-risk patients, increased potassium (usually transient), hyponatremia with hypovolaemia, dehydration and postural hypotension. In addition for tabl. 8 mg + 2.5 mg: visual impairment and tinnitus (common).

Orally. Adults: 1 tabl. once a day. If possible, the dose should be selected using each of the active substances separately and selecting the most effective combination.Special groups of patients. In patients with moderate renal impairment (CCr 30-60 ml / min), it is recommended to start treatment with a correspondingly low dose of individual active substances in separate formulations; the maximum dose of a combination drug is 2 mg / 0.625 mg per day. No dose adjustment is required in patients with mild renal impairment (CCr> 60 ml / min) and in patients with mild or moderate hepatic impairment. In elderly patients, treatment should be started with a low dose of individual active substances in separate preparations or, if possible, from one 2 mg / 0.625 mg tablet once a day; if necessary, the dose of perindopril can be carefully increased to 4 mg a day, after a month of treatment.Way of giving. The tablets should be taken in the morning before meals. The 8 mg / 2.5 mg tablets have a dividing line that facilitates the crushing of the tablet for easier swallowing - it is not used to divide the drug into two equal doses.