Index of drugs

Replacement therapy of essential hypertension and / or stable coronary artery disease in patients who have received adequate control when coadministered with Perindopril and Amlodipine at the same doses.

1 tabl contains perindopril tosylate and amlodipine (as azoate): 5 mg + 5 mg, 5 mg + 10 mg, 10 mg + 5 mg or 10 mg + 10 mg, respectively. The tablets contain lactose.

Combined preparation containing perindopril - angiotensin converting enzyme inhibitor and amlodipine - Calcium antagonist. Perindopril is an inhibitor of angiotensin I converting enzyme into angiotensin II (angiotensin converting enzyme (ACE)). Suppression of ACE activity results in a decrease in plasma angiotensin II, which leads to an increase in plasma renin activity and a reduction in aldosterone secretion. Inhibition of ACE activity also increases the activity of circulating and local kallikrein-kinin systems (and thus also activation of the prostaglandin system). Amlodipine is a calcium antagonist that inhibits the inflow of calcium ions to the cells of the myocardium and vascular smooth muscle (a slow-acting channel blocker or calcium ion antagonist). The mechanism of hypotensive action results from direct action to reduce the tension of the smooth muscle of blood vessels. After oral administration perindopril is absorbed quickly, C_max reaches within 1 hour. T_0,5 perindopril in plasma is 1 hour. Perindopril is a prodrug. 27% of the administered dose of perindopril is absorbed into the blood in the form of the active metabolite, perindoprilat. C_max perindoprilat in plasma is achieved within 3-4 h. Taking meals reduces the conversion to perindoprilat, and thus bioavailability - the drug should be taken in the morning before a meal. The binding of perindoprilat to plasma proteins is 20%, mainly with angiotensin convertase, however, it depends on concentration. Perindoprilat is removed in the urine and the final T_0,5 the unbound fraction is approx. 17 h, which results in a dynamic equilibrium within 4 days. After oral administration, amlodipine is well absorbed, reaching C_max in the blood after 6-12 h of administration. The absolute bioavailability is estimated at 64-80%. Approx. 97.5% of circulating amlodipine is associated with plasma proteins. Bioavailability does not change under the influence of food. Final T_0,5 in the elimination phase, it is about 35-50 h for once daily dosing. Amlodipine is extensively metabolised in the liver to inactive metabolites. Approx. 60% of the administered dose is excreted in the urine as metabolites, 10% unchanged.

Hypersensitivity to perindopril (or other ACE inhibitor), amlodipine (or dihydropyridine derivatives) or to any of the excipients. Angioedema associated with prior treatment with ACE inhibitors. Hereditary or idiopathic angioneurotic edema. II and III trimester of pregnancy. Severe hypotension. Shock, including cardiogenic shock. Narrowing the outflow path from the left ventricle (eg aortic valve stenosis). Haemodynamically unstable heart failure after having acute myocardial infarction. The concomitant use of perindopril and aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (GFR <60 ml / min / 1.73 m²).

Related to perindopril. In case of angioedema, the preparation should be immediately discontinued and the patient should be observed until the symptoms have completely resolved. In cases where the swelling only covers the face and lips, the symptoms usually disappear without treatment, however, antihistamines may be used to relieve symptoms. If the swelling affects the tongue, glottis or larynx, which may cause airway obstruction, urgent treatment should be initiated; it may involve the administration of adrenaline and / or maintenance of airway patency. The patient should remain under strict medical supervision until the symptoms have completely and permanently resolved.In patients with a history of angioneurotic edema, which is unrelated to treatment with an ACE inhibitor, there may be an increased risk of angioneurotic edema when receiving an ACE inhibitor. Occurrence of angioneurotic edema should be considered in the differential diagnosis of patients receiving ACE inhibitors who report abdominal pain. Due to the risk of life-threatening anaphylactoid reactions, an ACE inhibitor should be temporarily discontinued prior to each apheresis of low-density lipoprotein (LDL) with dextran sulphate. Due to the risk of life-threatening anaphylactoid reactions, ACE inhibitors should be used with caution in allergy patients during desensitisation, and should be avoided in patients undergoing Hymenoptera venom immunotherapy (bees, wasps). In patients requiring both the use of an ACE inhibitor and desensitisation therapy, these reactions can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before the de-sensitization treatment. Due to the risk of neutropenia or agranulocytosis, thrombocytopenia and anemia, perindopril should be used with caution in patients with vascular collagenosis receiving immunosuppressive therapy, treatment with Allopurinol or procainamide or who have several risk factors, especially if there has been a previous dysfunction kidney. Some of these patients developed severe infections, which in some cases were resistant to intensive antibiotic treatment. If perindopril is used in such patients, it is recommended to periodically determine the number of white blood cells, and patients should be advised to report any signs of infection (eg sore throat, fever). In patients at high risk of symptomatic hypotension, blood pressure, renal function and serum potassium should be carefully monitored when perindopril and amlodipine are used. Similar recommendations apply to patients with ischemic heart disease or cerebrovascular disease in whom excessive hypotension may result in a myocardial infarction or cerebrovascular accident. If hypotension occurs, the patient should be placed in supine position and, if necessary, administered 0.9% sodium chloride solution by intravenous infusion. Transient hypotension is not a contraindication for further treatment, which usually occurs without difficulty after the increase in blood pressure due to the replenishment of the volume of fluids. In some patients with congestive heart failure, with normal or low blood pressure, taking perindopril may cause a fall in blood pressure. This effect is expected and usually does not require discontinuation of treatment. If symptomatic hypotension occurs, it may be necessary to reduce the dose or discontinue perindopril. Perindopril should be used with caution in patients with mitral stenosis and with narrowing of the left ventricle outflow pathway, eg as aortic valve stenosis or hypertrophic cardiomyopathy. In patients with renal insufficiency (creatinine clearance <60 ml / min), separate dose adjustments of the individual components and routine determination of potassium and creatinine are recommended. In some patients with bilateral renal artery stenosis or stenosis of the artery supplying the only active kidney treated with ACE inhibitors, increases in serum urea and creatinine, usually reversible upon discontinuation of therapy, have been observed. This is particularly likely in patients with renal insufficiency. If there is also renovascular hypertension, there is an increased risk of severe hypotension and renal failure. In some hypertensive patients with no previous history of renal vascular disease, there has been a moderate and transient increase in serum urea and serum creatinine, particularly when co-administered with perindopril and a diuretic. This is more likely in patients with pre-existing renal impairment. Dose reduction and / or discontinuation of the diuretic and / or perindopril may be required. In case of jaundice or a significant increase in liver enzymes, ACE inhibitors should be discontinued and appropriate medical treatment should be instituted.The use of ACE inhibitors is associated with a higher incidence of angioneurotic edema in black patients than in patients of other breeds. Perindopril may be less effective in lowering blood pressure in black patients, possibly due to the higher incidence of low plasma renin activity in black hypertensive patients. During differential diagnosis of cough, cough caused by the use of an ACE inhibitor should be considered. In patients undergoing major surgery or receiving anesthesia with agents that cause hypotension, the combination of perindopril with amlodipine may block the formation of angiotensin II, secondary to the compensatory release of renin. Treatment should be discontinued one day before the planned surgery. If hypotension occurs due to the above mechanism, it can be compensated by increasing the volume of fluids. While using the drug, there is a risk of increasing serum potassium. Risk factors for developing hyperkalemia are: renal failure, decreased renal function, age (> 70), diabetes, concomitant disorders, in particular dehydration, acute decompensation of heart failure, metabolic acidosis and concomitant use of potassium-sparing diuretics (eg spironolactone, eplerenone , triamterene or amiloride), potassium supplements and potassium-containing salt substitutes, as well as other drugs that cause an increase in serum potassium (eg heparin). If concomitant use of any of the above-mentioned preparations with perindopril is necessary, caution should be exercised and serum potassium should be determined regularly. In diabetic patients treated with oral antidiabetic agents or insulin, Glucose monitoring should be closely monitored during the first month of ACE inhibitor administration. There are no data on the use of perindopril in patients who have recently had a kidney transplant. In patients undergoing dialysis with membranes of high permeability and simultaneously treated with ACE inhibitors anaphylactoid reactions have been observed. In these patients, the use of other type of dialysis membranes or an antihypertensive drug from another group should be considered. If an unstable angina pectoris occurs during the first month of treatment with perindopril (regardless of its severity), a thorough risk / benefit assessment should be performed before continuing treatment. The concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of hypotension, hyperkalaemia and renal dysfunction (including acute renal failure) - therefore, dual blocking of the RAA system is not recommended by concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren. If the use of a dual RAA blockade is absolutely necessary, it should only be carried out under the supervision of a specialist, and the vital parameters of the patient, such as kidney function, electrolyte concentration and blood pressure should be closely monitored. In patients with diabetic nephropathy, ACE inhibitors and angiotensin II receptor antagonists should not be used concurrently.Related to amlodipine. The safety and efficacy of amlodipine at hypertensive crisis has not been established. Patients with heart failure should be treated with caution (in patients with severe heart failure (NYHA class III and IV) there is an increased risk of pulmonary edema). Amlodipine should be used with caution in patients with congestive heart failure (increased risk of cardiovascular events and death). In patients with hepatic impairment, the use of amlodipine should be started with the lowest dose possible and be cautious both when initiating therapy and increasing the dose. In patients with severe hepatic impairment, a gradual dose escalation and careful monitoring may be required. Increasing the dose in elderly patients requires caution. Amlodipine is not dialysable. Co-administration of perindopril and amlodipine / lithium, potassium-sparing diuretics, potassium supplements and dantrolene is not recommended. The preparation contains lactose - should not be used in patients with rare, hereditary galactose intolerance, malabsorption of glucose and galactose or Lapp lactase deficiency.

The use of the preparation in the first trimester of pregnancy is not recommended (there is a risk of teratogenic effect). The preparation is contraindicated in the second and third trimester of pregnancy.The use of perindopril in the second and third trimester of pregnancy is a factor damaging the fetus (deterioration of renal function, oligohydramnios, delayed ossification of the skull) and toxic to the newborn (renal failure, hypotension, hyperkalemia) - in the case of exposure to an ACE inhibitor from the second trimester of pregnancy, it is recommended ultrasound examination of fetal skull and kidneys; infants whose mothers took the drug during pregnancy should be closely monitored for hypotension. The use of the preparation during feeding is not recommended. Therefore, a decision should be made whether to discontinue breast-feeding or discontinue the preparation, taking into account the importance of treatment for the mother. Some patients treated with calcium channel blockers have reported transient biochemical changes in the sperm head. In one rat study, adverse reactions were observed following male fertility amlodipine.

perindopril. Common: pain and dizziness (especially at the beginning of treatment), dysgeusia, paresthesia, labyrinthine dizziness, blurred vision (including double vision), tinnitus, hypotension (and symptoms associated with it), shortness of breath, cough, abdominal pain , nausea, vomiting, indigestion, diarrhea, constipation, pruritus, rash, rash, muscle cramps, asthenia. Uncommon: allergic reactions, mood changes (including anxiety), sleep disturbances, bronchospasm, dry mouth, angioneurotic edema (face, limbs, lips, mucous membranes, tongue, glottis and / or larynx), excessive sweating hives, impaired renal function, impotence. Rare: increase in serum bilirubin and increase in liver enzymes. Very rare: leukopenia / neutropenia, agranulocytosis or pancytopenia, thrombocytopenia, haemolytic anemia in patients with congenital G-6PDH deficiency, decrease in hemoglobin and hematocrit values, confusion, angina pectoris, myocardial infarction (probably secondary to excessive hypotension in patients in the group high risk), arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), stroke (probably secondary to excessive pressure reduction in high-risk patients), rhinitis, eosinophilic pneumonia, pancreatitis, cytolytic or cholestatic hepatitis, erythema multiforme, acute renal failure. Not known: hypoglycaemia, vasculitis, increased blood urea and serum creatinine, hyperkalemia.amlodipine. Common: drowsiness (especially at the beginning of treatment), headache and dizziness (especially at the beginning of treatment), palpitations, sudden redness (especially of the face), abdominal pain, nausea, swelling of the ankles, swelling, fatigue. Uncommon: insomnia, mood changes (including anxiety), depression, taste disorders, tremors, hypoaesthesia, paresthesia, syncope, visual disturbances (including double vision), tinnitus, hypotension (and symptoms associated with it), dyspnea, inflammation nasal mucus, vomiting, indigestion, change in the frequency of bowel movements, dry mouth, diarrhea, constipation, alopecia, purpura, skin discoloration, excessive sweating, pruritus, rash, rash, joint pain, muscle pain, muscle cramps, back pain , micturition disorders, nocturia, frequent urination, impotence, gynecomastia, chest pain, asthenia, pain, malaise, weight gain, weight loss. Rare: confusion. Very rare: leukopenia / neutropenia, thrombocytopenia, allergic reactions, hyperglycemia, hypertonia, peripheral neuropathy, myocardial infarction (probably secondary to excessive pressure reduction in high-risk patients), arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation) ), vasculitis, cough, gingivitis, pancreatitis, gastritis, hepatitis, jaundice, increased liver enzymes (mostly as a consequence of cholestasis), Quincke's edema, angioneurotic edema (face, limbs, lips, membranes) mucous, tongue, glottis and / or larynx), erythema multiforme, urticaria, Stevens-Johnson syndrome, exfoliative dermatitis, hypersensitivity to light. Isolated cases of extrapyramidal syndrome have been reported with the use of calcium antagonists.

Orally. The use of a combined preparation is not suitable for initiating treatment. If dosage adjustment is necessary, the dose may be modified or the dose of individual active substances may be considered.Special groups of patients. In elderly patients and patients with renal insufficiency, standard treatment controls include frequent determination of creatinine and potassium levels. The combination of perindopril with amlodipine can be used in patients with a creatinine clearance ≥60 ml / min, but it is not suitable for patients with creatinine clearance <60 ml / min. In these patients, it is recommended to adjust the dose of individual components separately. Elderly patients are advised to follow the usual dosing regimens, but increasing the dosage should be done with caution. Changes in amlodipine plasma levels do not correlate with the degree of renal failure. Amlodipine can not be removed by dialysis. No dosage recommendations have been made for patients with mild or moderate hepatic impairment, therefore caution should be used and treatment should be started at the lowest dose. To determine the optimal starting and maintenance dose in patients with hepatic impairment, the individual active substances (amlodipine and perindopril) must be adjusted separately. In patients with severe hepatic impairment, the use of amlodipine should be initiated at the lowest dose and should be slowly increased (no studies in this patient group). It should not be used in children and adolescents (efficacy and safety of use has not been established).Method of administration. One tablet once a day, in a single dose, preferably in the morning, before a meal.