Tarka capsules (pills) of prolonged action 2mg + 180mg N28
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Active ingredients
Verapamil + Trandolapril
Release form
Capsules
Composition
Active ingredient: Trandolapril (Trandolapril), Verapamil hydrochloride Concentration of the active substance (mg): 182
Pharmacological effect
Combined antihypertensive drug containing trandolapril (an ACE inhibitor) and verapamil (a blocker of slow calcium channels of prolonged action). TrandolaprilIs a ethyl ester (prodrug) of a non-sulfhydryl ACE inhibitor trandolaprilat. Suppresses the activity of the renin-angiotensin-aldosterone system of blood plasma. Renin is an enzyme that is synthesized by the kidneys and enters the bloodstream, where it causes the conversion of angiotensinogen to angiotensin I (low-active decapeptide). The latter is converted under the action of ACE (peptidyl dipeptidase) into angiotensin II, a powerful vasoconstrictor that causes arteries to narrow and increase blood pressure, as well as stimulating the secretion of aldosterone by the adrenal glands. Inhibition of ACE leads to a decrease in the concentration of angiotensin II in the blood plasma, which is accompanied by a decrease in vasopressor activity, and decreases in angiotensin II in the blood plasma, which is accompanied by a decrease in vasopressor activity, and decreases in angiotensin II in the blood plasma, which is accompanied by a decrease in vasopression. Although the production of aldosterone decreases slightly, nevertheless, a slight increase in serum potassium concentration can be observed in combination with loss of sodium and water. Reducing the level of angiotensin II by the feedback mechanism leads to an increase in plasma renin activity. Another function of ACE is the destruction of kinins (bradykinin), which have potent vasodilator properties, to inactive metabolites. In this regard, the suppression of ACE leads to an increase in circulating and tissue levels of kallikrein-kinins, which contributes to the expansion of blood vessels due to the activation of the prostaglandin system. This mechanism may partly determine the hypotensive effect of ACE inhibitors and is the cause of some side effects. In patients with arterial hypertension, the use of ACE inhibitors leads to a comparable decrease in blood pressure in a sitting position and standing without a compensatory increase in heart rate. OPS decreases, cardiac output does not change or increases. The renal blood flow increases and the glomerular filtration rate usually remains unchanged. The drastic cessation of therapy was not accompanied by a rapid increase in blood pressure.The hypotensive effect of trandolapril manifests itself 1 hour after ingestion and persists for at least 24 hours. In some cases, optimal control of blood pressure can be achieved only a few weeks after the start of treatment. With prolonged therapy, the hypotensive effect persists. Trandolapril does not impair the circadian blood pressure profile. Verapamil Blocks the transmembrane current of calcium ions in smooth muscle cells of the myocardium and coronary vessels. It causes a decrease in blood pressure at rest and during physical activity due to the expansion of peripheral arterioles. As a result of a reduction in round focal disease (afterload), myocardial oxygen demand and energy consumption decrease. Reduces myocardial contractility. The negative inotropic effect of the drug can be offset by a decrease in OPSS. Cardiac index does not decrease, with the exception of patients with left ventricular dysfunction. Verapamil does not affect the sympathetic regulation of cardiac activity, because it does not block β-adrenoreceptors. angiotensin system. Consequently, the synergism of the two drugs reflects their complementary pharmacodynamic effects. In clinical studies, the drug Tarka reduced blood pressure to a greater extent than both drugs separately.
Pharmacokinetics
TrandolaprilAbsorptionAfter ingestion, trandolapril is rapidly absorbed. Absolute bioavailability is about 10%. Tmax in plasma is about 1 hour. The distribution of trandolapril binding to plasma proteins is about 80% and does not depend on concentration. Tradolapril Vd about 18 liters. T1 / 2 is less than 1 hour. With repeated use of Css, it is reached in about 4 days, both in healthy volunteers and in young and old patients with arterial hypertension. Metabolism In plasma, trandolapril undergoes hydrolysis to form the active metabolite of trandolaprilat. Tmax of trandolaprilat in the blood plasma is 4-10 hours. Cmax or AUC does not depend on food intake. Absolute bioavailability of trandolaprilat is about 70%. Binding to blood proteins depends on the concentration and varies from 65% at a concentration of 1000 ng / ml to 94% at a concentration of 0.1 ng / ml.Trandolaprilat has a high affinity for ACE. InjectionThe renal clearance of trandolaprilat varies from 1 to 4 l / h, depending on the dose. With Css, the effective T1 / 2 of trandolaprilat, together with a small fraction of the administered drug, varies between 16 h and 24 h, which probably reflects the binding to plasma and tissue ACE. In the form of trandolaprilat, 10-15% of the dose of trandolapril is excreted by the kidneys, less than 0.5% of the dose is excreted by the kidneys unchanged. After ingestion of labeled trandolapril, 33% of radioactivity is detected in urine and 66% in feces. Pharmacokinetics in special clinical situations Trandolapril pharmacokinetics has not been studied in children younger than 18. The plasma trandolapril concentration is increased in elderly patients (over 65). However, the plasma concentration of trandolaprilat and its ACE-inhibiting activity in elderly patients with arterial hypertension are the same for both sexes. Renal failure. Compared with healthy volunteers, hemodialysis patients and patients with CC less than 30 ml / min have a plasma concentration of trandolaprilat about 2 times higher, and the renal clearance is reduced by about 85%. Hepatic insufficiency. Compared with healthy volunteers in patients with mild alcoholic cirrhosis, plasma concentrations of trandolapril and trandolaprilat increased 9 and 2 times, respectively, but ACE inhibitory activity does not change. Verapamil Absorption After ingestion, about 90-92% of the dose of verapamil is rapidly absorbed in the small intestine. Bioavailability is only 22% due to the pronounced effect of the first passage through the liver. With repeated use, the average bioavailability may increase to 30%. The time to reach Cmax in plasma is 4-15 hours. The distribution of Css with repeated use of 1 time per day is achieved in 3-4 days. Binding to plasma proteins is about 90%. Metabolism One of the 12 metabolites found in the urine is norverapamil, the pharmacological activity of which is 10-20% of that of verapamil; its share is 6% of the output of the drug. The css of norverapamil and verapamil are similar. The release of T1 / 2 with repeated use is equal to an average of 8 hours. 3-4% of the dose is excreted by the kidneys in unchanged form. Metabolites are excreted by the kidneys (70%) and through the intestines (16%). Pharmacokinetics in special clinical situations. The pharmacokinetics of verapamil do not change with impaired renal function.Impaired renal function does not affect the elimination of verapamil. The bioavailability and T1 / 2 of verapamil increase in patients with cirrhosis of the liver. However, the pharmacokinetics of verapamil remains unchanged in patients with compensated hepatic dysfunction.
Indications
Essential arterial hypertension (in patients undergoing combination therapy).
Contraindications
- a history of angioedema associated with treatment with ACE inhibitors; - cardiogenic shock; - chronic heart failure IIB and stage III; - simultaneous use of beta-blockers; - AV block II and III (except for patients with an artificial pacemaker) - acute myocardial infarction; - SSS (with the exception of patients with an artificial pacemaker); - acute heart failure; - atrial fibrillation / flutter; - Wolff-Parkinson-White syndrome; - Launa-Ganong-Levine syndrome; - marked bradycardia; - at Severe arterial hypotension; - renal dysfunction (QC - pregnancy; - breastfeeding period; - age up to 18 years (efficacy and safety not established); - known hypersensitivity to any component of the drug Tarka or to any other ACE inhibitor.
Precautionary measures
Do not exceed the recommended dose. With caution, you should use the drug for aortic stenosis, hypertrophic obstructive cardiomyopathy, abnormal liver and / or kidney function, systemic connective tissue diseases (including SLE, scleroderma), bone marrow suppression, AV block I degree , bradycardia, hypotension, conditions accompanied by a decrease in the BCC (including diarrhea, vomiting), bilateral stenosis of the renal arteries, stenosis of the artery of a single kidney, condition after kidney transplantation, patients restraining a salt-restricted diet on hemodialysis, when used in combination with diuretics.
Use during pregnancy and lactation
The use of the drug is contraindicated during pregnancy and during breastfeeding. The safety of using Tarka in pregnant women has not been established. There are separate observations of lung hypoplasia in newborns, intrauterine growth retardation, open arterial duct and skull hypoplasia after the use of ACE inhibitors during pregnancy. ACE inhibitors can cause arterial hypotension, accompanied by anuria in the fetus or newborn, or oligohydroamnion. The risk of teratogenic effects is highest when prescribing ACE inhibitors in the second and third trimesters of pregnancy. There is no information on the possible teratogenicity or embryo / fetotoxicity of ACE inhibitors in the first trimester of pregnancy. Verapamil is excreted in breast milk. During treatment with Tarka, you should stop breastfeeding.
Dosage and administration
Inside, without chewing (the capsule is swallowed whole), washed down with a small amount of water, before or after meals, 1 capsule 1 time per day (in the morning).
Side effects
Infections: bronchitis. From the hematopoietic system: leukopenia, neutropenia, lymphopenia, thrombocytopenia. From the side of metabolism and nutrition: hyperkalemia, hyponatremia. From the nervous system: imbalance, insomnia, drowsiness, syncope, hypesthesia, paresthesia, anxiety, insomnia, thinking. On the part of the organ of vision: visual impairment, fog before the eyes. On the side of the organ of hearing and the vestibular apparatus: dizziness, tinnitus. On the side of the cardiovascular system: complete AV-blockade, angina pectoris, bradycardia, palpitations, tachycardia, blockade of the bundle of His, acute myocardial infarction, ventricular premature beats, nonspecific changes of ST-T segment on ECG, marked reduction of blood pressure, flushing of the face. From the respiratory system: shortness of breath, congestion of the sinuses. From the side of the gastrointestinal tract: nausea, diarrhea , dyspepsia, dyspepsia, dry mouth. On the side of the skin and subcutaneous fat: angioedema, pruritus, rash. On the musculoskeletal system: arthralgia, myalgia, gout (hyperuricemia). On the part of the kidneys and urinary tract: frequent urine transmission, polyuria, hematuria, proteinuria, nocturia. On the sexual system: impotence,endometriosis. General and local reactions: chest pain, peripheral edema, fatigue. Laboratory values: increased liver enzymes (AST, ALT, LDH, alkaline phosphatase) and / or bilirubin, serum creatinine, residual urea nitrogen. Significant adverse events that were observed during use of verapamil From the side of the cardiovascular system: AV block I, II, III degree, sinus stop, AV dissociation, intermittent claudication, the occurrence or weighting of heart failure, angina pectoris, arrhythmia, pulmonary edema, tachycardia I, bradycardia, severe arterial hypotension, flushing of the face. On the side of the nervous system: acute cerebrovascular accident, confusion, drowsiness, psychotic symptoms, tremor, headache, dizziness, paresthesia. On the part of the organ of hearing and balance: dizziness. The sides of the digestive tract: gingival hyperplasia, abdominal pain or discomfort, reversible non-obstructive bowel obstruction, nausea, vomiting, constipation. On the side of the skin and subcutaneous fat: angioedema, Stevens-Johnson syndrome, rapiva, purpura, pruritus, ecchymosis, bruising, hair loss, hyperkeratosis, increased sweating, erythema multiforme, maculopapular rash. For the musculoskeletal system: muscle weakness, myalgia, arthralgia. , impotence. Immune disorders: hypersensitivity, allergic reactions. On the part of the kidneys and urinary tract: frequent urination. General reactions: peripheral edema, fainting, fatigue. Laboratory indices: hyperpro lactinemia, increased activity of hepatic transaminases. Significant adverse events that were observed with the use of tradolapril. From the side of the hematopoietic system: agranulocytosis. From the side of the gastrointestinal tract: vomiting, abdominal pain, pancreatitis. On the part of the genitourinary system: decreased libido. General symptoms: fever. Adverse effects that have been reported with the use of all APPS inhibitors. CNS: a transient cerebral disorder ovoobrascheniya, headache bol.So the cardiovascular system: myocardial infarction,cardiac arrest, cerebral hemorrhage, arterial hypotension. From the skin and subcutaneous fat: exudative erythema multiforme, toxic epidermal necrolysis, angioedema, rash. From the kidneys and urinary tract: acute renal failure. Other: pain in the kidney and urinary tract: acute renal failure. cough. Laboratory parameters: pancytopenia, decrease in hemoglobin and hematocrit, neutropenia, agranulocytosis, hyperkalemia.
Overdose
In clinical studies, the maximum dose of trandolapril was 16 mg. However, there were no signs of intolerance. In case of an overdose of the drug Tarka, the following symptoms caused by verapamil are possible: marked reduction in blood pressure, AV blockade, bradycardia, asystole. Deaths from overdose have been recorded. In case of an overdose of drug Tarka, the following symptoms caused by Trandolapril are possible: marked reduction in blood pressure, shock, stupor, bradycardia, electrolyte disturbances, renal failure. Treatment: symptomatic. Treatment of verapamil overdose includes parenteral administration of calcium supplements, the use of beta adrenomimetics and gastric lavage. Given the slow absorption of the drug of prolonged action, the patient’s condition should be monitored for 48 hours; hospitalization may be required during this period. Verapamil is not removed by hemodialysis.
Interaction with other drugs
With simultaneous use of lithium with the drug Tarka, neurotoxicity of lithium is increased. With simultaneous use of rifampicin with the drug Tarka, the hypotensive effect of verapamil can be reduced. With simultaneous use of sulfinpyrazone with the drug Tarka, the hypotensive effect of verapamil can be reduced. At the same time, the effect of muscle relaxants can be enhanced. use of acetylsalicylic acid with verapamil increases bleeding. At simultaneous use SRI verapamil plasma level of ethanol povyshaetsya.Odnovremennoe use with verapamil may lead to increased serum levels of simvastatin or lovastatina.Patsientam receiving verapamil treatment inhibitors of HMG-CoA reductase inhibitors (i.e.simvastatin / lovastatin) should begin with the lowest possible doses with a gradual increase in the course of therapy. If, however, it is necessary to prescribe verapamil to patients already receiving HMG-CoA reductase inhibitors, then their doses should be revised and reduced, respectively, to serum cholesterol concentrations. Similar tactics should be followed when verapamil is prescribed with atorvastatin. Fluvastatin, pravastatin and rosuvastatin are not metabolized by the CYP3A4 isoenzyme, therefore their interaction with verapamil is the least likely. Interactions caused by tradolapril or diuretics or other antihypertensive drugs can be used to create a interaction. Trandolapril can reduce the loss of potassium when used together with thiazide diuretics. Kaliysaving diuretics (spironolactone, amiloride, triamterene) or potassium drugs increase the risk of hyperkalemia while using trandolapril at the same time. hypoglycemic agents) may increase the hypoglycemic effect and lead to an increased risk of hypoglycemia.
special instructions
Patients with impaired liver function need to be carefully monitored during the period of treatment with Tarka. Patients with uncomplicated arterial hypertension after taking the first dose of trandolapril, as well as after increasing it, noted the development of arterial hypotension, accompanied by clinical symptoms. The risk of arterial hypotension is higher when water and electrolyte imbalance is disturbed as a result of prolonged diuretic therapy, restriction of salt intake, dialysis, diarrhea or vomiting. In these patients, before starting treatment with tradolapril, diuretic therapy should be discontinued and the BCC and / or salt content should be replenished. It is necessary to monitor blood pressure especially carefully when prescribing or canceling NSAIDs during the use of the drug Tark. (See section Drug Interactions). When treating with ACE inhibitors, cases of agranulocytosis and suppression of bone marrow function are described. These adverse events are more common in patients with impaired renal function, especially with systemic connective tissue diseases.In such patients (for example, with SLE or scleroderma), it is advisable to regularly monitor the number of leukocytes in the blood and the protein content in the urine, especially when renal dysfunction, treatment of GCS and antimetabolite cytotoxic drugs. Trandolapril can cause angioedema of the face, tongue, pharynx and / or larynx. Verapamil is part of the drug Tarka, therefore, the use of the combined drug should be avoided in patients with severe left ventricular dysfunction (for example, with an ejection fraction less than 30%, an increase in pressure wedging Ia pulmonary capillary bolshe20 mm Hg. v. or symptomatic heart failure) in patients with any degree of left ventricular dysfunction, if they get beta adrenoblokator.Pri evaluation of patients with arterial hypertension should always evaluate kidney function. Patients with chronic heart failure, bilateral renal artery stenosis or unilateral renal artery stenosis in patients with a single kidney (for example, after its transplantation) have an increased risk of impaired renal function, and in patients with renal insufficiency the risk of further deterioration in renal function. In some patients with arterial hypertension without kidney disease, when prescribing trandolapril in combination with a diuretic, an increase in blood urea nitrogen and serum crest may be observed Tinina. In patients with arterial hypertension, especially with impaired renal function, the drug Tarka can cause hyperkalemia. When undergoing surgical interventions or general anesthesia using drugs that cause arterial hypotension, tradolapril can block the formation of angiotensin II associated with compensatory renin release. Caution should be taken to select doses of inhalation anesthetics with simultaneous use with verapamil. With simultaneous use of colchicine and verapamil, the development of tetra has been reported aparesis. Combined use is not recommended (see section Drug Interactions). Some patients receiving diuretics, especially recently, after administration of tradolapril, have a sharp decrease in blood pressure. Since there are no data on the interaction of verapamil and disopyramide,Disopyramide should not be used within 48 hours before or 24 hours after taking verapamil. Use in pediatricsTarc's use of the drug has not been studied in children under 18 years old, so its use in this age group is not recommended. Impact on ability to drive vehicles and control mechanisms. Refrain from driving and working with mechanisms in the early stages of treatment, since the ability to drive or use complex machinery may deteriorate.