Trade name of the drug:
International Nonproprietary Name:
active ingredients: indapamide – 1,500 mg, lisinopril dihydrate – 5.444 mg (equivalent to lisinopril – 5,000 mg). excipients: lactose monohydrate – 84,000 mg, calcium hydrogen phosphate dihydrate – 58.566 mg, hypromellose (type 2208) – 49,500 mg, mannitol – 16.670 mg, corn starch – 12.150 mg, microcrystalline cellulose, type 102 – 9,000 mg, croscarmellose sodium – 3,000 mg , talc – 2.500 mg, magnesium stearate – 2.420 mg, colloidal silicon dioxide – 0.750 mg, opadry II white – 4.500 mg (contains: polyvinyl alcohol – 40.0%, titanium dioxide – 25.0%, macrogol-3350-20, 20%, talc 14.80%), hard gelatin capsule – 76 mg (contains: iron dye red oxide – 0.1180%, titanium dioxide – 2.2263%, gelatin – 83.1600%, in Yes – 14.5000%). Dosage 1.5 mg + 10 mg active ingredients: indapamide – 1,500 mg, lisinopril dihydrate – 10.888 mg (equivalent to lisinopril – 10,000 mg). excipients: lactose monohydrate – 84,000 mg, calcium hydrogen phosphate dihydrate – 53,122 mg, hypromellose (type 2208) – 49,500 mg, mannitol – 16.670 mg, corn starch – 12,150 mg, microcrystalline cellulose, type 102 – 9,000 mg, croscarmellose sodium – 3,000 mg , talc – 2.500 mg, magnesium stearate – 2.420 mg, colloidal silicon dioxide – 0.750 mg, opadry II white – 4.500 mg (contains: polyvinyl alcohol – 40.0%, titanium dioxide – 25.0%, macrogol-3350-20, 20%, talc – 14.80%), hard gelatin capsule – 76 mg (contains: crimson dye (Ponzo 4R) – 0.3832%, titanium dioxide – 2.0000%, gelatin – 83.1200%, water – 14.5000%). Dosage 1.5 mg + 20 mg active ingredients: indapamide – 1,500 mg, lisinopril dihydrate – 21.776 mg (equivalent to lisinopril – 20,000 mg). excipients: lactose monohydrate – 84,000 mg, calcium hydrogen phosphate dihydrate – 106.244 mg, hypromellose (type 2208) – 49,500 mg, mannitol – 33.340 mg, corn starch – 24,300 mg, microcrystalline cellulose, type 102 – 9,000 mg, croscarmellose sodium – 6 mg talc – 5,000 mg, magnesium stearate – 4,090 mg, colloidal silicon dioxide – 0,750 mg, opadry II white – 4,500 mg (contains: polyvinyl alcohol – 40.0%, titanium dioxide – 25.0%, macrogol-3350 – 20, 20%, talc 14.80%), hard gelatin capsule – 76 mg (contains: iron dye red oxide – 0.5000%, crimson dye (Ponso 4R) – 0.2156%, ty ana dioxide -0.8000% gelatin – 83.9800%, water – 14.5000%).
Dosage 1.5 mg + 5 mg Solid, light pink pink gelatin capsules, size No. 1. Capsules 1 is an oval, film-coated, biconvex, film-coated tablet of white color (contains indapamide) with “CP3” engraved on one side and painted on. the other and 1 round, biconvex tablet of white color (contains lisinopril) with “CN3” engraving on one side. Dosage 1.5 mg + 10 mg Pink hard gelatin capsules, size No. 1. The contents of the capsules are 1 oval, biconvex film-coated tablet of white color (contains indapamide) with “CP3” engraved on one side and risky on the other. and 1 round, biconvex tablet of white color (contains lisinopril) with “CN4” engraving on one side. Dosage 1.5 mg + 20 mg Solid gelatin capsules of red-brown color, size No. 1. Capsules contents – 1 oval, biconvex film-coated tablet, white (contains indapamide) with “CP3” engraved on one side and with a risk on the other and 2 round, biconvex tablets of white color (contain lisinopril), with engraving “CN4” on one side.
Pharmacodynamics Dyroton ® Plus is a combination drug with fixed doses of lisinopril and indapamide. Indapamide Is a sulfonamide derivative containing an indole ring. By its pharmacological properties, indapamide is close to thiazide-like diuretics, which inhibit the reabsorption of sodium ions in the cortical segment of the loop of Henle. This is accompanied by an increase in the excretion of sodium ions, chlorides and potassium and, to a lesser extent, of magnesium ions, which leads to increased diuresis and an antihypertensive effect. In clinical studies of phase II and phase, the use of indapamide as monotherapy in doses that did not cause a pronounced diuretic effect caused a 24-hour antihypertensive effect. The antihypertensive activity of indapamide leads to an improvement in the elasticity index of the large arteries and to a decrease in the total peripheral and arteriolar resistance. Indapamide reduces left ventricular hypertrophy. In certain doses, an optimal therapeutic effect of thiazide and thiazide-like diuretics is achieved, but with a further increase in dose, the frequency of side effects increases. Thus, the dose should not be increased if the therapeutic effect is not observed when using the drug at the recommended therapeutic doses. In short-term, medium-term and long-term studies, in which patients with hypertension took part, it was shown that indapamide:
- does not affect lipid metabolism, including the concentration of triglycerides, cholesterol, low and high density lipoproteins.
- does not affect carbohydrate metabolism, including in patients with diabetes.
It is an inhibitor of angiotensin-converting enzyme ACE, which inhibits the conversion of angiotensin I to angiotensin II. The decrease in the concentration of angiotensin II leads to a direct decrease in the secretion of aldosterone. Lisinopril inhibits the degradation of bradykinin and increases prostaglandin synthesis. Reduces total peripheral vascular resistance, blood pressure, preload and pressure in the pulmonary capillaries. In patients with chronic heart failure, lisinopril increases the minute volume of blood and increases the myocardial tolerance to stress. Expands arteries to a greater extent than veins. Some effects are attributed to effects on tissue reninangiotensin systems. With prolonged use, hypertrophy of the myocardium and the walls of resistive arteries is reduced. Lisinopril improves blood supply to the ischemic myocardium. In patients with chronic heart failure, ACE inhibitors increase life expectancy; in patients with myocardial infarction in a history without clinical manifestations of heart failure, lisinopril slows down the progression of left ventricular dysfunction. Lisinopril begins to act within 1 hour after ingestion. The maximum effect is achieved within 6-7 hours; effect duration 24 hours. In patients with arterial hypertension, the effect is manifested during the first days after the start of treatment; stable effect occurs within 1-2 months of treatment. Cases of a marked increase in blood pressure (BP) after abrupt withdrawal of the drug are not registered. Lisinopril reduces both blood pressure and albuminuria. In patients with hyperglycemia, lisinopril helps to restore impaired function of the glomerular endothelium. In patients with diabetes, lisinopril does not affect the plasma glucose concentration; taking the drug is not associated with an increased risk of hypoglycemia.
Pharmacokinetics Indapamide The active substance is applied to a special carrier matrix that provides a slow, controlled release of indapamide in the gastrointestinal tract. Absorption: The released indapamide is rapidly and completely absorbed in the gastrointestinal tract. Meal slightly increases the time of absorption of indapamide, while not affecting the amount of suction. Indapamide is achieved 12 hours after a single dose. With repeated use of the drug changes in the concentration of the drug in the blood plasma between doses of the drug smoothed out. Individual variability of the magnitude of absorption is noted. Distribution and binding to proteins: approximately 79% of the drug is bound to plasma proteins. The half-life (T½) is 14-24 hours (average, 18 hours). Equilibrium concentrations are reached 7 days after the start of therapy. Repeated administration does not lead to drug accumulation. Excretion: Indapamide is excreted mainly as an inactive metabolite by the urica (70% of the dose taken) and through the intestines (22%). Patients at high risk: the pharmacokinet of indapamide does not change in patients with renal insufficiency. Lisinopril Absorption: When taking lisinopril inside the gastrointestinal tract absorbs about 25% of the drug. Food intake does not affect absorption. The average level of absorption is 30%; bioavailability – 29%. Distribution and binding to plasma proteins: the maximum plasma concentration (C max) is reached 6-8 hours after ingestion. The degree of binding to plasma proteins is low. Lisinopril poorly penetrates the blood-brain barrier. Metabolism: lisinopril does not undergo biotransformation in the human body. Excretion: half-life (T½) – 12 hours.
Indications for use
- Hypersensitivity to lisinopril or other ACE inhibitors.
- Hypersensitivity to indapamide or other sulfonamide derivatives.
- Hypersensitivity to drug excipients.
- Angioedema in history, including Quincke edema, associated with the use of ACE inhibitors.
- Hereditary or idiopathic angioedema.
- Severe renal failure (creatinine ® Plus clearance and drugs containing aliskiren, patients with diabetes mellitus or renal dysfunction (glomerular filtration rate (GFR) 2).
- Pregnancy or breastfeeding.
- Age up to 18 years (efficacy and safety have not been established).
- Lactose intolerance, galactosemia, glucose malabsorption syndrome and galactose.
Aortic stenosis, hypertrophic obstructive cardiomyopathy, cerebrovascular diseases (including cerebral circulatory insufficiency), coronary heart disease, coronary insufficiency, severe autoimmune systemic diseases of the connective tissue (including systemic lupus erythematosus, scleroderma), myelosuppression, myelean, heart, heart, heart, heart disease, myelogenesis, myelogenesis, myeteropathy, myelogenesis, myeloid suppression, myeloid suppression, myeloid suppression, myelogenesis, myeloid suppression renal artery stenosis in patients with a single kidney, condition after kidney transplantation, renal failure, azotemia, primary aldosteronism, a salt-restricted diet, conditions associated with a decrease in circulating blood volume (including vomiting and diarrhea), elderly patients, and liver failure. Attenuated patients or patients receiving combination therapy with other antiarrhythmic drugs (see the section “Interaction with Other Drugs”); violations of water and electrolyte balance; prolongation of the QT interval on the ECG; high concentration of uric acid in the blood serum; hyperparathyroidism.
Use during pregnancy and during breastfeeding
Pregnancy Dyroton ® Plus is contraindicated during pregnancy. Adequately controlled clinical studies of the use of the drug Diroton ® Plus in pregnant women have not been conducted. When pregnancy occurs, you must immediately stop taking the drug Dirotonk Plus. When planning pregnancy, patients should stop taking Diroton ® Plus and consult a doctor to select another antihypertensive drug with an established safety profile during pregnancy. Indapamide Diuretics are usually contraindicated during pregnancy. It is forbidden to use these drugs to reduce the physiological edema during pregnancy. Diuretics can lead to placental insufficiency and impaired fetal development. Lisinopril Acceptance of ACE inhibitors in pregnant women in 2-3 trimester can lead to death of the fetus or newborn. Careful monitoring of the condition of newborns and infants, whose mothers took ACE inhibitors during the prenatal period, is shown to identify a possible significant reduction in blood pressure, oliguria, and hyperkalemia. Perhaps the development of water deficiency, as well as hypoplasia of the facial bones, deformation of the bones of the face and skull, hypoplasia of the lungs and impaired development of the kidneys in newborns. Lisinopril can penetrate the placental barrier. Women of childbearing age should use reliable methods of contraception. Do not start treatment with lisinopril during pregnancy. Breastfeeding Dyroton ® Plus is contraindicated during breastfeeding. Indapamide Not recommended for nursing mothers (indapamide passes into breast milk). Lisinopril There are no data on the penetration of lisinopril into breast milk. During treatment with lisinopril, breastfeeding should be stopped.
Dosage and administration
Method of use Inside. Dyroton ® Plus can be taken regardless of the meal. Doses As a rule, fixed-dose combination drugs should not be used for initial therapy. The drug Diroton ® Plus is prescribed to adult patients who have achieved adequate control of arterial hypertension while receiving lisinopril and indapamide, which the patient takes at the same time in the same doses as in the combined preparation. The recommended dose is 1 capsule per day, preferably in the morning, at the same time every day. The maximum daily dose is 1 capsule. If necessary, dose selection should be used drugs indapamide and lisinopril separately. Special patient groups Patients with impaired renal function Against the background of therapy with Dyroton ® Plus, it is necessary to monitor renal function, as well as the content of potassium and sodium in the blood plasma. When renal function deteriorates, Dyroton ® Plus should be canceled and replaced with individually selected drugs. Children and adolescents (® Plus in children and adolescents has not been established. Elderly patients (>65 years) This drug should be used with caution in elderly patients. It is necessary to monitor the concentration of creatinia in the blood plasma and assess its consistency with age, body weight and sex.
- Cancel diuretics three days before the appointment of ACE inhibitors. In the future, if necessary, it is possible to resume taking diuretics.
- Or the appointment of ACE inhibitors in smaller doses with a gradual increase in dose, if necessary.
In the case of chronic heart failure, ACE inhibitors should be given in lower doses with a possible preliminary reduction in the dose of diuretics. In all cases, the control of renal function in the first week after the appointment of an ACE inhibitor (plasma creatinine concentration) is shown. Other drugs that can cause hypokalemia: amphotericin B (w / w), gluco-and mineralocorticosteroids (with systemic use), tetracosactide, laxatives that stimulate intestinal motility.
Increased risk of hypokalemia (additive effect). The regular monitoring of the content of potassium in the blood plasma and, if necessary, its correction are shown. Patients receiving cardiac glycosides require special attention. The use of laxatives that do not stimulate intestinal motility is recommended. Baclofen An increase in antihypertensive effect has been reported. Patients need to replenish fluid loss and monitor renal function at the beginning of treatment. Cardiac glycosides: Hypokalemia enhances the toxic effects of cardiac glycosides. With the combined use of indapamide and cardiac glycosides, the control of potassium in the blood plasma, as well as the ECG, is shown. If necessary, the therapy should be corrected. Combinations of drugs requiring attention Potassium-sparing diuretics (amiloride, spironolactone, triamterene) The combined administration of potassium-sparing diuretics and indapamide is effective in some patients. Despite this, the risk of hypokalemia (especially in patients with diabetes mellitus and renal insufficiency) or hyperkalemia cannot be ignored. Control and, if necessary, correction of the content of potassium in the blood plasma, as well as ECG control are shown. Metformin
Functional renal failure, which may occur with the use of diuretics, especially loopbacks, increases the risk of lactic acidosis with the combined use of metformin. Metformin should not be used with a creatinine concentration of more than 15 mg / l (135 μmol / l) in men and 12 mg / l (110 μmol / l) in women. Iodine-containing radiopaque drugs Dehydration with the use of diuretics may increase the risk of acute renal failure, especially when using iodine-containing drugs in high doses. It is necessary to compensate for the loss of fluid before the appointment of iodine-containing X-ray contrast agents. Tricyclic antidepressants, antipsychotics (neuroleptics) Preparations of this class enhance the antihypertensive effect of indapamide and increase the risk of orthostatic hypotension (additive effect). Calcium salts With the combined use increases the risk of hypercalcemia due to a decrease in calcium excretion by the kidneys. Cyclosporine, tacrolimus It is possible to increase the concentration of creatinine in the blood plasma with an unchanged concentration of the circulating cyclosporine, even with a normal volume of circulating blood and the sodium content in the blood plasma. Corticosteroid drugs, tetrakozaktid (with systemic use) Reduced antihypertensive effects (fluid and sodium retention caused by corticosteroids). Interactions with lisinopril Potassium preparations, potassium-sparing diuretics, or potassium-containing salt substitutes Simultaneous use of lisinopril with potassium-sparing diuretics (spironolactone, triamterene, amiloride), potassium preparations, and potassium-containing salt substitutes is associated with an increased risk of hypercalprosmery for the effect of the effect of the effect of the effect of the effect of the effect of the problem by the effect of the effect of the effect of the disease, by the effect of the effect of the effect of the effect of the development of the disease, by the effect of the effect of the effect of the pressure, by the effect of the effect of the pressure, by the effect of the pressure, by the effect of the pressure, by the effect of the pressure, by the pressure, by the pressure of the pressure, by the cause of the pressure, by the pressure of the pressure, by the cause of the pressure, by the pressure of the pressure, by the pressure of the pressure, by the pressure, by the pressure, by the pressure, by the pressure of the pressure, by the pressure of the man, by the pattern of the man, and by the man, by the way he has come. Diuretics Simultaneous use with other diuretics leads to a significant reduction Other antihypertensive drugs Combined use with other antihypertensive drugs leads to an additive effect. Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid dose > 3 g / day Combined use with nonsteroidal anti-inflammatory drugs (indomethacin and
Hepatic dysfunction When thiazide and thiazide-like diuretics are prescribed to patients with impaired liver function, hepatic encephalopathy may develop, especially in the presence of electrolyte imbalance. In this case, it is necessary to stop the use of diuretics. Photosensitization When using thiazide and thiazide-like diuretics, there have been cases of photosensitization (see the “Side Effects” section). With the development of photosensitivity during therapy shows the abolition of these drugs. If necessary, continue the treatment recommended protection of the skin from sunlight or artificial UV radiation. Water-electrolyte balance Sodium content in blood plasma Sodium content in blood plasma must be determined before the start of treatment. During the entire period of therapy is shown regular monitoring of this parameter. All diuretics can cause hyponatremia, which can sometimes have very serious consequences. Constant monitoring of sodium in the blood plasma is necessary, since at the beginning of therapy such a decrease may not be accompanied by the appearance of pathological symptoms. Sodium should be monitored particularly carefully in patients with cirrhosis of the liver and in elderly patients (see the “Side Effects” and “Overdose” sections). Potassium content in blood plasma During therapy with thiazide and thiazide-like diuretics, a drastic decrease in potassium in blood plasma, as well as the development of hypokalemia, is possible. It is necessary to minimize the risk of hypokalemia (® Plus, a positive doping test is possible in athletes. Lactose) The drug contains lactose, so it should not be taken in patients with rare hereditary intolerance to galactose, lactase deficiency or glucose-galactose malabsorption syndrome. Associated with lisinopril Symptomatic arteries. often a significant reduction in blood pressure is associated with hypovolemia caused by the use of diuretics, a decrease in the amount of salt in food, dialysis, diarrhea and whether vomiting (see “Interaction with other drugs”, “Side effects”). In patients with chronic heart failure, regardless of whether it is associated with renal insufficiency, arterial hypotension may be observed. It has been found that in patients with severe heart disease failure this condition occurs more often due to the appointment of high doses of diuretics, hyponatremia or renal dysfunction. These patients require careful medical supervision (careful selection of doses of lisinopril is shown and diuretics). The same guidelines apply to patients with ischemic heart disease and cerebrovascular insufficiency, in which a sharp decrease in blood pressure can lead to myocardial infarction or stroke. With a significant decrease in blood pressure, the patient must take a horizontal position; intravenous administration of 0.9% sodium chloride solution is possible. Transient hypotensive reactions are not a contraindication to the use of the next dose of lisinopril. In patients with chronic heart failure with normal or reduced blood pressure, the use of lisinopril may lead to a decrease in blood pressure; this is usually not a reason to discontinue the drug. If arterial hypotension is accompanied by clinical manifestations, consideration should be given to reducing the dose or canceling lisinopril. In patients at risk of developing symptomatic arterial hypotension (with a low-salt or salt-free diet), regardless of the presence of hyponatremia, as well as in patients receiving high-dose diuretics, these conditions (hypovolemia or sodium deficiency) must be compensated before starting treatment. The control of the effect of the initial dose of lisinopril on blood pressure is shown. Acute myocardial infarction Recommended standard treatment (thrombolytics, acetylsalicylic acid, beta-blockers). Lisinopril can be used in combination with intravenous nitroglycerin or transdermal nitroglycerin. In patients with acute myocardial infarction and the risk of further deterioration of hemodynamics, worsening of symptoms after the administration of vasodilators, lysinopril should not be started. Such patients include patients with systolic blood pressure of 177 μmol / l and / or proteinuria >500 mg / day) lisinopril is contraindicated. With the development of renal impairment during treatment (serum creatinine concentration >265 µmol / l or a doubling in comparison with the initial indicator) shows the abolition of lisinopril. Allergic reactions, Quincke edema. In rare cases, while using ACE inhibitors, including lisinopril, it has been reported that angioedema of the face, extremities, lips, tongue, epiglottis and / or larynx develops. In such cases, the immediate abolition of lisinopril is required; control of a condition of patients is shown to the full permission of symptomatology. Usually, angioedema of the face and lips is temporary and does not require treatment; however, antihistamine medications may be prescribed. Angioedema of the larynx can cause death. Swelling of the tongue, epiglottis, or larynx can lead to secondary obstruction of the airways. In this case, you must immediately enter 0.3-0.5 ml of 1: 1000 solution of epinephrine subcutaneously, as well as to ensure the airway patency. It was reported that Quincke’s edema treated with ACE inhibitors in Negroid race occurred more often than in patients of other ethnic groups. In patients with a history of angioedema, not associated with the use of ACE inhibitors, the risk of developing angioedema when using ACE inhibitors is higher (see “Contraindications”). Anaphylactic reactions associated with desensitization with hymenoptera poison In very rare cases, patients taking ACE inhibitors may develop life-threatening anaphylactic reactions during desensitization with hymenoptera venom, and therefore it is necessary to temporarily cancel the ACE inhibitors before desensitization. Patients on hemodialysis Anaphylactic reactions also occurred in patients who underwent hemodialysis using dialysis membranes with high permeability (for example, AN69) with the concomitant use of ACE inhibitors. In these patients, the use of other dialysis membranes or other antihypertensive drugs is indicated. Cough Therapy with ACE inhibitors can cause cough, which should be considered when conducting a differential diagnosis. Prolonged dry cough usually stops after discontinuation of ACE inhibitors. Surgical interventions / general anesthesia The use of antihypertensive drugs during surgery or during general anesthesia may result in the inhibition of the formation of angiotensin II due to compensatory renin secretion. A significant decrease in blood pressure associated with this effect can be prevented by increasing the volume of circulating blood. Patients taking ACE inhibitors should report this to the surgeon / anesthesiologist prior to surgery (including dental procedures). Potassium blood plasma Cases of hyperkalemia have been reported. Risk factors for hyperkalemia include renal failure, diabetes mellitus, therapy with potassium-sparing diuretics (spironolactone, triamterene and amiloride), the use of potassium preparations and potassium-based salt substitutes, especially in patients with impaired renal function. If necessary, the combined use of lisinopril and these drugs shows regular monitoring of the content of potassium in the blood plasma. Double blockade of RAAS It has been proven that the simultaneous administration of ACE inhibitors. angiotensin II receptor blockers or aliskiren increases the risk of arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure). Thus, it is not recommended to prescribe ACE inhibitors, angiotensin II receptor blockers, or aliskiren for a double blockade of RAAS. If there are absolute indications for a double blockade of RAAS, then it should be carried out under the close supervision of a specialist with frequent monitoring of blood pressure, kidney function and electrolyte content. ACE inhibitors and angiotensin II receptor blockers should not be used simultaneously in patients with diabetic nephropathy.
Influence on ability to drive vehicles and mechanisms
There is no data on the effect of lisinopril on the ability to drive vehicles and work with mechanisms. However, you should consider the likelihood of dizziness. In this regard, care must be taken when driving and working with machinery. Indapamide does not cause impairment of psychomotor functions, however, in some patients, with a decrease in blood pressure, various individual reactions may develop, especially at the beginning of therapy or when an additional antihypertensive drug is administered to the main regimen. In this case, the ability to drive and operate machinery can be reduced.