Ramazid N pills 5mg+12.5mg, 30pcs

Composition

Active ingredients: hydrochlorothiazide – 12.5 mg, ramipril-5.0 mg. Auxiliary substances: sodium bicarbonate-5.0 mg, calcium sulfate dihydrate-195.9 mg, pregelatinized corn starch-36.4 mg, sodium stearyl fumarate-2.6 mg, reddish-brown dye RV 24823-2.6 mg (pregelatinized corn starch-89.86%, black iron oxide-0.13%, red iron oxide-10.00%, yellow iron oxide-0.01%).

Pharmacological action

Pharmacodynamicaramazide H (12.5 / 5 mg) is a combination of an angiotensin converting enzyme (ACE) inhibitor, also called dipeptidyl carboxydipeptidase I, kinase II – ramipril and a thiazide diuretic-hydrochlorothiazide. Ramipril and hydrochlorothiazide are used in monotherapy or simultaneously as antihypertensive agents. Their combination has an additive antihypertensive effect, reducing blood pressure (BP) to a greater extent than each of these drugs separately. When taking a combination of ramipril and hydrochlorothiazide, there was no change in the serum potassium content (due to the opposite effect of both drugs on the serum potassium content). Ramipril Ramipril and, to a much greater extent, the active metabolite of ramipril, ramiprilate, formed under the influence of liver enzymes (enzymes that catalyze the hydrolysis of esters), are long-acting ACE inhibitors (see the section “Pharmacokinetics”). In blood plasma and tissues, ACE catalyzes the conversion of angiotensin I to angiotensin II (an active vasoconstrictor) and the breakdown of an active vasodilator, bradykinin. Therefore, when taking ramipril, the formation of angiotensin II decreases and bradykinin accumulates, which leads to vasodilation and a decrease in blood pressure, and also contributes to the cardioprotective effect of ramipril. Ramipril causes an increase in the activity of the kallikreinkinin system in blood and tissues with activation of the prostaglandin system and an increase in the synthesis of prostaglandins that stimulate the formation of nitric oxide (N0) in endotheliocytes, which determines its cardioprotective and endothelioprotective effects. It is assumed that the increase in bradykinin activity is also associated with the occurrence of some undesirable reactions (“dry” cough). Angiotensin II stimulates the release of aldosterone, so taking ramipril leads to a decrease in aldosterone secretion and an increase in the content of potassium ions in the blood serum. Due to the presence of a negative inverse relationship between angiotensin II activity and renin secretion, a decrease in angiotensin II activity leads to an increase in renin activity in blood plasma. In patients with arterial hypertension, taking ramipril causes a decrease in blood pressure in the “lying” and “standing” positions without a compensatory increase in heart rate. Taking ramipril leads to a significant decrease in total peripheral vascular resistance (OPSS), usually without causing changes in renal blood flow and glomerular filtration rate. After taking the drug orally, the onset of antihypertensive action occurs in 1-2 hours, and the maximum antihypertensive effect develops in 3-6 hours and persists for 24 hours. With a course of use, the full antihypertensive effect of ramipril usually develops by 3-4 weeks of its continuous use. The antihypertensive effect of the drug persists with prolonged use at the recommended doses. When you stop taking ramipril, there is no “withdrawal”syndrome. With prolonged use in patients with arterial hypertension, ramipril promotes the reverse development of myocardial and vascular wall hypertrophy. ACE inhibitors are also effective in patients with arterial hypertension and low plasma renin activity. On average, the antihypertensive effect of ACE inhibitors is less pronounced in patients of the black race (especially with low plasma renin activity) compared to patients of other races. Ramipril increases the sensitivity of tissues to insulin and has a beneficial effect on the metabolism of carbohydrates and lipids, increases the concentration of fibrinogen, reduces platelet aggregation, and stimulates the synthesis of a tissue activator of profibrinolysis (plasminogen), which promotes thrombolysis. In patients with diabetic and non-diabetic clinically expressed nephropathy, the drug reduces the rate of progression of renal failure, and in the preclinical stage of diabetic and non-diabetic nephropathy, ramipril reduces albuminuria. Hydrochlorothiazide is a thiazide diuretic. Thiazide diuretics inhibit sodium and chloride reabsorption in the distal renal tubules in approximately equivalent amounts. An increase in the renal excretion of these ions is accompanied by an increase in the amount of urine (due to osmotic binding of water). Hydrochlorothiazide reduces the volume of blood plasma, increases the activity of renin in blood plasma and the secretion of aldosterone. The excretion of potassium and magnesium increases, while the excretion of uric acid decreases. When taken in high doses, hydrochlorothiazide increases the excretion of bicarbonates, with prolonged use it reduces the excretion of calcium. The suggested mechanisms of the antihypertensive effect of hydrochlorothiazide are a change in the sodium balance, a decrease in the amount of extracellular fluid and blood plasma volume, and a change in the resistance of renal vessels to norepinephrine and angiotensin II. After oral use of hydrochlorothiazide, the onset of diuresis (elimination of water and salts) occurs in the first 2 hours after taking it, the maximum effect is achieved in about 3-6 hours, the effect of the drug persists for about 6-12 hours. To develop an antihypertensive effect, it takes several days of taking hydrochlorothiazide (3-4 days), after stopping taking the drug, its antihypertensive effect may persist for up to 1 week. With long-term treatment, a decrease in blood pressure is achieved with the use of lower doses, in comparison with the doses necessary to achieve a diuretic effect. The antihypertensive effect of the drug is accompanied by a slight increase in glomerular filtration rate, renal vascular resistance and renin activity in blood plasma. Thiazide diuretics are ineffective for indications of creatinine clearance Thiazide diuretics may inhibit lactation. Pharmacokinetics No significant pharmacokinetic interactions were observed between ramipril and hydrochlorothiazide administered as a tablet or combination. Ramipril Absorption After oral use, ramipril is rapidly absorbed from the gastrointestinal tract; peak plasma concentrations of ramipril are reached within one hour. The degree of absorption is at least 56% and practically does not depend on the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite of ramiprilate after oral use of 2.5 mg and 5 mg of ramipril is 45%. Distribution The maximum concentration of the active Active ingredient (ramiprilate) in plasma is reached 2-4 hours after oral use of ramipril. After taking the usual doses of ramipril once a day, the steady-state plasma concentration of ramiprilate is reached approximately on the fourth day of treatment. The binding of ramipril and ramiprilate to proteins is about 73% and about 56%, respectively. Metabolism Ramipril is almost completely metabolized to ramiprilate, diketopiperazine ester, diketopiperazic acid, and the glucuronides ramipril and ramiprilate. Deduction Metabolites are mainly excreted through the kidneys. Plasma concentrations of ramiprilate decrease in a multiphase manner. Ramiprilate has a longer elimination phase at very low plasma concentrations. After multiple doses of ramipril once a day, the effective half-life of ramiprilat was 13-17 hours for doses of 5-10 mg and was longer for lower doses of 1.25-2.5 mg. This difference is related to the ability of enzymes to bind ramiprilate. In patients with impaired renal function, the renal excretion of ramiprilate decreases in patients with impaired renal function, and the renal clearance of ramiprilate is proportionally related to creatinine clearance. This leads to an increase in the concentration of ramiprilate in the blood plasma, which decreases more slowly than in patients with normal renal function. In patients with impaired hepatic functionand patients with impaired liver function, the conversion of ramipril to ramiprilate was delayed due to reduced activity of hepatic esterases, and plasma levels of ramipril in these patients were increased. However, the peak concentrations of ramiprilate in these patients did not differ from those observed in patients with normal liver function. Breast-feeding A single oral dose of ramipril 10 mg is not detected in breast milk. However, the effect of multiple doses is not known. Hydrochlorothiazide absorption After oral use, approximately 70% of hydrochlorothiazide is absorbed from the gastrointestinal tract. The peak concentration of hydrochlorothiazide in blood plasma is reached from 1.5 to 5 hours. Distribution Approximately 40% of hydrochlorothiazide binds to plasma proteins. Metabolism Hydrochlorothiazide undergoes little hepatic metabolism. No activity inducing or inhibiting CYP450 isoenzymes was detected. Deduction Hydrochlorothiazide is mainly excreted by the kidneys (more than 95%) in unchanged form. After oral use of a single dose,50-70% is eliminated within 24 hours. The elimination half-life is 5-6 hours. In patients with impaired renal function, the renal excretion of hydrochlorothiazide is reduced in patients with impaired renal function and the renal clearance of hydrochlorothiazide is proportionally related to creatinine clearance. This leads to an increase in plasma concentrations of hydrochlorothiazide, which decrease more slowly than in patients with normal renal function. The pharmacokinetics of hydrochlorothiazide did not change significantly in patients with hepatic impairment and patients with cirrhosis of the liver.The pharmacokinetics of hydrochlorothiazide have not been studied in patients with heart failure. Ramipril and hydrochlorothiazide Simultaneous use of ramipril and hydrochlorothiazide does not affect their bioavailability. The use of a combined preparation can be considered bioequivalent to the use of products containing individual components.

Indications

Arterial hypertension (patients who are indicated for combination therapy).

Use during pregnancy and lactation

Pregnancyramazide H (12.5 / 5 mg) should not be used during pregnancy. Therefore, before starting taking the drug in women of reproductive age, pregnancy should be excluded, and during treatment they should use reliable methods of contraception. If pregnancy occurs during treatment with the drug, it is necessary to stop taking it as soon as possible and transfer the patient to other antihypertensive drugs, with the use of which the risk to the child will be minimal. Because of the risk of adverse effects of ramipril and hydrochlorothiazide on the fetus, it is recommended to avoid conception for women who cannot be transferred to another treatment for hypertension (without the use of ACE inhibitors and diuretics). It is not known whether exposure to Ramazid H (12.5 / 5 mg) in the first trimester of pregnancy may have a negative effect on fetal development. The use of ACE inhibitors in the second and third trimesters of pregnancy is associated with disorders that may occur in the fetus and newborn, including a decrease in blood pressure, cranial hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnion has also been reported, apparently due to impaired fetal kidney function; oligohydramnion in such cases was accompanied by the development of fetal limb contractures, craniofacial deformities, and pulmonary hypoplasia. Preterm labor, intrauterine growth retardation, and non-infection of the Botall duct have also been reported, although it is not known whether these manifestations are due to exposure to an ACE inhibitor. Careful monitoring of newborns who have been exposed to intrauterine ACE inhibitors is recommended to detect low blood pressure, oliguria, and hyperkalemia. With oliguria, it is necessary to maintain blood pressure and renal perfusion by introducing appropriate fluids and vasoconstrictors. These newborns are at risk of developing oliguria and neurological disorders, due to a possible decrease in renal and cerebral blood flow due to a decrease in blood pressure caused by ACE inhibitors. It is assumed that when using hydrochlorothiazide in the second trimester of pregnancy, thrombocytopenia may develop in newborns. Breast-feeding As ramipril and hydrochlorothiazide are excreted in breast milk, if necessary, the use of Ramazid H (12.5/5 mg) during lactation should stop breastfeeding.

Contraindications

• Hypersensitivity to ramipril or other ACE inhibitors, hydrochlorothiazide, other thiazide diuretics, sulfonamide derivatives, or any of the excipients of Ramazid H (12.5 / 5 mg) (see “composition”).
• Angioedema in the anamnesis (hereditary, idiopathic, and also associated with ACE inhibitor therapy).
• Severe renal insufficiency with creatinine clearance less than 30 ml / min per 1.73 m2 of body surface area.
• Hemodialysis or hemofiltration using certain negatively charged surface membranes, such as high-strength polyacrylonitrile membranes (risk of hypersensitivity reactions, including severe anaphylactoid reactions), and low-density lipoprotein apheresis using dextran sulfate (risk of hypersensitivity reactions, including severe anaphylactoid reactions.
• Hemodynamically significant bilateral renal artery stenosis, stenosis of the artery of a single kidney.
• Clinically significant disorders of the blood electrolyte balance, such as hypokalemia, hypomagnesemia or hypercalcemia (the possibility of their aggravation during treatment with Ramazid H (12.5 / 5 mg)).
• Severe hepatic dysfunction (more than 9 points on the Child-Pugh scale), hepatic encephalopathy (lack of clinical experience; it is known that in these conditions, minimal disturbances in the water-electrolyte balance can provoke a hepatic coma).
• Anuria (due to the presence of hydrochlorothiazide in the preparation).
• Pregnancy.
• Breast-feeding period.
• Children and adolescents (under 18 years of age) (insufficient data on the efficacy and safety of this drug in children).
• Severe arterial hypotension.
• Concomitant use with aliskiren-containing medications in patients with diabetes mellitus or moderate to severe renal insufficiency (GFR
• Concomitant use with angiotensin II receptor antagonists in patients with diabetic nephropathy.

With caution

• Concomitant use of Ramazid H (12.5 / 5 mg) and drugs containing aliskiren or angiotensin II receptor antagonists (with double blockade of the renin-angiotensin-aldosterone system [RAAS], there is an increased risk of a sharp decrease in blood pressure, hyperkalemia and deterioration of renal function) (see the section “Special instructions”).
• In conditions accompanied by increased activity of the RAAS, in which ACE inhibition is associated with a risk of a sharp decrease in blood pressure with deterioration of renal function (see the section “Special instructions”): – severe arterial hypertension, especially malignant arterial hypertension; – chronic heart failure, especially severe or for which other medications with hypotensive effects are taken (see the section “Special instructions”); – hemodynamically significant violation of blood outflow from the left ventricle or blood flow to the left ventricle (hemodynamically significant aortic or mitral valve stenosis or hypertrophic obstructive cardiomyopathy [HOCMP]); – renovascular diseases, including hemodynamically significant unilateral renal artery stenosis (careful monitoring of blood creatinine concentration is required, see the section “Special instructions”, “Side effect”); – previous treatment with diuretics; – violations of the water-electrolyte balance as a result of insufficient fluid intake and/or table salt, diarrhea, vomiting, heavy sweating (with inadequate replenishment of fluid and sodium losses).
• In conditions where an excessive decrease in blood pressure becomes particularly dangerous (hemodynamically significant stenosis of the coronary or cerebral arteries, regular monitoring of the patient’s condition is required, especially at the beginning of treatment with the drug).
• In patients with impaired renal function with a creatinine clearance of 60-30 ml / min per 1.73 m2 of body surface area due to the risk of hyperkalemia and leukopenia (dosage adjustment is required, see section “Dosage and use” and regular monitoring of renal function, especially at the beginning of treatment, see section “Special Instructions”).
• In the condition after kidney transplantation (regular monitoring of renal function is required, especially at the beginning of treatment).
• In case of impaired liver function (risk of deterioration of liver function, lack of sufficient clinical experience with the drug, see the section “Special instructions”, “Side effect”).
• With systemic connective tissue diseases, such as systemic lupus erythematosus or scleroderma (the risk of impaired immune responses increases, the risk of a decrease in the number of white blood cells in the peripheral blood).
• When bone marrow hematopoiesis is suppressed, concomitant therapy with corticosteroids (glucocorticoids and mineralocorticoids), immunomodulators, cytostatics, antimetabolites, allopurinol, procainamide (the risk of reducing the number of leukocytes in peripheral blood increases, see the section “Special instructions”, “Side effects”, “Interaction with other drugs”).
• With diabetes mellitus (risk of hyperkalemia, and in the case of hypoglycemic agents (insulin preparations and hypoglycemic agents for oral use (sulfonylurea derivatives)) – the risk of hypoglycemic reactions due to the presence of ramipril in the drug; the risk of increased blood glucose concentration due to the presence of hydrochlorothiazide in the drug) (see the section “Special instructions”, “Side effects”, “Interaction with other drugs”).
• In elderly patients (older than 65 years) (risk of more pronounced antihypertensive effects, little experience with the drug, more regular monitoring of renal function is required).

Side effects

Since the drug Ramazid H (12.5 / 5 mg) is a hypotensive drug, many adverse reactions during its use are secondary to its blood pressure-lowering effect, which can cause reflex activation of the sympathetic nervous system or hyperfusion of various organs. Many other undesirable effects, such as effects on the water-electrolyte balance, some anaphylactoid reactions or inflammatory reactions of the mucous membranes, are due to ACE inhibition or other pharmacological effects of ramipril or hydrochlorothiazide. According to the World Health Organization (WHO), the frequency of adverse reactions is distributed as follows: very common (>1/10); common (>>1/100 to >><1/10); infrequent (>1/1000 to <1/10); infrequent (><1/100); rare (>1/10,000 to <1/100); rare (><1/1000); very rare (> Cardiac disorders Infrequently: myocardial ischemia, including the development of angina pectoris; tachycardia, cardiac arrhythmias, palpitations, peripheral edema. Frequency unknown: myocardial infarction. Disorders of the blood and lymphatic system Infrequently: a decrease in the number of white blood cells in the peripheral blood, a decrease in the number of red blood cells in the peripheral blood, a decrease in hemoglobin, hemolytic anemia, a decrease in the number of platelets in the peripheral blood. Frequency unknown: impaired bone marrow hematopoiesis, including agranulocytosis (a sharp decrease or disappearance of granulocytes from peripheral blood), pancytopenia, eosinophilia, hemoconcentration due to a decrease in the content of fluid in the body and, including, in peripheral blood. Disorders of the nervous system Often: headache, dizziness (a feeling of “lightness” in the head). Infrequently: vertigo, paresthesia, tremor, imbalance, burning sensation of the skin, dysgeusia (violation of taste sensations), ageusia (loss of taste sensations). Frequency unknown: cerebral ischemia, including ischemic stroke and transient cerebrovascular accident; psychomotor reaction disorder, parosmia (olfactory disorder, including subjective sensation of any smell in its objective absence). Visual disturbances Infrequently: visual disturbances, including blurred vision, conjunctivitis. Frequency unknown: xanthopsia, decreased production of tear fluid (due to the presence of hydrochlorothiazide in the drug). Hearing disorders and labyrinth disorders Infrequently: ringing in the ears. Frequency unknown: hearing loss. Disorders of the respiratory system, chest and mediastinal organs Often: unproductive (“dry”) cough, bronchitis. Infrequently: sinusitis, shortness of breath, nasal congestion. Frequency unknown: bronchospasm, including increased symptoms of bronchial asthma; allergic alveolitis (pneumonitis); non-cardiogenic pulmonary edema (due to the presence of hydrochlorothiazide in the preparation). Disorders of the gastrointestinal tract Infrequently: inflammatory reactions of the gastrointestinal mucosa, digestive disorders, abdominal discomfort, dyspepsia, gastritis, nausea, constipation; gingivitis (due to the presence of hydrochlorothiazide in the preparation). Very rare: vomiting, aphthous stomatitis, glossitis, diarrhea, epigastric pain, dryness of the oral mucosa. The frequency is unknown: pancreatitis (in exceptional cases, when taking ACE inhibitors, pancreatitis with a fatal outcome is observed); increased activity of “pancreatic” enzymes in the blood: angioedema of the small intestine; sialoadenitis (due to the presence of hydrochlorothiazide in the preparation). Kidney and urinary tract disorders Infrequently: impaired renal function, including acute renal failure; an increase in the amount of urine excreted, an increase in the concentration of urea in the blood, an increase in the concentration of creatinine in the blood (even a slight increase in the concentration of creatinine in unilateral renal artery stenosis may indicate impaired renal function). Frequency unknown: increased pre-existing proteinuria; interstitial nephritis (due to the presence of hydrochlorothiazide in the preparation). Skin and subcutaneous tissue disorders Infrequently: angioedema: in exceptional cases, airway obstruction due to angioedema can lead to death; psoriasis-like dermatitis; increased sweating; skin rash, in particular, macular-papular skin rash; pruritus; baldness. Frequency unknown: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravation, exfoliative dermatitis, photosensitization reaction, onycholysis, pemphigoid or lichenoid exanthema or enanthema, urticaria; systemic lupus erythematosus (due to the presence of hydrochlorothiazide in the preparation). Musculoskeletal and connective tissue disorders Infrequently: myalgia. Frequency unknown: arthralgia, spastic muscle contractions; muscle weakness, muscle rigidity, tetany (due to the presence of hydrochlorothiazide in the preparation). Endocrine disorders Frequency unknown: syndrome of inadequate secretion of antidiuretic hormone (ADH SNA). Metabolic and nutritional disorders are common: decompensation of diabetes mellitus, decreased glucose tolerance, increased blood glucose concentration, increased uric acid concentration in the blood, increased gout symptoms, increased cholesterol and triglyceride concentrations in the blood (due to the presence of hydrochlorothiazide in the preparation). Infrequently: anorexia, decreased appetite; decreased blood potassium (due to the presence of hydrochlorothiazide in the preparation). Rarely: increased blood potassium (due to the presence of ramipril in the drug). Frequency unknown: decreased blood sodium, glucosuria, metabolic alkalosis, hypochloremia, hypomagnesemia, hypercalcemia, dehydration (due to the presence of hydrochlorothiazide in the preparation). Vascular disorders Infrequently: excessive decrease in blood pressure, orthostatic hypotension (violation of orthostatic regulation of vascular tone), fainting, “hot flashes” of blood to the skin of the face. The frequency is unknown: thrombosis with severe fluid loss, vascular stenosis, the occurrence or increase of circulatory disorders against the background of stenotic vascular lesions, Raynaud’s syndrome, vasculitis. General disorders and disorders at the injection site Often: increased fatigue, asthenia. Infrequently: chest pain, fever. Immune system disorders Frequency unknown: anaphylactic or anaphylactoid reactions to ramipril (with ACE inhibition, severe anaphylactic or anaphylactoid reactions to insect venom may increase) or anaphylactic reactions to hydrochlorothiazide; increased titer of antinuclear antibodies. Liver and biliary tract disorders Infrequently: cholestatic or cytolytic hepatitis (in exceptional cases with a fatal outcome), increased activity of “liver” enzymes and/or increased concentration of conjugated bilirubin in the blood; calculous cholecystitis (due to the presence of hydrochlorothiazide in the preparation). Frequency unknown: acute hepatic insufficiency, cholestatic jaundice, hepatocellular lesions. Genital and breast disorders Infrequently: transient erectile dysfunction. Frequency unknown: decreased libido, gynecomastia. Mental disorders Infrequently: depressive mood, apathy, anxiety, nervousness, sleep disorders (including drowsiness). Frequency unknown: confusion, anxiety, attention disorders (decreased concentration).

Interaction

Contraindicated combinations • Extracorporeal treatments that cause blood to come into contact with negatively charged surfaces, such as hemodialysis or hemofiltration with certain high-strength membranes (polyacrylonitrile membranes) and low-density lipoprotein apheresis with dextrin sulfate. Risk of developing severe anaphylactoid reactions (see section “Contraindications”, “Special instructions”). • Concomitant use of Ramazid H (12.5 / 5 mg) and drugs containing Aliskiren Simultaneous use of Ramazid H (12.5 / 5 mg) and drugs containing aliskiren in patients with diabetes mellitus or moderate to severe renal insufficiency and creatinine clearance less than 60 ml / min is contraindicated and is not recommended in other patients (see section “Contraindications”, “With caution”, “Special instructions”). • Concomitant use of Ramazid H (12.5 / 5 mg) and angiotensin II receptor antagonists Concomitant use of Ramazid H (12.5 / 5 mg) and angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see section “Contraindications”, “With caution”, “Special instructions”).

Not recommended combinations • With kya salts, potassium-sparing diuretics (for example, spironolactone), epleron [a derivative of spironolactone], amiloride, triamterene), other drugs that can increase the content of potassium in the blood serum (including angiotensin II receptor antagonists, tacrolimus, cyclosporine, trimethoprim, sulfamethoxazole, which are part of co-trimoxazole [a combined antibacterial agent containing trimethoprim and sulfamethoxazole]). It is possible to increase the content of potassium in the blood serum, sometimes significantly pronounced (with simultaneous use, careful monitoring of the content of potassium in the blood serum is required).

Combinations that should be used with caution • With antihypertensive drugs and other drugs that have antihypertensive effects (nitrites, tricyclic antidepressants) Potentiation of the antihypertensive effect is possible. • With general anesthesia, barbiturates, and ethanol Orthostatic hypotension may occur. Ramipril may potentiate the vasodilating effect of ethanol. * With diuretics There may be an excessive decrease in blood pressure at the beginning of treatment (for concomitant use with diuretics, see the section “Contraindications”, “With caution”, “Special instructions”). * With vasopressor sympathomimetics (epineurin (epinephrine), isoproterenol, dobutamine, dopamine) Reduction of the antihypertensive effect of Ramazid H (12.5 / 5 mg). It is recommended to carefully monitor blood pressure. In addition, the vasopressor effect of sympathomimetics can be weakened by hydrochlorothiazide. * With allopurinol, immunosuppressive agents, corticosteroids (glucocorticoids and mineralcorticoids), procainamide, cytostatics and other drugs that can change the picture of peripheral blood The probability of blood disorders increases (see the section “Side effects”, “Special instructions”). • With lithium salts It is possible to reduce the excretion of lithium, leading to an increase in serum concentrations of lithium and an increase in its toxicity. Therefore, serum lithium concentrations should be monitored regularly. * With hypoglycemic agents (for example, insulins, hypoglycemic agents for oral use (sulfonylureas)) ACE inhibitors may reduce insulin resistance. In some cases, in patients receiving hypoglycemic agents, such a decrease in insulin resistance may lead to the development of hypoglycemia. This effect may develop after a few days or months of treatment. Hydrochlorothiazide may weaken the effect of hypoglycemic agents. Therefore, at the initial stage of simultaneous use of hypoglycemic agents and Ramazid H (12.5/ 5 mg), especially careful monitoring of blood glucose concentration is required. * With vildagliptin, other glyptins and estramustine Increased incidence of angioedema. • With mTOR (mammalian Target of Rapamycin) inhibitors, for example, temsirolimus

Combinations to take into account • With nonsteroidal anti-inflammatory drugs (Indometacin, acetylsalicylic acid (more than 3 g / day)) It is possible to weaken the effect of Ramazid H (12.5 / 5 mg), increase the risk of impaired renal function and increase the content of potassium ions in the blood serum. Strict monitoring of serum creatinine concentrations and serum potassium levels is recommended. • With heparin Possible increase in the content of potassium in the blood serum. • With corticosteroids (glucocorticoids and mineralcorticoids), carbenoxolone, preparations containing licorice root, laxatives (for long-term use) and other kaliuretic agents The risk of hypokalemia increases. • With cardiac glycosides, drugs that can prolong the QT interval, antiarrhythmics The potential development of hypokalemia or hypomagnesemia (due to the content of hydrochlorothiazide in the preparation), which may lead to potentiation of the proarrhythmogenic effect of these drugs or a decrease in the antiarrhythmic effect of antiarrhythmics. • With methyldopa Possible hemolysis • With calcium salts and drugs that increase the content of calcium in blood plasma When used concomitantly with hydrochlorothiazide, it is possible to increase the content of calcium in the blood serum. * With vitamin D When used concomitantly with hydrochlorothiazide, it is possible to increase the content of calcium in the blood serum (due to a slowdown in the excretion of calcium by the kidneys), careful monitoring of the content of calcium in the blood serum is required. • With carbamazepine Risk of hyponatremia due to the potentiating effect of hydrochlorothiazide. • With iodine-containing contrast agents If dehydration occurs due to diuretics, including hydrochlorothiazide, there is an increased risk of acute renal failure, especially with high doses of contrast media. • With penicillin Hydrochlorothiazide is excreted by the distal renal tubules and therefore reduces the excretion of penicillin. • With quinidine Hydrochlorothiazide reduces the elimination of quinidine. • With ingested ion exchange resins such as colestipol and colestyramia The absorption of hydrochlorothiazide decreases. • With non-depolarizing muscle relaxants Possible enhancement and prolongation of the muscle relaxant effect. • With table salt With a large amount of table salt coming from food, it is possible to weaken the antihypertensive effect of Ramazid H (12.5/5 mg). • With desensitizing therapy The likelihood and severity of anaphylactic reactions to insect venom increases with ACE inhibition. It is assumed that similar reactions are possible to other allergens. * With warfarin, acenocoumarol When used concomitantly with ramipril, there was no effect on the anticoagulant effect of these drugs.

Impact on laboratory results • Assessment of parathyroid gland function Hydrochlorothiazide stimulates renal calcium reabsorption and may cause hypercalcemia. This should be taken into account when evaluating the function of the parathyroid glands (see the section “Special instructions”).

How to take, course of use and dosage

The drug is not intended for the initial course of treatment of arterial hypertension, since patients who have not previously received treatment with antihypertensive drugs, who are immediately treated with ramipril and a diuretic, may have an excessive decrease in blood pressure. Method of application Tablets should be swallowed whole, washed down with a sufficient amount of liquid, tablets should not be crushed and chewed. Food intake does not significantly affect the bioavailability of the drug, so it can be taken before, during or after a meal. It is usually recommended that the daily dose be taken once and at the same time of day, mainly in the morning. Recommended doses and dosage regimen of the drug are selected individually. The choice of doses is carried out by the doctor in accordance with the severity of arterial hypertension and the presence of associated risk factors, as well as the tolerability of the drug. The dose of the drug is selected by titrating (gradually increasing or, if necessary, reducing) the doses of individual drugs ramipril and hydrochlorothiazide. Special care should be taken when titrating doses in patients undergoing hemodialysis. After the patient has been selected for ramipril and hydrochlorothiazide doses, for greater patient convenience, they can be replaced with Ramazid H in the appropriate dosage, which ensures that these doses of ramipril and hydrochlorothiazide are taken in one tablet. Recommended doses and dosage regimen in special clinical situationstreatment of patients receiving diuretics Patients who have received previous treatment with diuretics, before taking Ramazid H (12.5 / 5 mg), if possible for 2-3 or more days (depending on the duration of action of diuretics), they should be discontinued or at least reduce the dose. If discontinuation of diuretics is not possible, it is recommended to start treatment with the lowest dose of ramipril (1.25 mg / day) in this combination, taking separate ramipril and hydrochlorothiazide medications. It is recommended that further transfer to combination therapy should be carried out in such a way that the initial daily dose does not exceed 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide. Treatment of patients with impaired renal function Amazid H (12.5 / 5 mg) is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml / min)When creatinine clearance is between 30 and 60 ml / min per 1.73 m2 of body surface area, treatment begins with ramipril monotherapy. After gradually increasing the dose of ramipril, treatment with the combined drug begins with the lowest fixed dosages of ramipril and hydrochlorothiazide. The maximum permitted daily dose for patients with renal insufficiency is 5 mg ramipril and 25 mg hydrochlorothiazide. Patients with mild (Child-Pugh score 5-6) or moderate (Child-Pugh score 7-9) hepatic impairment Treatment with Ramazid H (12.5 / 5 mg) should be initiated under close medical supervision and the maximum daily dose should not exceed 2.5 mg ramipril and 12.5 mg hydrochlorothiazide. The drug is contraindicated in severe hepatic impairment (see section “Contraindications”). Treatment of elderly patients Treatment should start with lower doses, and the increase in doses should be more gradual (with a smaller dose increase step) due to the greater likelihood of side effects, especially in weakened elderly patients. Skipping a dose If you skip the next dose of the drug, the missed dose should be taken as soon as possible. However, if this is detected very close to the time of taking the next dose, then it is necessary to skip taking the missed dose and return to the usual dosage regimen, not allowing doubling the dose in a short period of time.

Overdose

Symptoms In case of overdose, a persistent increase in the amount of urine released, excessive peripheral vasodilation (with a pronounced decrease in blood pressure, the development of shock), bradycardia, impaired water and electrolyte balance, renal failure, heart rhythm disorders, depression of consciousness, up to the development of coma; cerebral convulsions, paresis and paralytic intestinal obstruction.

In patients with impaired outflow of urine (for example, with prostatic hyperplasia), excessive diuresis can provoke acute urinary retention with overextension of the bladder.

Treatment If possible, during the first 30 minutes, gastric lavage should be performed, adsorbents and sodium sulfate should be taken. In the case of a persistent decrease in blood pressure, in addition to therapy aimed at replenishing the volume of circulating blood and electrolytes, the introduction of alpha-1-adrenergic receptor agonists (norepinephrine, dopamine) is indicated. If bradycardia is refractory to medical treatment, it may be necessary to install a temporary artificial pacemaker. In case of overdose, it is necessary to monitor serum creatinine concentrations and the content of electrolytes in the blood serum.

There is no experience regarding the effectiveness of forced diuresis, changes in urine pH, hemofiltration or hemodialysis to accelerate the elimination of ramipril and ramiprilate. Hydrochlorothiazide can be eliminated by hemodialysis. If hemodialysis or hemofiltration is still planned, the risk of anaphylactoid reactions should be taken into account when using high-flow membranes and do not use iz (see the section “Contraindications”, “Special instructions”, “Interaction with other drugs”).

Special instructions

Concomitant use of Ramazid H (12.5 / 5 mg) with drugs containing aliskiren or with angiotensin II receptor antagonists, resulting in double blockade of the RAAS, is not recommended due to the risk of excessive lowering of blood pressure, hyperkalemia and deterioration of renal function. Concomitant use of Ramazid H (12.5 / 5 mg) with drugs containing aliskiren in patients with diabetes mellitus and / or renal insufficiency with creatinine clearance Angioedema of the face, neck, or extremities (see section “Side effects”). Angioedema has been reported in patients treated with ACE inhibitors, mainly after the first dose. If angioedema develops during treatment with an ACE inhibitor, it is necessary to immediately stop taking it. Since angioedema involving the larynx can lead to death, in case of swelling of the face, limbs, lips, tongue or vocal cords and, especially, the development of stridorous respiration, you should immediately stop taking Ramazid H (12.5/5 mg) and immediately start treatment aimed at stopping angioedema. In cases where swelling is localized to the face and lips, this condition is usually resolved without treatment, however, antihistamines can be used to relieve symptoms. If edema spreads to the tongue, vocal cords, or pharynx, airway obstruction may occur, and appropriate treatment should be initiated immediately (including immediate subcutaneous or slow intravenous use of epinephrine (epinephrine) under ECG and blood pressure monitoring). It is recommended to be hospitalized for at least 12-24 hours and discharged from the hospital only after the symptoms of angioedema have completely stopped. Angioedema of the small intestine In patients treated with an ACE inhibitor, the development of angioedema of the small intestine was reported, which was manifested by abdominal pain (with or without nausea or vomiting), and in some cases, angioedema of the face was observed simultaneously. The diagnosis is established by computed tomography of the abdominal cavity, ultrasound, or during surgery. Symptoms of intestinal angioedema resolved after discontinuation of the ACE inhibitor. Acute myopathy and secondary angle closure glaucoma Hydrochlorothiazide is a sulfonamide derivative. Sulfonamide and sulfonamide derivatives can cause idiosyncratic reactions, leading to the development of transient myopathy and acute angle-closure glaucoma, the symptoms of which are acute visual acuity loss or pain in the eyes. They usually occur within a few hours to several weeks of starting the drug. If left untreated, acute angle-closure glaucoma can lead to complete vision loss. It is necessary to stop taking the drug as soon as possible. Urgent medical or surgical treatment may be required if intraocular pressure remains uncontrolled. Risk factors for developing acute myopathy or secondary angle-closure glaucoma include a history of allergy to sulfonamide derivatives or penicillins. Cough When taking Ramazid H (12.5 / 5 mg), a “dry” cough may occur, usually disappearing after discontinuation of the drug. This probability should be taken into account when making a differential diagnosis of cough (see the section “Side effects”). Anaphylactoid reactions to ACE inhibitorswhen taking ACE inhibitors, life-threatening, rapidly developing anaphylactoid reactions have been described, sometimes up to the development of shock during hemodialysis using certain high-flow membranes (for example, polyacrylonitrile membranes) (see also the instructions of membrane manufacturers). The combined use of Ramazid H (12.5 / 5 mg) and this type of membrane should be avoided, for example, for urgent hemodialysis or hemofiltration. In this case, it is preferable to use other types of membranes or exclude the use of ACE inhibitors. Similar reactions were observed in low-density lipoprotein apheresis with dextran sulfate. These reactions were avoided by temporarily stopping ACE inhibitor therapy before the next apheresis. Antihistamines are ineffective in treating these reactions. There have been isolated reports of patients with long-term life-threatening anaphylactoid reactions that occur during desensitizing treatment with bee venom, wasps, etc. in some patients, these reactions were avoided with preliminary temporary withdrawal of ACE inhibitors for a period of at least 24 hours. Hypersensitivity reactions to hydrochlorothiazide do not depend on the presence of a history of allergies or bronchial asthma. Excessive lowering of blood pressure After ramipril, usually after the first or second dose, or after increasing the dose, an excessive decrease in blood pressure is possible, which is most likely in patients whose circulating blood volume has been reduced as a result of diuretic therapy, limited intake of table salt with food, dialysis, diarrhea, vomiting or heavy sweating. It is usually recommended that dehydration, hypovolemia, and hyponatremia be corrected before starting the drug (however, in patients with heart failure, replenishment of the volume of circulating blood should be carried out with great caution, since there is a risk of decompensation due to excessive volume loading). Transient excessive BP reduction is not a contraindication for continuing treatment after BP stabilization. In case of repeated excessive decrease in blood pressure, the dose should be reduced or the drug should be discontinued. Patients with RAAS activation In conditions where RAAS activation occurs and / or renal function depends on its activity (see section “With caution”), ACE inhibition is associated with an increased risk of a marked decrease in blood pressure and impaired renal function. Therefore, in such cases, at the beginning of treatment or at the beginning of an increase in the initial dose, careful monitoring of blood pressure is required until no further decrease in blood pressure is expected. In patients with severe heart failure (including those accompanied by renal failure), ACE inhibitor therapy may cause an excessive decrease in blood pressure and be accompanied by oliguria and/or progressive azotemia with acute renal failure, up to a fatal outcome. In such patients, treatment with Ramazid H (12.5/5 mg) should be initiated or continued only after taking measures against excessive blood pressure reduction and deterioration of renal function. Patients for whom an excessive decrease in blood pressure may pose a particular danger, an excessive decrease in blood pressure is particularly dangerous for patients with coronary heart disease or severe atherosclerosis of the cerebral vessels, since in this case it is possible to develop a myocardial infarction or stroke (see the section “With caution”). Such patients are subject to strict monitoring at the beginning of treatment and when increasing the dose of the drug. Patients with dehydration All patients should be warned that dehydration due to increased sweating (including during hot weather or physical exertion), vomiting, diarrhea may lead to an excessive decrease in blood pressure, and in these cases, the question of the applied doses of ramipril and hydrochlorothiazide should be decided by the doctor. Alcohol (ethanol) intake during treatment with Ramazid H (12.5 / 5 mg)During treatment with Ramazid H (12.5/5 mg), it is not recommended to consume alcohol (ethanol) (see the section “Interaction with other drugs”). In cases of excessive lowering of blood pressure, it is necessary to lay the patient with raised legs, and, if necessary, start an intravenous infusion of 0.9% sodium chloride solution to replenish the BCC (volume of circulating blood). Surgery and ANAESTHESIOLOGY Before surgery (including dental procedures), the surgeon/anaesthetist should be warned about taking ACE inhibitors. If there is an excessive decrease in blood pressure during anesthesia, it can be corrected by filling the BCC. Thiazide diuretics may increase the effects of tubocurarin. It is recommended that treatment with ACE inhibitors, including ramipril, be discontinued (if possible) one day before surgery. Primary hyperaldosteronismpatients with primary hyperaldosteronism usually do not respond to antihypertensive drugs acting through RAAS inhibition. Therefore, Ramazid H (12.5 / 5 mg) is not the drug of choice for the treatment of primary hyperaldosteronism.Monitoring of hematological parameters When taking Ramazid H (12.5 / 5 mg), it is recommended to monitor the number of white blood cells to detect possible leukopenia. Regular monitoring is recommended at the beginning of treatment and in patients with impaired renal function, connective tissue diseases (systemic lupus erythematosus, scleroderma) or in patients receiving other drugs that can change the picture of peripheral blood (see the section “Side effects”, “Interaction with other drugs”). If symptoms due to leukopenia appear (for example, fever, enlarged lymph nodes, tonsillitis), urgent monitoring of the peripheral blood picture is necessary. In case of signs of bleeding (small petechiae, red-brown rashes on the skin and mucous membranes), it is also necessary to monitor the number of platelets in the peripheral blood. Liver function monitoring A complete liver function exam and other liver tests should be performed if patients develop the following symptoms that are suspected of being impaired: flu-like symptoms that occur in the first weeks or months of treatment (such as fever, malaise, muscle pain, skin rash or adenopathy that indicate hypersensitivity reactions), abdominal pain, nausea or vomiting, loss of appetite, jaundice, pruritus or other symptoms that have no other explanation. If liver dysfunction is confirmed, discontinue Ramazid H (12.5/5 mg) and, if necessary, prescribe appropriate treatment. In patients with impaired liver function or with progressive liver diseases, the use of thiazide diuretics requires caution, since in such patients even minimal violations of the water-lectrolyte balance can provoke the development of hepatic coma. Controlled clinical trials involving patients with cirrhosis and / or impaired liver function, who should determine the state of liver function before starting the drug and regularly monitor it during treatment. Renal function control As a result of RAAS suppression, renal function may worsen in predisposed patients, and this risk increases with concomitant use of diuretics. It is recommended that renal function be carefully monitored during the first weeks of treatment and thereafter, especially in the following groups of patients::- patients with heart failure ; – patients with renovascular diseases, including hemodynamically significant unilateral renal artery wall (in such patients, even a slight increase in serum creatinine concentrations may be a manifestation of a unilateral decrease in renal function); – patients with impaired renal function; – patients after kidney transplantation. In patients with renal insufficiency, special caution is required when treating with Ramazid H (12.5/5 mg), and in these cases, lower doses of the drug are used (see the section “Dosage and use”). Hydrochlorothiazide may contribute to the development or exacerbation of azotemia. Cumulative effects of the drug are possible in patients with impaired renal function. If increasing azotemia and oliguria develop during treatment of severe progressive kidney disease, diuretic therapy should be discontinued. Insufficient experience has been gained with the use of Ramazid H (12.5 / 5 mg) in patients with severe renal impairment (creatinine clearance less than 30 ml / min per 1.73 m2 of body surface area) and in patients undergoing hemodialysis. Monitoring of electrolytes and serum glucose Blood circulation with Ramazid II (12.5 / 5 mg) requires regular monitoring of serum sodium, potassium, calcium, uric acid and glucose levels. Patients with impaired renal function, impaired water and electrolyte balance require regular monitoring of the potassium content in the blood serum. Other Cautions Thiazide diuretics can reduce the blood concentration of protein-bound iodine without causing signs of thyroid dysfunction. Thiazide diuretics can cause a temporary and slight increase in serum calcium levels in the absence of known calcium metabolism disorders. Severe hypercalcemia may indicate latent hyperparathyroidism. Thiazide diuretics should be discontinued before evaluating parathyroid function. Risk factors for hyperkalemia include renal failure, diabetes mellitus, and concomitant use of medications for the treatment of hypokalemia or other medications that may increase the level of potassium in the blood serum (see the section “Interaction with other medications”). Patients should be warned not to use salt substitutes containing potassium without first consulting their healthcare provider. It should be borne in mind that when using hydrochlorothiazide, positive doping control is possible. Effects on the ability to drive vehicles and engage in potentially dangerous activities Some undesirable effects of the drug Ramazid H (12.5 / 5 mg) (some symptoms of lowering blood pressure, such as dizziness, a feeling of “lightness” in the head), as well as visual disturbances, etc., can disrupt the ability of patients to concentrate and reduce psychomotor reactions, which poses a risk in situations requiring increased concentration and speed of psychomotor reactions (for example, when driving vehicles, working with mechanisms or engaging in other potentially dangerous activities).

Form of production

Tablets 12.5 mg+5.0 mg. 10 tablets in a blister of A1/A1, laminated PVC; 3 or 10 blisters together with the instructions for use in a cardboard pack.

Storage conditions

At a temperature not exceeding 25 °C.

Shelf

life is 2 years.

Active ingredient

Ramipril, Hydrochlorothiazide

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Hypertension