Amprilan ND tabs 5mg + 25mg #30

Amprilan ND instruction for use

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Composition

on 1 tablet
Active ingredients:
Hydrochlorothiazide 25.0 mg Ramipril 5.0 mg
Excipients: sodium bicarbonate, lactose monohydrate, croscarmellose sodium, pregelatinized starch, sodium stearyl fumarate

Description

Flat capsule-shaped tablets of white or almost white color, with a facet and engraving “25” on one side, the figures are divided by a deep risk that goes beyond the edges of the tablet.
Pharmacotherapeutic group:
combined antihypertensive agent (angiotensin-converting enzyme [ACE] inhibitor + diuretic)
ATX Code: C09BA05

Pharmacodynamics

Amprilan ND is a combination of an ACE inhibitor, also called dipeptidylcarboxydipeptidase I, kininase II - ramipril and thiazide diuretic hydrochlorothiazide. Ramipril and hydrochlorothiazide are used in monotherapy or at the same time as antihypertensive drugs.

Ramipril

Ramipril and a significantly more active metabolite of ramipril -ramiprilat, formed under the influence of liver enzymes (enzymes catalyzing the hydrolysis of esters), are long-acting ACE inhibitors (see the Pharmacokinetics subsection). In plasma and tissues, ACE catalyzes the conversion of angiotensin I to angiotensin II (active vasoconstrictor) and the breakdown of the active vasodilator - bradykinin. Therefore, the use of ramipril reduces the formation of angiotensin II and there is an accumulation of bradykinin, which leads to the expansion of blood vessels and lower blood pressure (BP), and also contributes to the cardioprotective action of ramipril. The ramipril-induced increase in the activity of the kallikrein-kinin system in blood plasma 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 endothelial cells causes its cardioprotective and endothelial-protective effect. It is assumed that the increase in the serum activity of bradykinin is also partially associated with the occurrence of some undesirable reactions ("dry" cough).
Angiotensin II stimulates the release of aldosterone, so taking ramipril reduces aldosterone secretion and increases the content of potassium ions in blood serum. Due to the presence of negative feedback between the activity of angiotensin II and renin secretion, a decrease in the activity of angiotensin II leads to an increase in the activity of renin 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 (HR). Intake of ramipril leads to a significant decrease in the total peripheral vascular resistance (OPS), as a rule, without causing changes in the renal blood flow and glomerular filtration rate.
After taking Amprilan ND inside the beginning of the antihypertensive effect occurs after 1 -2 hours, and the maximum antihypertensive effect develops after 3-6 hours and persists for 24 hours. In exchange intake, the full antihypertensive effect of ramipril usually develops by 3-4 weeks of its constant intake. The antihypertensive effect of Amprilan ND is maintained with prolonged use in recommended doses. At the termination of reception of a ramipril the withdrawal syndrome is not observed.
With long-term use in patients with arterial hypertension, ramipril contributes to the reverse development of myocardial and vascular wall hypertrophy. ACE inhibitors are also effective in patients with arterial hypertension with low renin activity in the blood plasma.
On average, the antihypertensive effect of ACE inhibitors is less pronounced in patients of the Negroid race (especially with low renin activity in the blood plasma) compared to patients of other races. Ramipril increases the sensitivity of tissues to insulin and favorably affects the metabolism of carbohydrates and lipids, increases the concentration of fibrinogen, reduces platelet aggregation, stimulates the synthesis of tissue activator profibrinolysis (plasminogen), contributing to thrombolysis. In patients with diabetic and non-diabetic nephropathy clinically, the drug reduces the rate of progression of renal failure, and at the preclinical stage of diabetic and non-diabetic nephropathy ramipril reduces albuminuria.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. Thiazide diuretics inhibit the reabsorption of sodium and chlorine ions in the distal kidney 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 the osmotic binding of water). Hydrochlorothiazide decreases plasma volume, increases plasma renin activity and aldosterone secretion. The excretion of potassium and magnesium ions is increased, and the excretion of uric acid is reduced. When taken in high doses, hydrochlorothiazide increases the excretion of bicarbonates, with prolonged use reduces the excretion of calcium.
The proposed mechanisms of the antihypertensive effect of hydrochlorothiazide are changes in sodium balance, a decrease in the amount of extracellular fluid and plasma volume, a change in renal vascular resistance, and a decrease in vascular response to norepinephrine and angiotensin II. After taking hydrochlorothiazide inside the beginning of diuresis (elimination of water and salts) occurs in the first 2 hours after it is taken, the maximum effect is achieved in about 3-6 hours, the effect of the drug lasts about 6-12 hours. For the development of the antihypertensive effect, several days of hydrochlorothiazide are required (3-4 days), after discontinuing Amprilan ND, its antihypertensive effect can last up to 1 week. With long-term treatment, a decrease in blood pressure is achieved with the use of smaller doses, in comparison with the doses needed 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 the blood plasma. Thiazide diuretics are ineffective with creatinine clearance (CK) ≤30 ml / min.
Thiazide diuretics can suppress lactation.

Clinical efficacy and safety

The simultaneous use of ramipril and hydrochlorothiazide

In clinical studies, the use of this combination led to a more pronounced decrease in blood pressure than when using any of the drugs separately. With the simultaneous use of ramipril and hydrochlorothiazide, there is a tendency to prevent the loss of potassium ions associated with the use of these diuretics, presumably due to the blockade of the renin-angiotensin-aldosterone system (RAAS). The use of a combination of an ACE inhibitor and thiazide diuretic causes a synergistic effect, and also reduces the risk of hypokalemia caused by the use of a diuretic separately.

Double blockade of RAAS

Two large-scale, randomized, controlled trials (a global endpoint study with continued Telmisartan treatment alone and in combination with ramipril and a nephropathy study in patients with diabetes mellitus conducted by the US Department of Veterans Affairs) studied the use of an ACE inhibitor and angiotensin II receptor antagonist combination ( ARA II).
The first study, mentioned above, was conducted with the participation of patients with a history of cardiovascular diseases or vascular diseases of the brain, or diabetes mellitus type 2, accompanied by signs of target organ damage. The second study was conducted with the participation of patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant positive effect on kidney and / or cardiovascular outcomes and mortality, while there was an increased risk of hyperkalemia, acute renal failure and / or arterial hypotension compared with monotherapy. Given the similar pharmacodynamic properties of the drugs, these results are also applicable to other ACE inhibitors and ARA II.
Therefore, ACE inhibitors and ARA II should not be used simultaneously in patients with diabetic nephropathy.
A study of the use of aliskiren in patients with type 2 diabetes mellitus using endpoints of the cardiovascular system and kidney diseases was developed to evaluate the benefits of the additional use of aliskiren for standard therapy with an ACE inhibitor or ARA II in patients with type 2 diabetes and chronic kidney disease -vascular disease or both of these diseases. The study was terminated early due to increased risk of undesirable outcomes. The incidence and rates of cardiovascular mortality and stroke were quantitatively higher in the aliskiren group than in the placebo group, and adverse events and serious adverse events of interest (hyperkalemia, hypotension and renal impairment) were more frequently recorded in the aliskiren group in the placebo group.

Pharmacokinetics

Ramipril

After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract (50-60%). Meal slows down its absorption, but does not affect the completeness of absorption. Ramipril is subjected to intensive presystemic metabolism / activation (mainly in the liver by hydrolysis), necessary for the formation of the only active metabolite, ramiprilat, whose activity in relation to ACE inhibition is about 6 times higher than the serum activity of ramipril. The half-life of ramipril (T½) is approximately 1 hour. In addition to ramiprilat, the pharmacologically inactive diketopiperazine is formed as a result of ramipril metabolism, which is then conjugated with glucuronic acid. Ramiprilat is also glucuronated and metabolized to diketopiperazinic acid.
As a result of absorption and metabolism / activation of ramipril, its bioavailability after oral administration ranges from 15% (for a dose of 2.5 mg) to 28% (for a dose of 5 mg). The bioavailability of the active metabolite - ramiprilat - after oral administration of 2.5 mg and 5 mg of ramipril is approximately 45% (compared with its intravenous administration in the same doses).
After ingestion of ramipril, maximum plasma concentrations of ramipril and ramiprilat are reached after 1 and 2-4 hours, respectively. The decrease in plasma concentration of ramiprilat occurs in several stages: the initial phase of distribution and elimination with T½ ramiprilat, approximately 3 hours, then the intermediate phase with T½ ramiprilat, approximately 15 hours, and the final phase with a very low concentration of ramiprilat in blood plasma and T½ ramiprilat, approximately 4-5 days. This final phase is due to the slow release of ramiprilat from a strong bond with the ACE receptors. Despite the prolonged final phase with a single dose of ramipril during a day at a dose of 2.5 mg or more, the equilibrium plasma concentration of ramiprilat is reached after approximately 4 days of treatment. In the course application of Amprilan ND "effective" T½, important for the choice of the dosing regimen, depending on the dose is 13-17 hours.
The link to plasma proteins is approximately 73% for ramipril, and approximately 56% for ramiprilat.
After intravenous administration, the volume of distribution of ramipril and ramiprilat is approximately 90 L and 500 L, respectively.
After ingestion of radiolabeled ramipril (10 mg), 39% of the radioactivity is excreted through the intestines and about 60% by the kidneys. After intravenous ramipril, 50-60% of the dose is found in the urine as ramipril and its metabolites. After intravenous ramiprilat, about 70% of the dose is found in the urine as ramiprilat and its metabolites, in other words, with intravenous ramipril and ramiprilat, a significant portion of the dose is eliminated, bypassing the kidneys (50% and 30%, respectively). After ingestion of 5 mg of ramipril in patients with bile duct drainage, almost the same amount of ramipril and its metabolites are excreted by the kidneys and excreted into the bile during the first 24 hours after ingestion.
Approximately 80-90% of metabolites in urine and bile were identified as ramiprilat and ramiprilat metabolites. The share of ramipril glucuronide and ramipril diketopiperazine accounts for approximately 10-20%, and the concentration in the urine of unmetabolized ramipril is approximately 2%.
In animal studies, ramipril has been shown to be secreted into human milk.
In older volunteers (65-76 years), the pharmacokinetics of ramipril and ramiprilat are similar to those of younger individuals.
With impaired renal function (CC less than 60 ml / min), the excretion of ramiprilat and its metabolites by the kidneys slows down. This leads to an increase in the plasma concentration of ramiprilat, which decreases more slowly than in patients with normal renal function.
Impaired liver function (when taking ramipril in high doses - 10 mg) leads to a delay in the transfer of ramipril to active ramiprilat, as well as to a delay in the removal of ramiprilat.
In volunteers, in patients with arterial hypertension after two weeks of ramipril treatment in a daily dose of 5 mg, there is no clinically significant accumulation of ramipril and ramiprilat. Patients with heart failure after two weeks of ramipril treatment at a daily dose of 5 mg show a 1.5–1.8 fold increase in ramiprilat plasma concentrations and area under the concentration-time pharmacokinetic curve (AUC).
Acceptance of antacids containing magnesium and aluminum hydroxide does not affect the bioavailability and ramipril pharmacokinetics.

Hydrochlorothiazide

After ingestion, the absorption and bioavailability of hydrochlorothiazide is about 70%.
Communication with proteins of a blood plasma makes about 40%.
When ingestion of 12.5 mg of hydrochlorothiazide, the maximum plasma concentration is reached in 1.5-4 hours and is 70 ng / ml, and when ingested 25 mg of hydrochlorothiazide, the maximum plasma concentration is reached in 2-5 hours and is 142 ng / ml.
Hydrochlorothiazide is slightly metabolized in the liver and it has not revealed inducing or inhibiting cytochrome P450 activity. Hydrochlorothiazide is excreted almost completely (more than 95%) by the kidneys in unchanged form. 50-70% of the ingested dose is eliminated within 24 hours. T½ of hydrochlorothiazide from the body is 5-6 hours. In renal failure, elimination slows down, and T½ is lengthened. Renal clearance of hydrochlorothiazide is closely related to CC. In patients with glomerular filtration rate less than 10 ml / min, only 10% of the dose taken is found in the urine. Hydrochlorothiazide is excreted in small amounts into breast milk. There was no change in the pharmacokinetics of hydrochlorothiazide in liver cirrhosis.

Hydrochlorothiazide / ramipril combination

It was established that ramipril and hydrochlorothiazide do not affect the pharmacokinetics (maximum plasma concentration and area under the concentration-time pharmacokinetic curve) and, accordingly, the bioavailability of each other when taken orally, both as a single drug, and as part of a combined drug.

Indications for use

Arterial hypertension (in patients for whom combined antihypertensive therapy is indicated).

Contraindications

• Hypersensitivity to ramipril, other ACE inhibitors, hydrochlorothiazide, other thiazide diuretics, sulfonamide derivatives, or any of the excipients of Amprilan ND (see the “Composition” section).
• Angioedema in history (hereditary or idiopathic, as well as after the use of ACE inhibitors).
• Severe renal impairment (glomerular filtration rate [GFR] <30 ml / min per 1.73 m2 of body surface area) or hemodialysis.
• Hemodynamically significant renal artery stenosis (bilateral or unilateral in the case of a single functioning kidney).
• Clinically significant deviations from the normal content of electrolytes in the blood plasma, such as hypokalemia, hypomagnesia or hypercalcemia (the possibility of their aggravation during treatment with Amprilan ND).
• Severe dysfunction of the liver (more than 9 points on the Child-Pugh scale) (lack of clinical experience with application, it is known that in these conditions, minimal disruption of water and electrolyte balance can provoke hepatic coma).
• Anuria (due to the presence of hydrochlorothiazide in the formulation).
• Pregnancy.
• Breastfeeding period.
• Children and adolescents (under 18) (insufficient data on the efficacy and safety of this drug in children).
• Hemodialysis or hemofiltration using some negatively charged membranes, such as high-flow 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).
• Severe arterial hypotension.
• Simultaneous intake with drugs containing aliskiren in patients with diabetes mellitus or with moderate and severe renal insufficiency (CC less than 60 ml / min).
• Simultaneous intake with ARA II in patients with diabetic nephropathy.
    Lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

Carefully

• With simultaneous use of the drug Amprilan ND and drugs containing aliskiren, or ARA II (with a double blockade of the RAAS there is an increased risk of developing a sharp decrease in blood pressure, the development of hyperkalemia and deterioration of kidney function) (see the section "Special Instructions").
• In conditions associated with increased activity of the RAAS, in which, when inhibition of ACE, there is a risk of a sharp decrease in blood pressure with deterioration of the kidney function (see the section "Special Instructions"):
- severe arterial hypertension, especially malignant arterial hypertension;
- chronic heart failure, especially severe or about which other medicines with antihypertensive effect are taken (see the section "Special Instructions");
- hemodynamically significant violation of the outflow of blood from the left ventricle or blood flow to the left ventricle (hemodynamically significant stenosis of the aortic or mitral valve or hypertrophic obstructive cardiomyopathy [GOKMP]);
- Renovascular diseases, including hemodynamically significant unilateral stenosis of the renal artery (careful control of plasma creatinine concentration is required, see sections "Specific instructions", "Side effects");
- previous treatment with diuretics;
- violations of water and electrolyte balance as a result of insufficient consumption of liquid and / or salt, diarrhea, vomiting, excessive sweating (with inadequate replacement of fluid and sodium losses).
• In conditions in which a pronounced decrease in blood pressure is 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 drug treatment).
• In cases of impaired renal function with GFR 30–60 ml / min per 1.73 m2 of body surface area due to the risk of hyperkalemia and leukopenia (correction of the dosing regimen is required, see the section “Route of administration and dosage” and regular monitoring of kidney function, especially at the beginning of treatment, see section "Special instructions").
• When the condition is after kidney transplantation (regular monitoring of renal function is required, especially at the beginning of treatment).
• In case of impaired liver function (risk of impaired liver function, lack of sufficient clinical experience with the drug, see the sections “Side Effects”, “Special Instructions”).
• In case of systemic connective tissue diseases, such as systemic lupus erythematosus or scleroderma (increases the risk of developing impaired immune responses, the risk of reducing the number of leukocytes in peripheral blood).
• When oppression of bone marrow hematopoiesis, concomitant therapy with corticosteroids (glucocorticosteroids and mineralocorticosteroids), immunomodulators, cytostatics, antimetabolites, allopurinol, procainamide (increases the risk of reducing the number of leukocytes in peripheral blood, see the section for the body, the pro- agarone, increases the risk of reducing the number of leukocytes in the peripheral blood, see the section for the body, the proacinamide, see the section for the body, the proacinamide, see the section for the body, the pro- againamide, see the section for the body, the pro- againamide, see the section for the body, the pro- againamide, see the section for the body, the proacinamide, for example, the body, the metrophoresis, the anti-metabolites, allopurinol, procainamide (increases the risk of reducing the number of leukocytes in the peripheral blood, see the section for the body, in the heart of the body, in the case of heart failure "Special instructions").
• In diabetes mellitus (the risk of hyperkalemia, and in the case of the use of hypoglycemic agents (insulin preparations and hypoglycemic agents for oral administration [sulfonylurea derivatives]) - the risk of hypoglycemic reactions due to the presence of ramipril in Amprilan ND and the risk of an increase in blood glucose concentration due with the presence of hydrochlorothiazide in the composition of the drug) (see the sections “Side Effects”, “Interaction with Other Medicines”).
• In elderly patients (over 65 years of age) (risk of developing a more pronounced antihypertensive effect, little experience with Amprilan ND, more regular monitoring of renal function is required).
• Primary hyper aldosteronism.
• Desensitization with hymenoptera venom.
• Surgical intervention / general anesthesia.
• Ischemic heart disease, cerebrovascular diseases.
• Use in patients of the Negroid race.
• Hyperkalemia, hypercalcemia.

Use during pregnancy and during breastfeeding

The use of the drug during pregnancy, women planning pregnancy, as well as women of reproductive age who do not use reliable methods of contraception, is contraindicated. When establishing the fact of pregnancy, it is necessary to immediately stop taking the drug and, if necessary, to begin alternative therapy with an established safety profile.

Pregnancy

Ramipril

The epidemiological evidence regarding the risk of teratogenicity after exposure to ACE inhibitors during the first trimester of pregnancy was inconclusive, however, a slight increase in risk cannot be ruled out. Except for cases when the continuation of therapy with an ACE inhibitor is considered necessary, patients planning a pregnancy should switch to treatment with alternative antihypertensive drugs with an established safety profile when used during pregnancy. When confirming pregnancy, you must immediately stop treatment with ACE inhibitors. and, if necessary, initiate alternative therapy.
It is known that an ACE / APA II inhibitor during a person's second and third trimesters of pregnancy has a toxic effect on the fetus (decreased kidney function, low water, delayed ossification of the skull) and the newborn (renal failure, arterial hypotension, hyperkalemia). In the case of exposure to an ACE inhibitor during the second trimester of pregnancy, an ultrasound examination of the function of the kidneys and the skull has been recommended. It is necessary to carefully monitor newborns whose mothers took ACE inhibitors. on the subject of arterial hypotension, oliguria and hyperkalemia.

Hydrochlorothiazide

Experience with hydrochlorothiazide during pregnancy, especially during the first trimester, is limited. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. In cases of prolonged exposure during the second and third trimester of pregnancy, hydrochlorothiazide may cause placental insufficiency and the risk of stunting. In addition, rare cases of hypoglycemia and thrombocytopenia in newborns were reported in the case of hydrochlorothiazide use shortly before delivery.
Hydrochlorothiazide may cause a decrease in plasma volume, as well as uteroplacental blood flow.
Hydrochlorothiazide should not be used to treat essential hypertension in pregnant women, with the exception of rare cases of inability to use other therapies.

Breastfeeding period

The use of the combination of hydrochlorothiazide / ramipril is contraindicated during breastfeeding.
Ramipril and hydrochlorothiazide are excreted in breast milk in an amount that is likely to affect the breastfed baby if pregnant women take ramipril and hydrochlorothiazide in therapeutic doses. Information regarding the use of ramipril during breastfeeding is insufficient, and it is preferable to use alternative drugs with the studied safety profile during breastfeeding, especially when breastfeeding a newborn or premature baby.
Hydrochlorothiazide is excreted in human breast milk. The use of thiazides by mothers during breastfeeding was accompanied by a decrease or even suppression of lactation. Hypersensitivity to sulfonamide derivatives, hypokalemia and nuclear jaundice is possible.
Because of the possibility of serious adverse reactions in breastfed babies, due to the effects of the hydrochlorothiazide / ramipril combination, it is necessary to decide whether to stop breastfeeding or discontinue therapy, given the importance of this therapy for the mother.

Dosage and administration

Mode of application

Tablets should be swallowed whole, drinking plenty of water (1/2 cup). Tablets can not be crushed and chewed. Eating does not have a significant impact on the bioavailability of Amprilan ND, so it can be taken before, during or after a meal. It is usually recommended that the daily dose be taken once at the same time of day, mostly in the morning.

Recommended doses and dosing regimen

The drug is not intended to start therapy of hypertension. Doses of the drug are selected individually. Selection of doses is carried out by a doctor in accordance with the severity of arterial hypertension and the presence of risk factors associated with it, as well as the tolerability of Amprilan ND.
The dose of the hydrochlorothiazide / ramipril combination is selected by selecting (gradually increasing or, if necessary, decreasing) the doses of the individual preparations of ramipril and hydrochlorothiazide. Particular caution should be titrated doses in patients on hemodialysis.
After the patient has been given a dose of hydrochlorothiazide and ramipril, for greater convenience of patients, their use can be replaced with the use of the drug Amprilan ND.
Usual initial dose: 2.5 mg ramipril and 12.5 mg hydrochlorothiazide 1 time per day (1/2 tablet of Amprilan ND). If necessary, the dose may be increased to achieve the target level of blood pressure with an interval of 2-3 weeks (1 tablet of the drug Amprilan ND). The maximum daily dose is 10 mg in terms of ramipril and 25 mg in terms of hydrochlorothiazide.
In patients who fail to achieve the necessary reduction in blood pressure with monotherapy with ramipril at a dose of 5 mg, or in patients in whom the necessary reduction in blood pressure is achieved with the use of ramipril in a dose of 5 mg and hydrochlorothiazide at a dose of 25 mg taken as separate drugs, it is possible use of the drug Amprilan ND (25 mg + 5 mg).
In most cases, blood pressure will decrease sufficiently when taking hydrochlorothiazide at a dose of 12.5 mg and ramipril at a dose of 2.5 mg (1/2 tablet of Amprilan ND) to 5 mg of ramipril and 25 mg of hydrochlorothiazide (1 tablet of Amprilan ND ).

Recommended doses and dosing regimen in special clinical situations

Treatment of patients receiving diuretics

Patients who received prior treatment with diuretics, before taking Amprilan ND, if possible for 2-3 days or more (depending on the duration of the action of diuretics) should be canceled or at least reduced doses.
If discontinuation of diuretics is not possible, it is recommended to start treatment with the lowest doses of ramipril (1.25 mg per day) in this combination, taking separate ramipril and hydrochlorothiazide preparations. It is recommended that further transfer to receive the combination of hydrochlorothiazide / ramipril 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 (1/2 tablet of the drug Amprilan ND).

Treatment of patients with impaired renal function

Treatment with Amprilan ND is contraindicated in severe renal dysfunction, since Amprilan ND contains hydrochlorothiazide (CC <30 ml / min).
Patients with impaired renal function may require a dose reduction of the hydrochlorothiazide / ramipril combination.
With GFR from 30 to 60 ml / min per 1.73 m2 of body surface area, treatment begins with ramipril monotherapy at a daily dose of 1.25 mg.
After a gradual increase in the dose of ramipril, treatment with a combination drug begins with a dose of 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide (1/2 tablet of the drug Amprilan ND). The maximum permissible daily dose for patients with renal insufficiency is 5 mg ramipril and 25 mg hydrochlorothiazide (1 tablet of the drug Amprilan ND).
Treatment of patients with lungs (5-6 points on the scale of Child-Pyo) or moderate (7-9 points on the scale of Child-Pugh) impaired liver function
Treatment with Amprilan ND should begin under close medical supervision and the maximum daily dose of ramipril should be 2.5 mg and hydrochlorothiazide 12.5 mg (1/2 tablet of the drug Amprilan ND). Amprilan ND is contraindicated in patients with severely impaired liver function.

Treatment of Elderly Patients

Treatment should begin with lower doses, and the dose increase should be more gradual (with a smaller dose increment) due to the greater likelihood of side effects, especially in debilitated elderly patients.

Treatment of pediatric patients

The drug Amprilan ND is contraindicated for use in children and adolescents under 18 years old, data on safety and efficacy are not enough.

Skip dose

When skipping the next dose of the drug Amprilan ND, the missed dose should be taken as soon as possible. However, if this is detected very close to the time of the next dose, then you should skip the missed dose and go back to the usual dosing regimen, not allowing the dose to double in a short period of time.

Side effect

The safety profile of the combination of hydrochlorothiazide / ramipril includes undesirable reactions that occur against the background of arterial hypotension and / or hypovolemia due to increased diuresis. The active ingredient ramipril can cause a permanent dry cough, while the active ingredient hydrochlorothiazide can worsen the metabolism of glucose, lipids and uric acid. Two active substances have the opposite effect on the content of potassium in the blood plasma. Serious adverse reactions include angioedema or anaphylactic reaction, impaired kidney or liver function, pancreatitis, severe skin reactions, and neutropenia / agranulocytosis.

Overdose

Symptoms

Overdose may develop a persistent increase in the amount of urine excreted, excessive peripheral vasodilation (with a pronounced decrease in blood pressure, development of shock), bradycardia, disorders of water and electrolyte balance, renal failure, cardiac rhythm disturbances, depression of consciousness, up to the development of coma, cerebral seizures, paresis and paralytic intestinal obstruction. In patients with impaired outflow of urine (for example, with prostatic hyperplasia), abundant diuresis can provoke an acute urinary retention with overstretching of the bladder.

Treatment

If possible, during the first 30 minutes should be gastric lavage, give to take adsorbents, sodium sulfate. In the case of the development of a persistent decrease in blood pressure, in addition to therapy aimed at replenishing the circulating blood volume and electrolytes, administration of agonists of alpha adrenergic receptors (norepinephrine, dopamine) is indicated. In the case of bradycardia refractory to drug treatment, implantation of a temporary pacemaker may be required. In case of overdose, it is necessary to control serum concentrations of creatinine and the content of electrolytes in the serum.
There is no experience regarding the effectiveness of forced diuresis, changes in urine pH, hemofiltration or hemodialysis to accelerate the removal of ramipril and ramiprilat. Hydrochlorothiazide can be eliminated by hemodialysis. If hemodialysis or hemofiltration is supposed to be carried out, the risk of anaphylactoid reactions when using high-flow membranes should be taken into account and not used (see sections "Contraindications", "Interactions with other drugs", "Special instructions").

Interaction with other drugs

Data from clinical studies show that double blockade of RAAS when using a combination of ACE inhibitors, ARA II or aliskiren is associated with a higher incidence of adverse events, such as arterial hypotension, hyperkalemia and reduced kidney function (including acute renal failure) compared to monotherapy with drugs acting on the RAAS.

Contraindications

• Extracorporeal treatments that cause blood to come in contact with negatively charged surfaces, such as hemodialysis or hemofiltration with some high-flow membranes (for example, polyacrylonitrile membranes) and low density apoperice lyoprotein with dextran sulfate. The risk of developing severe anaphylactoid reactions. If necessary, such treatment should consider the possibility of using a dialysis membrane of another type or an antihypertensive drug of another class.

Precautions for use

• Potassium salts, potassium-sparing diuretics (for example, spironolactone, eplerenone [a derivative of spironolactone], amiloride, triamterene), heparin, and other drugs that can increase serum levels of acacia (including APA II, tacrolimus, cyclosporine, trimethoprimum. composition of co-trimoxazole [combined antibacterial agent containing sulfamethoxazole and trimethoprim]) The development of hyperkalemia is possible. with simultaneous use requires careful monitoring of the content of potassium in the serum.
• Antihypertensive drugs and other drugs that have antihypertensive effects (for example, nitrates, cyclic antidepressants, anesthetics, ethanol, baclofen, alfuzosin, doxazosin, prazosin, tamsulozin, terazosin)
Possible increase in the risk of arterial hypotension.
• With diuretics
Perhaps a pronounced decrease in blood pressure at the beginning of treatment (for simultaneous use with diuretics, see sections "Dosage and administration", "Special instructions").
• Vasopressor sympathomimetics (epinephrine [epinephrine], isoprotereiol, dobutamine, dopamine)
Reduced antihypertensive effects of ramipril. It is recommended to carefully monitor blood pressure. In addition, the vasopressor effect of sympathomimetics can be weakened by hydrochlorothiazide.
• Allopurinol, immunosuppressive agents, corticosteroids (glucocorticosteroids and mineralocorticosteroids), procainamide, cytotoxic drugs and other drugs that can change the pattern of peripheral blood
Increases the likelihood of developing disorders of the blood.
• Lithium salts
It is possible to reduce the excretion of lithium, leading to an increase in its toxicity. Therefore, it is necessary to regularly monitor the serum lithium content. The simultaneous use of thiazide diuretics can increase the risk of the toxic action of lithium and increase the already increased risk of the toxic action of lithium when using ACE inhibitors. Therefore, the simultaneous use of the combination of hydrochlorothiazide / ramipril with lithium is not recommended.
• Hypoglycemic agents (including insulin)
Perhaps the development of hypoglycemic reactions. Hydrochlorothiazide may decrease the effects of hypoglycemic agents. Therefore, at the initial stage of simultaneous use of hypoglycemic agents and Amprilan ND
Amprilan NL requires particularly careful monitoring of blood glucose concentrations.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) (indomethacin, acetylsalicylic acid [more than 3 g / day])
Perhaps a decrease in the antihypertensive effect of the drug Amprilan ND. In addition, the simultaneous use of ACE inhibitors and NSAIDs may increase the risk of impaired renal function and lead to increased kalemia.
• Anticoagulants for oral administration.
The effect of anticoagulants may decrease with simultaneous use of hydrochlorothiazide.
• Corticosteroids, adrenocorticotropic hormone (ACTH), amphotericin B, carbenoxolone, preparations containing licorice root, laxatives (if taken for a long time), and other potassium uretic agents or agents that lower the plasma potassium content
The risk of hypokalemia increases.
• Cardiac glycosides, drugs that can prolong the QT interval, antiarrhythmics
It is possible to increase their proarrhythmic toxicity or reduce their antiarrhythmic effect in the presence of water and electrolyte disorders (for example, hypokalemia, hypomagnesemia).
• methyldopa
Possible hemolysis.
• With vitamin D
With simultaneous use with hydrochlorothiazide, it is possible to increase the calcium content in the blood serum (due to the slowing down of calcium excretion by the kidneys), careful monitoring of the calcium content in the blood serum is required.
• Kolestiramin or other ion exchange resins for oral administration.
Hydrochlorothiazide absorption decreases. Sulfonamide diuretics can be taken at least one hour before or 4-6 hours after taking these medications.
• Curare-like muscle relaxants
Possible enhancement and prolongation of muscle relaxant action.
    Calcium salts and drugs that increase the calcium content in the blood plasma
With simultaneous use with hydrochlorothiazide may increase the calcium content in the blood plasma, therefore, requires careful control of the calcium content in serum.
    Carbamazepine
The risk of hyponatremia due to the potentiating effect of hydrochlorothiazide.
    Iodine-containing contrast agents
In the case of dehydration caused by diuretics, including hydrochlorothiazide, there is an increased risk of developing acute renal dysfunction, especially with the administration of high doses of contrast media.
    Penicillin
Hydrochlorothiazide is excreted by the distal renal tubules and therefore reduces the elimination of penicillin.
    Quinine
Hydrochlorothiazide reduces quinine excretion.
    Heparin
Possible increase in serum potassium.
    Rapamycin target inhibitors in mammalian cells (mammalian Target of Rapamycin - mTOR) or vildagliptin
There may be an increased risk of angioedema in patients who are simultaneously taking drugs, such as mTOR inhibitors (for example, temsirolimus, everolimus, sirolimus) or vildagliptin. Caution should be exercised at the beginning of therapy.
    Racecadotril
With the simultaneous use of ACE inhibitors and inhibitors of neutral endopeptidase (NEP), such as racecadotril. an increased risk of developing angioedema was reported.
    With table salt
With a large amount of salt, coming from food, it is possible to weaken the antihypertensive effect of Amprilan ND.
    With desensitization therapy
The likelihood and severity of anaphylactic and anaphylactoid reactions to insect insects increases with ACE inhibition. It is assumed that similar reactions are possible for other allergens.

Impact on laboratory results

Evaluation of the function of the parathyroid glands
Hydrochlorothiazide stimulates renal calcium reabsorption and may cause hypercalcemia.
This must be taken into account when evaluating the function of the parathyroid glands (see section "Special Instructions").

special instructions

Special patient groups

Pregnancy

During pregnancy, treatment with an ACE inhibitor, such as ramipril, or ARA II, should not be initiated. Except for cases when the continuation of therapy with an ACE / APA II inhibitor is considered necessary, patients planning a pregnancy should switch to treatment with alternative antihypertensive drugs with an established safety profile when used during pregnancy. If pregnancy is confirmed, it is necessary to immediately discontinue treatment with ACE / APA II inhibitors, and, if necessary, initiate alternative therapy.

Patients with a special risk of developing hypotension

    Patients with pronounced activation of the RAAS
    In patients with RAAS activation, there is a risk of marked reduction in blood pressure and deterioration of kidney function as a result of ACE inhibition, especially when using an ACE inhibitor or while using a diuretic at the beginning of treatment or at the beginning of an increase in the initial dose. Given the likelihood of pronounced activation of the RAAS, should be carefully monitored blood pressure, for example, in:
        patients with severe arterial hypertension;
        patients with decompensated chronic heart failure;
        patients with a hemodynamically significant violation of the outflow of blood from the left ventricle or blood flow to the left ventricle (for example, aortic or mitral stenosis);
        patients with unilateral renal artery stenosis with a second functioning kidney;
        patients whose circulating blood volume (BCC) was reduced as a result of diuretic therapy, limited intake of table salt from food, dialysis, diarrhea, vomiting, or profuse sweating;
        patients with cirrhosis and / or ascites;
        patients with extensive surgery or during anesthesia with the use of drugs that cause arterial hypotension. It is usually recommended that dehydration, hypovolemia and hyponatremia be corrected before the use of Amprilan ND (however, in patients with heart failure, the BCC should be replenished with great care, as there is a risk of decompensation due to excessive volume loading).
    Patients at risk of developing myocardial infarction or stroke with arterial hypotension
    In conditions in which a pronounced decrease in blood pressure is 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 drug treatment). Such patients are subject to strict observation at the beginning of treatment.

Primary hyperaldosteronism

Treatment with a hydrochlorothiazide / ramipril combination is not the treatment of choice for primary hyperaldosteronism. When using the combination of hydrochlorothiazide / ramipril in patients with primary hyper aldosteronism, careful monitoring of plasma potassium is necessary.

Elderly patients

Initial doses should be lower, further dose selection should be more gradual, given the higher likelihood of undesirable effects, especially in elderly patients and in a state of exhaustion.

Patients with liver disease

In patients with liver disease, water-electrolyte imbalance caused by diuretic therapy, including hydrochlorothiazide, can cause hepatic encephalopathy.

Surgical intervention

It is recommended that, if possible, discontinue therapy with ACE inhibitors. including ramipril, one day before surgery.

Kidney function control

It is necessary to evaluate kidney function before and during treatment, and adjust the dose, especially during the first weeks of therapy. Especially careful monitoring is required for patients with impaired renal function. There is a risk of impaired renal function, especially in patients with congestive heart failure or undergoing kidney transplantation, or with renovascular arterial hypertension, including patients with hemodynamically significant unilateral renal artery stenosis.

Renal dysfunction

In patients with kidney disease, thiazide diuretics may contribute to the development of azotemia. Cumulative effects of Amprilan ND are possible in patients with impaired renal function. If there is evidence of progressive impairment of renal function in the form of increased azotemia, it is necessary to reevaluate therapy and consider stopping diuretic therapy.

Water and electrolyte imbalance

As with any patient receiving diuretic therapy, it is necessary to periodically determine the serum electrolyte content at regular intervals. Thiazide diuretics, including hydrochlorothiazide, can cause impaired water-electrolyte balance (hypokalemia, hyponatremia, and hypochloraemic alkalosis). Despite the fact that the use of thiazide diuretics may develop hypokalemia, simultaneous therapy with ramipril may reduce the hypokalemia caused by diuretics. The risk of developing hypokalemia is highest in patients with cirrhosis of the liver, in patients with forced diuresis, in patients receiving an inadequate amount of electrolytes, and in patients simultaneously receiving therapy with corticosteroids or ACTH. The first determination of potassium in the blood plasma should be carried out during the first week after the start of treatment. If low potassium levels are detected in the blood plasma, correction is required. Cultivation hyponatremia may develop. At the beginning of therapy, a decrease in sodium content in the blood plasma may be asymptomatic, therefore it is recommended to regularly monitor this indicator. Determination of potassium in the blood plasma should be carried out more often in elderly patients and patients with cirrhosis of the liver.
Thiazide diuretics increase the excretion of magnesium by the kidneys, which can lead to hypomagnesemia.

Hyperkalemia

Hyperkalemia has been observed in some patients treated with ACE inhibitors, including the hydrochlorothiazide / ramipril combination. The risk of developing hyperkalemia includes patients with renal insufficiency, elderly patients (over 70 years old), patients with decompensated diabetes mellitus, or receiving potassium salts, potassium-sparing diuretics and other drugs that increase plasma potassium, or patients in a state of dehydration, patients with acute heart failure, metabolic acidosis. If the simultaneous use of the above funds is considered appropriate, it is recommended that regular monitoring of the content of potassium in the blood plasma.

Hyponatremia

Some patients receiving treatment with ramipril had SNG ADH followed by hyponatremia. In patients of advanced age and other patients at risk of developing hyponatrism, it is recommended to carry out regulatory control of serum sodium content.

Hepatic encephalopathy

In patients with liver disease, impaired water and electrolyte metabolism caused by diuretic therapy, including hydrochlorothiazide, can cause hepatic encephalopathy. If hepatic encephalopathy develops, treatment should be stopped immediately.

Hypercalcemia

Hydrochlorothiazide stimulates calcium reabsorption in the kidney and can cause hypercalcemia. Hydrochlorothiazide may affect the result of the analysis of the function of the parathyroid glands.

Angioedema

In patients treated with ACE inhibitors. including ramipril, cases of angioedema have been reported. This risk may increase in patients who are simultaneously taking medications, such as mTOR inhibitors (for example, temsirolimus, everolimus, sirolimus) or vildagliptin. With the development of angioedema during treatment with an ACE inhibitor, immediate discontinuation is required.
It is necessary to immediately begin treatment aimed at relief of anginaurotic edema. The patient should be hospitalized and under observation for at least 12-24 hours, and discharged from the hospital only after the relief of the symptoms of angioedema.
In patients treated with ACE inhibitors, there have been cases of angioedema of the intestines, which were manifested by abdominal pain (with nausea or vomiting, or without it).
Symptoms of angioedema of the intestine were resolved after discontinuation of the ACE inhibitor.

Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens increase with ACE inhibition. Before desensitization, it is necessary to consider the possibility of temporarily stopping treatment with Amprilan ND.

Neutropenia / Agranulocytosis

In rare cases, neutropenia / agranulocytosis has been observed, and bone marrow suppression has also been reported. To identify possible leukopenia, control of the number of leukocytes is recommended. More frequent monitoring is recommended at the beginning of treatment and in patients with impaired renal function, concomitant connective tissue disease (systemic lupus erythematosus, scleroderma) or in all patients receiving other drugs (for example, corticosteroids [glucocorticosteroids and mineralocorticosteroids], immunomodulators, cytostatics, antimetabolites, allopurinol, procainamide), capable of changing the pattern of peripheral blood.

Acute myopia and angle-closure glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, leading to acute transient myopia and acute angle-closure glaucoma. Symptoms include: acute decrease in visual acuity or pain in the eye and usually occur in the period from several hours to several weeks after the start of treatment with the drug. If untreated, acute angle-closure glaucoma can lead to permanent loss of vision. It is necessary as soon as possible to stop taking Amprilan ND. Urgent medical or surgical treatment may be required in case intraocular pressure remains uncontrolled. Risk factors for the development of acute angle-closure glaucoma are anamnestic indications of an allergy to sulfonamide or penicillin derivatives.

Ethnic features

The incidence of angioedema in the treatment of ACE inhibitors is higher in patients of the Negroid race than in patients not belonging to the Negroid race. Like other ACE inhibitors, ramipril has a less pronounced antihypertensive effect in patients of the Negroid race compared to other races, possibly due to the higher incidence of hypertension with low renin activity in patients of the Negroid race.

Athletes

Hydrochlorothiazide can give a positive result during doping control.

Metabolic and endocrine effects

Thiazide diuretic therapy may impair glucose tolerance. Patients with diabetes may require dose adjustment of insulin or hypoglycemic drugs for oral administration. During treatment with thiazide duretics, latent diabetes mellitus may manifest.
Thiazide diuretic therapy was accompanied by an increase in serum concentrations of cholesterol and triglycerides.
In some patients receiving thiazide diuretic therapy, it is possible to develop hyperuriaemia or gout.

Cough

When using ACE inhibitors, cough has been reported. As a rule, cough is unproductive, persistent and usually disappearing after drug withdrawal. This probability must be considered when conducting a differential diagnosis of cough.

Other

The hypersensitivity reactions to hydrochlorothiazide do not depend on the history of allergies or asthma.
It was reported about the possibility of exacerbation or activation of systemic lupus erythematosus.

Double blockade of RAAS

Proved an increased risk of arterial hypotension, hyperkalemia and reduced renal function (including acute renal failure) with simultaneous use of ACE inhibitors, ARA II or aliskiren. Therefore, the simultaneous use of ACE inhibitors, ARA II or aliskiren, leading to a double blockade of RAAS, is not recommended.
With the absolute necessity of prescribing this therapy, it should be carried out only under medical supervision with regular careful monitoring of renal function, the content of electrolytes in blood plasma and blood pressure.
ACE inhibitors and ARA II should not be used simultaneously in patients with diabetic nephropathy.

Influence on ability to steer vehicles, mechanisms

Some undesirable effects of Amprilan ND (for example, some symptoms of lowering blood pressure, such as dizziness) may affect the patient’s ability to concentrate and reduce psychomotor reactions, which is a risk in situations requiring increased concentration and psychomotor reactions ( , when driving or working with mechanisms). This is most likely to occur at the beginning of treatment or when switching from treatment with other drugs. After taking the first dose or with a subsequent increase in the dose, it is recommended to refrain from driving a vehicle or working with mechanisms for several hours.

Release form

Tablets, 25 mg + 5 mg.
On 7 or 10 tablets in the blister from the combined material OPA / Al / PVC and aluminum foil.
2, 4, 8, 12, 14 blisters (7 tablets each) together with the instructions for use are placed in a cardboard box.
2, 6, 9 blisters (10 tablets) together with instructions for use are placed in a cardboard box.

Storage conditions

At a temperature not higher than 25 ° С, in the original package.
Keep out of the reach of children.
Shelf life - 2 years.
Do not use the drug after the expiration date.

Terms of sell

You can buy Amprilan ND without a prescription.