Accupro, 30 pcs., 10 mg, film-coated tablets

Pharmacological properties of the drug Accupro

Quinapril hydrochloride (INN - Quinaprilum) is an ethyl ester of the ACE inhibitor quinaprilate, which does not contain a sulfide group. When the drug is taken orally, quinapril rapidly deesterifies to quinapril (a diacid of quinapril, the main metabolite), which is an effective ACE inhibitor. The mechanism of action of quinapril is to inhibit circulating blood and tissue ACE, which reduces vasopressor activity and aldosterone secretion. A decrease in the level of angiotensin II through a feedback mechanism leads to an increase in the secretion of renin and its activity in the blood plasma. Although the main mechanism of the antihypertensive effect is believed to be through the renin-angiotensin-aldosterone system, quinapril exhibits antihypertensive effects even in patients with low-renin hypertension (arterial hypertension). Prescribing quinapril to patients with moderate to severe hypertension (arterial hypertension) at a dose of 10–40 mg leads to a decrease in blood pressure in both sitting and standing positions, with minimal effect on heart rate. The antihypertensive effect develops within 1 hour, the maximum effect occurs 2-4 hours after taking the drug. In some patients, a stable hypotensive effect is observed after 2 weeks of treatment. When used in recommended doses, the antihypertensive effect of the drug is maintained in most patients for 24 hours and persists with prolonged use of the drug. The decrease in blood pressure caused by quinapril is accompanied by a decrease in peripheral vascular resistance and renal vascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerular filtration rate and filtration fraction. After oral administration, the maximum concentration of quinapril in the blood plasma is achieved within 1 hour. Approximately 60% of the drug is absorbed, systemic bioavailability in the form of quinapril is 38%. The maximum plasma concentration of quinapril is achieved approximately 2 hours after oral administration of quinapril. The half-life of plasma elimination is about 1 hour. Quinaprilat is eliminated mainly by renal excretion and has a half-life of effective cumulation (approximately 3 hours). Approximately 97% of quinapril or quinaprilat circulating in blood plasma is protein bound. In patients with renal impairment, the half-life of quinaprilat increases with a decrease in creatinine clearance. Pharmacokinetic studies conducted in patients with severe renal impairment undergoing chronic hemodialysis or continuous ambulatory peritoneal dialysis indicate that dialysis does not have a significant effect on the clearance of quinapril and quinalaprilat. There is a linear correlation between plasma clearance of quinalaprilat and creatinine clearance. Elimination of quinalaprilat is also reduced in elderly patients (over 65 years of age). Concentrations of quinalaprilat are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. Quinapril and its metabolites do not penetrate the BBB.

Accupro, 30 pcs., 10 mg, film-coated tablets

During treatment with ACE inhibitors, cases of angioedema in the head and neck area have been described, incl. and in 0.1% of patients receiving Accupro®. If a guttural whistle or angioedema of the face, tongue or vocal folds occurs, Accupro® should be discontinued immediately. The patient must be given adequate treatment and observed until symptoms of edema resolve. Antihistamines may be used to reduce symptoms. Angioedema involving the larynx can be fatal. If swelling of the tongue, vocal folds or larynx threatens the development of airway obstruction, adequate emergency therapy is necessary, including subcutaneous administration of a solution of epinephrine (adrenaline) 1:1000 (0.3–0.5 ml).

Cases of intestinal angioedema have also been described during treatment with ACE inhibitors. Patients reported abdominal pain (with/without nausea or vomiting); in some cases without previous angioedema of the face and normal C1-esterase activity. The diagnosis was made using ultrasound, computed tomography of the abdominal region, or at the time of surgery. Symptoms disappeared after stopping the ACE inhibitors. Therefore, in patients with abdominal pain taking ACE inhibitors, when establishing a differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine.

Patients with a history of angioedema not associated with an ACE inhibitor may be at increased risk of developing it when treated with drugs of this group.

Patients receiving ACE inhibitors during desensitization therapy with hymenoptera venom may develop life-threatening anaphylactoid reactions. By temporarily stopping the use of ACE inhibitors, these reactions were avoided, but they occurred again with accidental use of these drugs.

Anaphylactoid reactions may also occur with the use of ACE inhibitors in patients undergoing LDL apheresis by absorption with dextran sulfate, or in patients undergoing hemodialysis using high-flux membranes such as polyacrylonitrile. Therefore, such combinations should be avoided by using either other antihypertensive drugs or alternative hemodialysis membranes.

Symptomatic arterial hypotension rarely occurs during treatment with Accupro in patients with uncomplicated arterial hypertension, but it can develop as a result of therapy with ACE inhibitors in patients with reduced blood volume, for example, when following a diet with limited salt intake, hemodialysis. If symptomatic arterial hypotension occurs, it is necessary to carry out symptomatic therapy (the patient should take a horizontal position and, if necessary, receive an intravenous infusion of 0.9% sodium chloride solution). Transient arterial hypotension is not a contraindication to further use of the drug, however, in such cases, its dose should be reduced or the advisability of simultaneous therapy with diuretics should be assessed.

Other causes of decreased blood volume, such as vomiting or diarrhea, can also lead to a pronounced decrease in blood pressure. In such cases, patients should consult a doctor.

In patients receiving diuretics, the use of Accupro® may also lead to the development of symptomatic arterial hypotension. For such patients, it is advisable to temporarily stop taking the diuretic 2-3 days before starting treatment with Accupro®, except for patients with malignant or difficult-to-treat arterial hypertension. If monotherapy with Accupro® does not provide the required therapeutic effect, then treatment with diuretics should be resumed. If it is impossible to cancel the diuretic, then Accupro® is used in a low initial dose.

In patients with CHF who are at increased risk of severe arterial hypotension, treatment with Accupro® should be started at the recommended dose under close medical supervision; patients should be observed during the first 2 weeks of treatment, as well as in all cases when the dose of Accupro® is increased.

When treated with ACE inhibitors in patients with uncomplicated arterial hypertension, in rare cases, agranulocytosis developed, which was more common in patients with impaired renal function and connective tissue diseases. Agranulocytosis rarely developed during treatment with Accupro®. When using this drug (as well as other ACE inhibitors) in patients with connective tissue diseases and/or kidney disease, the number of leukocytes in the blood should be monitored.

In susceptible patients, suppression of RAAS activity may lead to renal dysfunction. In patients with severe chronic heart failure, in whom renal function may be dependent on the activity of the RAAS, treatment with ACE inhibitors, including quinapril, may be accompanied by oliguria and/or progressive azotemia, and in rare cases, acute renal failure and/or death.

The use of ARA II, ACE inhibitors or aliskiren can lead to double blockade of RAAS activity. This effect may be manifested by a decrease in blood pressure, hyperkalemia and changes in renal function (including acute renal failure) compared with monotherapy. Blood pressure, renal function and plasma electrolyte levels should be carefully monitored in patients taking Accupro® and other drugs that affect the RAAS. The simultaneous use of RAAS-active agents and quinapril should be avoided. If it is necessary to use this combination, the ratio of the expected benefit to the possible risk of using the combination should be assessed in each individual case and renal function and potassium levels should be regularly monitored.

In patients with CHF or arterial hypertension with unilateral or bilateral renal artery stenosis, when treated with ACE inhibitors, an increase in the concentration of blood urea nitrogen and serum creatinine was observed in some cases. These changes were almost always reversible and disappeared after discontinuation of the ACE inhibitor and/or diuretic. In such cases, renal function should be monitored during the first few weeks of treatment.

T1/2 of quinaprilat increases with a decrease in creatinine clearance. In patients with creatinine Cl less than 60 ml/min, Accupro® should be used at a lower initial dose. In such patients, the dose of the drug should be increased taking into account the therapeutic effect, with regular monitoring of renal function, although in clinical studies no further deterioration of renal function was noted during treatment with the drug.

Accupro® in combination with diuretics should be used with caution in patients with impaired function or progressive liver disease, because slight changes in water and electrolyte balance can cause the development of hepatic coma.

ACE inhibitors, including quinapril, may increase serum potassium levels.

Accupro® may reduce the hypokalemia caused by thiazide diuretics when used concomitantly. The use of Accupro® in combination therapy with potassium-sparing diuretics has not been studied. Given the risk of a further increase in serum potassium levels, combination therapy with potassium-sparing diuretics should be carried out with caution, under the control of serum potassium levels.

Patients with diabetes mellitus may require more careful monitoring and dosage adjustments of oral hypoglycemic agents and insulin, especially during the first month of therapy with ACE inhibitors, including quinapril.

When treated with ACE inhibitors, including quinapril, the development of cough was noted. Typically, it is nonproductive, persistent, and resolves upon cessation of therapy. In the differential diagnosis of cough, its possible connection with ACE inhibitors should be taken into account.

Before surgery (including dentistry), the surgeon/anesthesiologist must be warned about the use of ACE inhibitors.

If any symptoms of infection appear (for example, acute tonsillitis, fever), the patient should immediately consult a doctor, because they may be a manifestation of neutropenia.

Impact on the ability to drive vehicles and operate machinery.

When using Accupro®, caution should be exercised when driving or performing other work that requires increased attention, especially at the beginning of treatment.

Use of the drug Accupro

Arterial hypertension (AH) Monotherapy: the recommended initial dose of Accupro for patients who do not take diuretics is 10–20 mg once a day. Depending on the clinical effect, the dose may be increased to 20–40 mg/day in 1–2 doses. If necessary, dose adjustments can be made at intervals of 2–4 weeks. Effective blood pressure control in most patients is achieved by taking the drug once a day. The maximum dose of quinapril is 80 mg/day.

Co-administration of diuretics: in patients who must continue treatment with diuretics, the initial recommended dose of Accupro is 5 mg; later it can be gradually increased until the optimal effect is achieved.

Congestive heart failure The recommended starting dose is 5 mg in 1–2 divided doses. If the initial dose of quinapril is well tolerated, it can be gradually increased to an effective dose, usually 10–40 mg/day in 2 equal doses. Elimination of quinapril depends on the functional state of the kidneys. The recommended starting dose of Accupro in patients with creatinine clearance above 30 ml/min is 5 mg, and in patients with creatinine clearance less than 30 ml/min - 2.5 mg. If the initial dose is well tolerated, the drug can be taken 2 times a day from the next day. In the absence of excessive hypotension or significant deterioration in renal function, the dose may be increased at 1-week intervals based on clinical and hemodynamic effect.

Accupro tab ppo 10mg No. 30

The drug should be prescribed with caution to patients with symptomatic arterial hypotension, who have previously taken diuretics and are on a diet with limited salt intake; for severe heart failure in patients at high risk of severe arterial hypotension; with a decrease in the volume of bcc (including with vomiting or diarrhea); with hyperkalemia; inhibition of bone marrow hematopoiesis; with aortic stenosis, hypertrophic obstructive cardiomyopathy, mitral stenosis; with cerebrovascular insufficiency, coronary artery disease, coronary insufficiency (a sharp decrease in blood pressure during therapy with ACE inhibitors can worsen the course of these diseases); condition after kidney transplantation, with bilateral renal artery stenosis or stenosis of the artery of a single kidney; with impaired renal function; in patients on hemodialysis (creatinine clearance less than 10 ml/min), because there is insufficient data on the use of Accupro® in such patients; for severe autoimmune systemic connective tissue diseases (including SLE, scleroderma); in case of liver dysfunction (especially when used simultaneously with a diuretic); in combination therapy with a potassium-sparing diuretic; for diabetes mellitus; extensive surgical interventions and general anesthesia; while taking other antihypertensive drugs, as well as mTOR and DPP-4 enzyme inhibitors.

Directions for use and doses

The drug is taken orally, regardless of food intake. The tablets should be swallowed whole, without chewing, with water.

When conducting monotherapy for arterial hypertension, the recommended initial dose of Accupro® in patients not receiving diuretics is 10 mg 1 time / day. Depending on the clinical effect, the dose can be increased (doubling) to a maintenance dose of 20 mg/day or 40 mg/day, which is usually prescribed in 1 or 2 doses. As a rule, the dose should be changed at intervals of 4 weeks. In most patients, the use of Accupro® 1 time per day allows achieving a stable therapeutic response. The maximum daily dose is 80 mg.

When combined with diuretics, the recommended initial dose of Accupro® in patients continuing to take diuretics is 5 mg 1 time / day, subsequently increased (as indicated above) until the optimal effect is achieved.

For chronic heart failure, the recommended initial dose of Accupro® is 5 mg 1 or 2 times a day. After taking the drug, the patient should be monitored for symptomatic hypotension. If the initial dose of Accupro® is well tolerated, it can be increased to 10-40 mg/day, divided into 2 doses.

Taking into account clinical and pharmacokinetic data in patients with impaired renal function, it is recommended to select the initial dose as follows.

The recommended starting dose of Accupro® in elderly patients is 10 mg 1 time/day; subsequently it is increased until the optimal therapeutic effect is achieved.

Storage conditions

Store out of the reach of children at a temperature not exceeding 25 °C.

Best before date

3 years. Do not use after the expiration date stated on the package.

special instructions

Angioedema of the tissues of the head and neck
During treatment with ACE inhibitors, cases of angioedema in the head and neck area have been described, including in 0.1% of patients receiving Accupro®. If a guttural whistle or angioedema of the face, tongue or vocal folds occurs, Accupro® should be discontinued immediately. The patient must be given adequate treatment and observed until symptoms of edema resolve. Antihistamines may be used to reduce symptoms. Angioedema involving the larynx can be fatal. If swelling of the tongue, vocal folds or larynx threatens the development of airway obstruction, adequate emergency therapy is necessary, including subcutaneous administration of a solution of epinephrine (adrenaline) 1:1000 (0.3-0.5 ml).

Patients receiving concomitant therapy with mTOR enzyme inhibitors (eg, temsirolimus) or DPP-4 inhibitors (gliptins) or neutral endopeptidase inhibitors (NEP) or estramustine may be at greater risk of developing angioedema. Caution should be exercised when using these drugs simultaneously with Accupro®.

Angioedema of the intestinal walls

Cases of intestinal angioedema have also been described during treatment with ACE inhibitors. Patients reported abdominal pain (with/without nausea or vomiting); in some cases without previous angioedema of the face and normal C1-esterase activity. Diagnosis was made using abdominal computed tomography, ultrasound, or at the time of surgery. Symptoms disappeared after stopping the ACE inhibitors. Therefore, in patients with abdominal pain taking ACE inhibitors, when establishing a differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine.

Patients with a history of angioedema not associated with an ACE inhibitor may be at increased risk of developing it when treated with drugs of this group.

Anaphylactoid reactions

Patients receiving ACE inhibitors during desensitization therapy with hymenoptera venom may develop life-threatening anaphylactoid reactions. By temporarily stopping the use of ACE inhibitors, these reactions were avoided, but they occurred again with accidental use of these drugs.

Anaphylactoid reactions may also occur with the use of ACE inhibitors in patients undergoing low-density lipoprotein absorption apheresis with dextran sulfate or in patients undergoing hemodialysis using high-flux membranes such as polyacrylonitrile. Therefore, such combinations should be avoided by using either other antihypertensive drugs or alternative hemodialysis membranes.

Arterial hypotension

Symptomatic arterial hypotension rarely occurs during treatment with Accupro in patients with uncomplicated arterial hypertension, but it can develop as a result of therapy with ACE inhibitors in patients with reduced blood volume, for example, when following a diet with limited salt intake, hemodialysis. If symptomatic arterial hypotension occurs, it is necessary to carry out symptomatic therapy (the patient should be laid down, legs elevated and, if necessary, given an intravenous infusion using 0.9% sodium chloride solution). Transient arterial hypotension is not a contraindication to further use of the drug, however, in such cases, its dose should be reduced or the advisability of simultaneous therapy with diuretics should be assessed.

Other causes of decreased blood volume, such as vomiting or diarrhea, can also lead to a pronounced decrease in blood pressure. In such cases, patients should consult a doctor. In patients receiving diuretics, the use of Accupro® may also lead to the development of symptomatic arterial hypotension. It is advisable for such patients to temporarily stop taking the diuretic 2-3 days before starting treatment with Accupro®, except for patients with malignant or difficult-to-treat hypertension. If monotherapy with Accupro® does not provide the required therapeutic effect, then treatment with diuretics should be resumed. If it is impossible to cancel the diuretic, then Accupro® is used in a low initial dose.

In patients with chronic heart failure who are at increased risk of severe hypotension, treatment with Accupro® should be started at the recommended dose under close medical supervision; Patients should be observed during the first two weeks of treatment, as well as in all cases when the dose of Accupro® is increased.

Agranulocytosis

When treated with ACE inhibitors in patients with uncomplicated arterial hypertension, in rare cases, agranulocytosis developed, which was more common in patients with impaired renal function and connective tissue diseases. Agranulocytosis rarely developed during treatment with Accupro®. When using this drug (as well as other AI1P inhibitors) in patients with connective tissue diseases and/or kidney disease, the number of leukocytes in the blood should be monitored.

Renal dysfunction

In susceptible patients, suppression of RAAS activity may lead to renal dysfunction. In patients with severe chronic heart failure, in whom renal function may be dependent on the activity of the RAAS, treatment with ACE inhibitors, including quinapril, may be accompanied by oliguria and/or progressive azotemia, and in rare cases, acute renal failure and/or death.

The use of ARA II, ACE inhibitors or aliskiren can lead to a “double” blockade of RAAS activity. This effect may be manifested by a decrease in blood pressure, hyperkalemia and changes in renal function (including acute renal failure) compared with monotherapy. Blood pressure, renal function and plasma electrolyte levels should be carefully monitored in patients taking Accupro® and other drugs that affect the RAAS. The simultaneous use of RAAS-active agents and quinapril should be avoided. If it is necessary to use this combination, the ratio of the expected benefit to the possible risk of using the combination should be assessed in each individual case and renal function and potassium levels should be regularly monitored.

In patients with chronic heart failure or arterial hypertension with unilateral or bilateral renal artery stenosis, an increase in blood urea nitrogen and serum creatinine was observed in some cases during treatment with ACE inhibitors. These changes were almost always reversible and disappeared after discontinuation of the ACE inhibitor and/or diuretic. In such cases, renal function should be monitored during the first few weeks of treatment.

The half-life of quinaprilat increases with a decrease in CC. In patients with CC less than 60 ml/min, Accupro® should be used at a lower initial dose. In such patients, the dose of the drug should be increased taking into account the therapeutic effect, with regular monitoring of renal function, although in clinical studies no further deterioration of renal function was observed during treatment with the drug.

Liver dysfunction

Accupro® in combination with diuretics should be used with caution in patients with impaired function or progressive liver disease, since small changes in water and electrolyte balance can cause the development of hepatic coma. Hyperkalemia

ACE inhibitors, including quinapril, may increase serum potassium levels.

The use of Accupro® in combination therapy with potassium-sparing diuretics has not been studied. Given the risk of a further increase in serum potassium, combination therapy with potassium-sparing diuretics or other drugs that increase serum potassium should be carried out with caution, under monitoring of serum potassium levels. Accupro® may reduce the hypokalemia caused by thiazide diuretics when used concomitantly.

Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIAD)

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and subsequent hyponatremia have been observed in some patients treated with other ACE inhibitors. It is recommended to regularly monitor serum sodium concentrations in elderly patients, as well as in patients of all age groups, for the risk of hyponatremia.

Hypoglycemia and diabetes mellitus

Patients with diabetes mellitus may require closer monitoring and dosage adjustments of oral hypoglycemic agents and insulin, especially during the first month of ACE inhibitor therapy, including quinapril.

Cough

When treated with ACE inhibitors, including quinapril, the development of cough was noted. Typically, it is nonproductive, persistent, and resolves upon cessation of therapy. In the differential diagnosis of cough, its possible connection with ACE inhibitors should be taken into account.

Patients undergoing surgery and/or anesthesia

Before surgery (including dentistry), the surgeon/anesthesiologist must be warned about the use of ACE inhibitors.

Neutropenia

If any symptoms of infection (eg, acute tonsillitis, fever) appear, the patient should consult a doctor immediately, as they may be a manifestation of neutropenia.

Conditions that impede the outflow of blood from the left ventricle

The use of Accupro® is contraindicated in patients with a condition that impedes the outflow of blood from the left ventricle (aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy).

Kidney transplant

The use of Accupro® is contraindicated in patients after kidney transplantation

Ethnic differences

ACE inhibitors are more likely to cause angioedema in black patients than in Caucasian patients. As with other ACE inhibitors, quinapril may be less effective in lowering blood pressure in black patients.

Elderly patients

Especially at the beginning of treatment, Accupro® should always be used in combination with careful monitoring of blood pressure and/or representative laboratory parameters.

Description

ACE inhibitor.

Dosage form

White film-coated tablets, triangular, biconvex, with a score line on both sides and the number “10” on one side.

Use in children

Contraindication: age under 18 years.

Pharmacodynamics

Antihypertensive drug, ACE inhibitor.
ACE catalyzes the conversion of angiotensin I to angiotensin II, which has a vasoconstrictor effect and increases vascular tone, incl. due to stimulation of aldosterone production by the adrenal cortex. Quinapril competitively inhibits ACE activity and reduces vasopressor activity and aldosterone production. Elimination of the negative effect of angiotensin II on renin secretion via a feedback mechanism leads to an increase in plasma renin activity. In this case, a decrease in blood pressure is accompanied by a decrease in peripheral vascular resistance and renal vascular resistance, while changes in heart rate, cardiac output, renal blood flow, glomerular filtration rate and filtration fraction are insignificant or absent.

Quinapril increases exercise tolerance. With long-term use, it helps reverse the development of myocardial hypertrophy in patients with arterial hypertension; improves blood supply to ischemic myocardium. Strengthens coronary and renal blood flow. Reduces platelet aggregation.

After taking a single dose, the antihypertensive effect develops after 1 hour and reaches a maximum after 2-4 hours. The duration of action depends on the size of the dose taken (up to 24 hours). A clinically pronounced effect develops several weeks after the start of therapy.

Side effects

Adverse reactions when using Accupro® are usually mild and transient.
The most common symptoms are headache (7.2%), dizziness (5.5%), cough (3.9%), fatigue (3.5%), rhinitis (3.2%), nausea and/or vomiting (2.8%), myalgia (2.2%) . It should be noted that in a typical case, the cough is non-productive, persistent and resolves after cessation of treatment. The incidence of discontinuation of the drug Accupro® as a result of adverse reactions was observed in 5.3% of cases.

Adverse reactions are distributed by organ system and frequency of occurrence (WHO classification): very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100) , rare (from >1/10,000 to <1/1000), very rare (from <1/10,000, including isolated reports).

From the nervous system: often - headache, dizziness, insomnia, paresthesia, increased fatigue; infrequently - depression, increased excitability, drowsiness, vertigo.

From the digestive system: often - nausea and/or vomiting, diarrhea, dyspepsia, abdominal pain; uncommon - dryness of the mucous membrane of the mouth or throat, flatulence, pancreatitis*, angioedema of the intestines, gastrointestinal bleeding; rarely - hepatitis.

From the hematopoietic system: uncommon - hemolytic anemia*, thrombocytopenia*.

From the cardiovascular system: often - a pronounced decrease in blood pressure; uncommon - angina pectoris, palpitations, tachycardia, heart failure, myocardial infarction, stroke, increased blood pressure, cardiogenic shock, postural hypotension*, fainting*, symptoms of vasodilation.

From the respiratory system, chest and mediastinal organs: often - cough, dyspnea, pharyngitis, chest pain.

From the skin and subcutaneous tissues: uncommon - alopecia*, exfoliative dermatitis*, increased sweating, pemphigus*, photosensitivity reactions*, itching, rash.

From the musculoskeletal system: often - back pain; infrequently - arthralgia.

From the urinary system: infrequently - urinary tract infections, acute renal failure.

From the reproductive system: infrequently - decreased potency.

From the side of the organ of vision: infrequently - visual impairment.

Allergic reactions: uncommon - anaphylactic reactions*; rarely - angioedema.

Laboratory indicators: agranulocytosis and neutropenia were very rarely noted, although a cause-and-effect relationship with the use of Accupro® has not yet been established.

Creatinine and blood urea nitrogen: increases (more than 1.25 times the ULN) in serum creatinine and blood urea nitrogen concentrations were observed in 2% and 2% of patients receiving Accupro monotherapy, respectively. The likelihood of an increase in these indicators in patients simultaneously receiving diuretics is higher than when using Accupro® alone. With further therapy, indicators often return to normal.

General reactions: uncommon - edema (peripheral or generalized), malaise, viral infections.

Other: rarely - eosinophilic pneumonitis.

With the simultaneous use of ACE inhibitors and gold preparations (sodium aurothiomalate, IV), a symptom complex has been described, including facial flushing, nausea, vomiting and decreased blood pressure.

* - less frequent adverse events or those noted during post-marketing studies.

Use during pregnancy and breastfeeding

Pregnancy
The use of Accupro® is contraindicated during pregnancy, in women planning pregnancy, as well as in women of reproductive age who do not use reliable methods of contraception.

Women of reproductive age taking Accupro® should use reliable methods of contraception.

If pregnancy is diagnosed, Accupro® should be discontinued as early as possible.

The use of ACE inhibitors during pregnancy is accompanied by an increased risk of developing abnormalities in the cardiovascular and nervous systems of the fetus. In addition, while taking ACE inhibitors during pregnancy, cases of oligohydramnios, premature birth, birth of children with arterial hypotension, kidney pathology (including acute renal failure), hypoplasia of the skull bones, contractures of the extremities, craniofacial deformities, pulmonary hypoplasia, delayed intrauterine development, patent ductus arteriosus, as well as cases of intrauterine fetal death and death of a newborn. Often, oligohydramnios is diagnosed after the fetus has been irreversibly damaged.

Neonates exposed to ACE inhibitors in utero should be monitored for hypotension, oliguria, and hyperkalemia. If oliguria occurs, blood pressure and renal perfusion should be maintained.

Breastfeeding period

A small amount of pharmacokinetic data suggests that human breast milk contains very low concentrations of Accupro®. However, although these concentrations appear to be clinically insignificant, Accupro® should not be used in breastfeeding premature newborns or in the first weeks after birth, as the potential risk of adverse effects on the cardiovascular system and kidneys cannot be excluded. infant, and there is no sufficient clinical experience of use during breastfeeding.

Interaction

Tetracycline and other drugs that interact with magnesium: simultaneous use of tetracycline with quinapril reduces the absorption of tetracycline by approximately 28-37% due to the presence of magnesium carbonate as an auxiliary component of the drug.
When used simultaneously, the possibility of such an interaction should be considered. Lithium: in patients simultaneously receiving lithium preparations and AIF inhibitors, an increase in serum lithium levels and signs of lithium toxicity due to increased sodium excretion were observed. These drugs should be used simultaneously with caution; During treatment, regular determination of lithium levels in blood serum is indicated. Concomitant use of diuretics may increase the risk of lithium toxicity.

Diuretics: with simultaneous use of quinairil with diuretics, an increase in antihypertensive effect is observed (see section "Special instructions").

Drugs that increase serum potassium: If potassium-sparing diuretics (for example, spironolactone, triamterene or amiloride), potassium supplements, salt substitutes containing potassium, and other drugs that increase serum potassium are indicated in a patient receiving quinairil, then they should be used carefully under monitoring the potassium content in the blood serum. In elderly patients and patients with impaired renal function, concomitant use of ACE inhibitors with sulfamethoxazole/trimethoprim was associated with severe hyperkalemia, which is believed to be caused by trimethoprim. Therefore, quinapril should be used with caution simultaneously with drugs containing trimethoprim, constantly monitoring the potassium level in the blood plasma.

Ethanol (drinks containing alcohol): Ethanol enhances the antihypertensive effect of quinapril.

Oral hypoglycemic agents and insulin: Therapy with ACE inhibitors is sometimes accompanied by the development of hypoglycemia in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents. Quinapril enhances the effect of oral hypoglycemic agents and insulin.

Cyclosporine: Hyperkalemia may occur when ACE inhibitors are used concomitantly with cyclosporine. Monitoring serum potassium levels is recommended.

Heparin: Hyperkalemia may occur when ACE inhibitors are used concomitantly with heparin. Monitoring serum potassium levels is recommended.

Antacids: may reduce the bioavailability of quinapril.

Neuroleptics: enhancing the hypotensive effect of Accupro®.

Systemic corticosteroids: decrease in the number of white blood cells in the blood (leukopenia).

Other drugs:

Quinapril increases the risk of developing leukopenia when used simultaneously with allopurinol, cytostatic agents, immunosuppressants, and procainamide. Antihypertensive drugs, narcotic analgesics, drugs for general anesthesia enhance the antihypertensive effect of quinapril.

Estrogens and nonsteroidal anti-inflammatory drugs (NSAIDs) (including selective cyclooxygenase-2 (COX-2) inhibitors) weaken the antihypertensive effect of quinapril due to fluid retention. The antihypertensive effect of quinapril may be reduced when using acetylsalicylic acid. The use of quinapril in combination with acetylsalicylic acid in low doses (used as an antiplatelet agent) is not contraindicated.

In addition, in elderly patients, in patients with reduced blood volume (including patients receiving diuretic therapy) or in patients with impaired renal function, concomitant use of NSAIDs (including selective COX-2 inhibitors, with ACE inhibitors, including quinapril, may cause to a deterioration in renal function, including possible acute renal failure.Renal function should be regularly monitored in patients receiving NSAIDs and quinapril concomitantly.

The use of ARA II, ACE inhibitors or aliskiren can lead to a “double” blockade of RAAS activity. This effect may be manifested by a decrease in blood pressure, hyperkalemia and changes in renal function (including acute renal failure) compared with monotherapy.

Do not use quinapril simultaneously with aliskiren and aliskiren-containing drugs or with ARA II or with other drugs that inhibit the RAAS (dual blockade of the RAAS):

• in patients with diabetes mellitus or in patients with diabetes mellitus with target organ damage (diabetic nephropathy);
• in patients with impaired renal function (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2);
• in patients with hyperkalemia (more than 5 mmol/l);
• in patients with chronic heart failure and arterial hypertension.

Medicines that cause bone marrow suppression increase the risk of developing neutropenia and/or agranulocytosis.
With the simultaneous use of ACE inhibitors and gold preparations (sodium aurothiomalate, intravenously), a symptom complex has been described, including facial flushing, nausea, vomiting and decreased blood pressure.

Patients receiving concomitant therapy with mTOR enzyme inhibitors (eg, temsirolimus) or DPP-4 inhibitors (gliptins) or neutral endopeptidase inhibitors (NEP) or estramustine may be at greater risk of developing angioedema. Caution should be exercised when using these drugs simultaneously with Accupro®.

Neutral endopeptidase inhibitors: An increased risk of angioedema has been reported with concomitant use of ACE inhibitors and racecadotril (an enkephalinase inhibitor).

When ACE inhibitors are used simultaneously with drugs containing sacubitril (neprilysin inhibitor), the risk of developing angioedema increases, and therefore the simultaneous use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril.

Prescription of drugs containing sacubitril is contraindicated in patients receiving ACE inhibitors, as well as within 36 hours after discontinuation of ACE inhibitors.

Tissue plasminogen activators: Observational studies have shown an increased incidence of angioedema in patients taking ACE inhibitors following the use of alteplase for thrombolytic therapy of ischemic stroke.

Pharmacokinetic interactions of quinapril: There were no signs of clinically significant pharmacokinetic interactions of quinapril with propranolol, hydrochlorothiazide, digoxin or cimetidine.

The use of quinapril 2 times a day did not significantly affect the anticoagulant effect of warfarin when administered once (assessed based on prothrombin time).

When simultaneous repeated use of atorvastatin at a dose of 10 mg with quinapril at a dose of 80 mg did not lead to significant changes in the equilibrium pharmacokinetic parameters of atorvastatin.

Overdose

Symptoms: marked decrease in blood pressure, dizziness, weakness, visual impairment.
Treatment is symptomatic. The patient should take a horizontal position; it is advisable to administer an intravenous infusion using 0.9% sodium chloride solution (to increase the volume of blood volume).

Hemodialysis and peritoneal dialysis are not effective.

Impact on the ability to drive vehicles and operate machinery

When using Accupro®, caution should be exercised when driving or performing other work that requires increased attention, especially at the beginning of treatment.

Side effects of the drug Accupro

Usually mild and short-lived. The most common side effects observed in controlled trials were headache (7.2%), dizziness (5.5%), cough (3.9%), fatigue (3.5%), rhinitis (3.2%). ), nausea and/or vomiting (2.8%), myalgia (2.2%). It should be noted that the cough is usually non-productive and persistent and disappears after cessation of therapy. Clinically, adverse reactions are probably, possibly or definitely associated or uncertainly associated with quinapril therapy (with or without concomitant diuretic therapy) in controlled and uncontrolled studies and less frequently reported in clinical studies or after registration surveillance * include.

Disorders of the hematopoietic and lymphatic system : hemolytic anemia*, thrombocytopenia*. From the immune system: anaphylactoid reactions*. From the side of the central nervous system: vertigo, nervousness, depression, drowsiness. From the organ of vision: amblyopia. From the cardiovascular system: angina pectoris, palpitations, tachycardia, postural hypotension*, syncope*, vasodilation. From the digestive system: dry mouth or throat, flatulence, pancreatitis*. For the skin: alopecia*, exfoliative dermatitis*, itching, increased sweating, pemphigus*, photosensitivity reactions*, skin rash. From the musculoskeletal system: arthralgia From the genitourinary system: urinary tract infections, impotence. General disorders and reactions at the injection site: edema (peripheral and generalized), Isolated side effects: angioedema* was observed in 0.1% of patients using quinapril. Sometimes, as with the use of other ACE inhibitors, eosinophilic pneumonitis* and hepatitis were observed with the use of quinapril. Results of clinical laboratory tests: rarely - agranulocytosis and neutropenia (their cause-and-effect relationship with the use of quinapril is unreliable), hyperkalemia. Creatinine and blood urea nitrogen. Increases (more than 1.25 times the upper limit of normal) in serum creatinine and urea nitrogen levels were observed in 2 and 2% of cases, respectively, during quinapril therapy. An increase is more likely in patients receiving the drug in combination with diuretics than in patients receiving quinapril monotherapy. Angioedema. Angioedema has been reported in patients receiving ACE inhibitors (including 0.1% of patients receiving quinapril). If the patient develops angioedema of the larynx, face, tongue, use of quinapril should be stopped immediately; the patient should be given adequate therapy and observed until the swelling completely disappears. If swelling appears only on the face and lips, specific treatment is not required in most cases; To eliminate symptoms, it is advisable to use antihistamines. Angioedema of the tongue, larynx and glottis can be life-threatening. If it develops, appropriate emergency therapy should be immediately prescribed, necessarily including the subcutaneous administration of 0.3–0.5 ml of adrenaline (epinephrine) solution (1:1000). Patients with a history of angioedema not related to ACE inhibitor therapy are also at increased risk of angioedema during treatment with an ACE inhibitor. In patients of the Negroid race who were treated with ACE inhibitors, cases of angioedema were more common than in patients of other races. In patients of the Negroid race, a slightly smaller effect of ACE inhibitors on blood pressure was also noted compared to other races. Intestinal angioedema. In patients using ACE inhibitors, manifestations of intestinal angioedema were observed. Such patients complained of abdominal pain (with/without nausea or vomiting); in some cases, there was no indication in the anamnesis of the development of angioedema of the face and a normal level of C-1 esterase was determined. The diagnosis of angioedema was made using abdominal computed tomography or ultrasound or during surgery. These manifestations disappeared after stopping the drug. Intestinal angioedema should be included in the differential diagnosis in patients with abdominal pain who are receiving ACE inhibitor therapy. Patients with a history of angioedema not related to ACE inhibitor therapy may have an increased risk of angioedema during treatment with an ACE inhibitor. Anaphylactoid reactions. Desensitization . Life-threatening anaphylactoid reactions have been observed in patients receiving ACE inhibitors during desensitization therapy to Hymenoptera venom. In some patients, these reactions did not occur during a temporary break in taking ACE inhibitors, but occurred again with an accidental re-provocation. Low-density lipoprotein apheresis. In patients who underwent LDL apheresis with dextran sulfate absorption, anaphylactoid reactions were observed with concomitant therapy with an ACE inhibitor. Hemodialysis Clinical data have shown that patients undergoing hemodialysis using certain types of high-flux membranes (polyacrylonitrile membranes) may develop anaphylactoid reactions while receiving an ACE inhibitor. This combination should be avoided by using alternative antihypertensive drugs or alternative hemodialysis membranes. Arterial hypotension. In patients with uncomplicated hypertension (arterial hypertension) receiving Accupro, hypotension rarely developed, but it was a likely consequence of therapy with ACE inhibitors in patients with impaired water and electrolyte balance due to taking diuretics, following a low-salt diet, or dialysis. In patients with congestive heart failure, in whom the risk of developing severe hypotension is particularly high, treatment with quinapril should be initiated at the recommended dose under medical supervision; These patients should be monitored during the first 2 weeks of treatment and whenever the dose of quinapril is increased. If symptomatic hypotension develops, the patient should be placed on his back and, if necessary, given an intravenous infusion of isotonic sodium chloride solution. A short-term hypotensive reaction is not a contraindication for further use of the drug; however, if such a reaction develops, the use of lower doses of the drug or discontinuation of diuretics should be considered. Patients who received diuretic therapy at the beginning of treatment with quinapril may develop symptomatic hypotension. It is advisable to discontinue the diuretic 2–3 days before starting treatment with quinapril. If blood pressure is not controlled with quinapril monotherapy, diuretics should be resumed. If the use of diuretics cannot be avoided, the use of Accupro should be started with a low initial dose. Neutropenia and agranulocytosis . Taking ACE inhibitors can sometimes be accompanied by agranulocytosis and bone marrow depression in patients with uncomplicated hypertension (arterial hypertension), but more often occurs, as a rule, in patients with renal failure, as well as collagen diseases. When using ACE inhibitors in patients with collagen diseases and/or renal failure, regular monitoring of the leukocyte count is necessary. Cough. Cough has sometimes occurred in patients using ACE inhibitors, including quinapril. Usually the cough was non-productive, persistent and disappeared after cessation of therapy. Cough induced by the use of ACE inhibitors should be considered in the differential diagnosis of cough.

Instructions for use of ACCUPRO

Angioedema of the head and neck

developed in 0.1% of patients receiving quinapril. If laryngeal stridor or angioedema of the face, tongue or glottis develops, quinapril/hydrochlorothiazide should be discontinued immediately. The patient must be treated in accordance with generally accepted treatment methods. The patient should remain under close observation until symptoms of swelling disappear. In cases where the swelling is limited to the face and lips, the disorder usually resolves without special treatment; Antihistamines may be used to relieve symptoms. Angioedema, which includes swelling of the larynx, can be fatal. In cases of swelling of the tongue, glottis and larynx, in which airway obstruction is likely to occur, appropriate emergency therapy should be immediately prescribed, incl. subcutaneous injection of epinephrine (adrenaline) solution 1:

• 1000 (0.3-0.5 ml).

Black patients treated with ACE inhibitors have a higher incidence of angioedema compared to patients of other races. It should also be noted that, in accordance with data from controlled clinical trials, the effectiveness of ACE inhibitors in black patients was less compared to the effectiveness in patients of other races. The incidence of angioedema in blacks and patients of color during treatment with quinapril was calculated in two large open-label clinical trials that assessed the effectiveness of quinapril in the treatment of hypertension. In one study including 1,656 blacks and 10,583 patients of other races, the incidence of angioedema, regardless of association with quinapril treatment, was 0.3% in black patients and 0.39% in patients of other races. In another trial (1443 blacks and 9300 patients of other races), the incidence of angioedema was 0.55% in blacks and 0.17% in patients of other races.

of intestinal angioedema have been described in patients treated with ACE inhibitors

. In such cases, abdominal pain appeared (with or without nausea and vomiting); in some cases, patients had no previous history of facial angioedema and C1-esterase levels were normal. The diagnosis of angioedema was made based on studies including abdominal computed tomography, ultrasound, or surgery. After stopping the ACE inhibitors, the symptoms disappeared. Angioedema of the intestine should be included in the list of disorders for differential diagnosis in patients taking ACE inhibitors and complaining of abdominal pain.

Patients with a history of angioedema not associated with the use of ACE inhibitors may have an increased risk of developing this disorder when treated with an ACE inhibitor.

Anaphylactoid reactions.

In patients taking ACE inhibitors, long-lasting life-threatening anaphylactoid reactions occur during desensitizing therapy with hymenoptera venom. Temporary discontinuation of ACE inhibitors avoided anaphylactoid reactions in such patients, but they reoccurred if these drugs were taken carelessly.

Anaphylactoid reactions have been reported in patients undergoing LDL apheresis using dextran sulfate during treatment with ACE inhibitors.

Clinical data have shown that patients undergoing hemodialysis using certain types of high-flux membranes (such as polyacrylonitrile membranes) with concomitant therapy with ACE inhibitors are likely to develop anaphylactoid reactions. To avoid such a combination, antihypertensive drugs of other groups or other types of membranes for hemodialysis should be used.

Symptomatic hypotension

in patients with uncomplicated arterial hypertension during treatment with quinapril, it was rarely observed, but it is a possible consequence of treatment with ACE inhibitors in patients with a decrease in salt content and extracellular fluid volume, for example, after treatment with diuretics, while on a salt-restricted diet, or during hemodialysis.

In patients receiving a diuretic, when quinapril is prescribed, symptomatic arterial hypotension may develop. In such cases, it is important, if possible, to stop taking the diuretic 2-3 days before starting treatment with quinapril. If taking quinapril alone does not provide a sufficient antihypertensive effect, diuretic treatment should be resumed. If the diuretic cannot be discontinued, then quinapril is prescribed at a low initial dose.

In patients with congestive heart failure who are at risk of developing severe arterial hypotension, treatment with quinapril should be initiated at the recommended dose under close medical supervision. Particularly careful clinical monitoring is required during the first 2 weeks of treatment and in all cases of increasing the dose of quinapril.

If symptomatic arterial hypotension develops, the patient should be placed and, if necessary, given an isotonic solution intravenously. The development of transient arterial hypotension is not a contraindication for continued treatment; however, in this case, it is necessary to consider the advisability of reducing the dose of quinapril or concomitant diuretic therapy.

Treatment with ACE inhibitors in patients with uncomplicated arterial hypertension has in rare cases been accompanied by suppression of bone marrow hematopoiesis and agranulocytosis.

These adverse reactions were more common in patients with impaired renal function, especially in connective tissue diseases. Agranulocytosis rarely developed during treatment with quinapril. As with the treatment of other ACE inhibitors, when using quinapril in patients with connective tissue diseases and/or kidney disease, the number of leukocytes in the blood should be monitored.

In susceptible patients, suppression of the RAAS may lead to changes in renal function. In patients with severe heart failure, in whom renal function may be dependent on the activity of the RAAS, treatment with quinapril may be accompanied by oliguria and/or increasing azotemia and, rarely, acute renal failure with a fatal outcome.

T1/2 of quinapril increases as CC decreases. In patients with CC <60 ml/min, quinapril should be prescribed at a lower initial dose. In such patients, the dose should be gradually increased based on the therapeutic effect while monitoring renal function, although in clinical studies no further deterioration of renal function was observed during treatment with the drug.

In some patients with hypertension or heart failure without obvious signs of renal vascular disease, increases in serum urea nitrogen and creatinine levels were observed when treated with Accupro, especially in combination with a diuretic, which was usually mild and reversible. The risk of such changes is higher in patients with impaired renal function. In such cases, it may be necessary to reduce the dose and/or discontinue the diuretic and/or quinapril.

In patients with arterial hypertension with unilateral or bilateral renal artery stenosis, when treated with ACE inhibitors, an increase in blood urea nitrogen and serum creatinine levels was observed in some cases. These changes were almost always reversible and disappeared after discontinuation of the ACE inhibitor and/or diuretic. In such cases, renal function should be monitored during the first few weeks of treatment.

Quinapril in combination with a diuretic should be used with caution in patients with impaired function or progressive liver disease, because slight changes in water and electrolyte balance can cause the development of hepatic coma.

The metabolism of quinapril to quinaprilate normally occurs under the action of hepatic esterase. Quinapril concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril.

In patients receiving quinapril, like other ACE inhibitors, there may be an increase in serum potassium levels. When quinapril is administered concomitantly with thiazide diuretics, quinapril is able to reduce the hypokalemia caused by these diuretics. Given the risk of a further increase in serum potassium levels, combination therapy with potassium-sparing diuretics should be carried out cautiously while monitoring serum potassium levels.

Therapy with ACE inhibitors has sometimes been associated with the development of hypoglycemia in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents; patients with diabetes mellitus may require more careful monitoring and dosage adjustment of hypoglycemic drugs.

When treated with ACE inhibitors, including quinapril, the development of cough was noted. Typically, it is nonproductive, persistent, and resolves upon cessation of therapy. In the differential diagnosis of cough, its possible connection with ACE inhibitors should be taken into account.

In patients undergoing surgery or general anesthesia, ACE inhibitors should be used with caution because they block the formation of angiotensin II caused by compensatory secretion of renin. This can lead to arterial hypotension, which is eliminated by administering plasma expanders.

Patients should be warned that insufficient fluid intake, increased sweating, or dehydration may lead to an excessive decrease in blood pressure due to a decrease in blood volume. Other causes of dehydration, such as vomiting or diarrhea, can also lead to a marked decrease in blood pressure. In such cases, patients should consult a doctor.

If any symptoms of infection (for example, sore throat, fever) appear, the patient should immediately consult a doctor, as they may be a manifestation of neutropenia.

Use in pediatrics

Safety and effectiveness of quinapril in children and adolescents under 18 years of age

not installed.

Patient Information

Angioedema.

In patients taking ACE inhibitors, incl. Angioedema, including laryngeal edema, may occur with Accupro, especially after the first dose. Patients should be instructed to stop taking Accupro immediately if they experience the first signs or symptoms suggesting the onset of angioedema (eg, swelling of the face, extremities, eyelids, lips, tongue; difficulty swallowing or breathing).

Arterial hypotension.

Patients should be warned about the possibility of mild dizziness, especially in the first days of taking Accupro. If fainting occurs, the patient should stop taking the drug and consult a doctor.

All patients should be warned that insufficient fluid intake, increased sweating, or dehydration may lead to an excessive decrease in blood pressure due to a decrease in blood volume. Other causes of dehydration, such as vomiting or diarrhea, can also lead to a marked decrease in blood pressure. In such cases, patients should consult a doctor.

Surgical interventions/anesthesia.

Patients should be warned that if they are undergoing surgery and/or anesthesia, they should tell their doctor that they are taking ACE inhibitors.

Hyperkalemia.

Patients should be warned not to take any supplements or salt substitutes containing potassium without consulting a physician.

Neutropenia.

Patients should be warned that if any symptoms of infection (eg, sore throat, fever) occur, they should seek immediate medical attention as they may be a manifestation of neutropenia.

Patients should follow the recommendations for taking Accupro, which contributes to the safe and effective use of the drug.

Impact on the ability to drive vehicles and operate machinery

There may be a decrease in the ability to perform potentially hazardous activities, such as driving vehicles and operating machinery, especially at the beginning of treatment with Accupro.

Results of preclinical studies

LD50 in mice and rats after oral administration of quinapril is 1440-4280 mg/kg.

In studies in mice and rats, quinapril hydrochloride at doses up to 75–100 mg/kg/day (50–60 times the maximum daily dose for humans) was not carcinogenic when administered for 104 weeks. No mutagenic effect was detected for quinapril and quinaprilat when performing the Ames bacterial test with or without metabolic activation. Negative results for quinapril were also obtained in the following genetic toxicology studies:

• point mutation of mammalian cells in vitro, sister chromatid exchange in cultured mammalian cells, micronucleus test in mice, chromosomal aberration in vitro in cultured V79 lung cells, in vivo cytogenetic study in rat bone marrow. At doses up to 100 mg/kg/day (60 times the maximum daily dose for humans), no side effects on fertility or reproduction were detected in rats.

In a study in rats, despite maternal toxicity at a daily dose of 150 mg/kg, fetotoxicity and teratogenicity were not detected at daily doses of quinapril up to 300 mg/kg (180 times the maximum daily dose for humans). When quinapril was administered to rats in late pregnancy and during breastfeeding at a daily dose of 25 mg/kg or more, a decrease in the body weight of rat pups was observed. No teratogenic effect of quinapril was found in rabbits; however, as noted for other ACE inhibitors, maternal toxicity and embryotoxicity were observed in some rabbits when administered at low doses of 0.5 mg/kg/day and 1 mg/kg/day, respectively.

Special instructions for the use of Accupro

Decreased renal function: The half-life of quinaprilat increases as creatinine clearance decreases. Recommended starting doses for patients with impaired renal function are:

*There is no experience to date to date specific dosing recommendations for these patients.

In persons with hypersensitivity due to inhibition of the activity of the renin-angiotensin-aldosterone system, renal function may be impaired. In patients with severe heart failure in whom renal function is dependent on the activity of the renin-angiotensin-aldosterone system, therapy with ACE inhibitors, including quinapril, can lead to the development of oliguria and/or progressive azotemia and, rarely, acute renal failure, including death. The elimination period of quinaprilat is increased due to a decrease in creatinine clearance. In patients with creatinine clearance ≤60 ml/min, quinapril should be prescribed at a lower dose (see APPLICATION). In such patients, the dose of the drug should be titrated from low to higher, taking into account the therapeutic effect, and renal function should be regularly monitored (although initial studies did not reveal further deterioration of renal function with quinapril). In some patients with hypertension (arterial hypertension) or heart failure without obvious signs of renal vascular damage, an increase in serum urea nitrogen and creatinine levels was observed when treated with quinapril, especially in combination with a diuretic. This increase is usually minor and reversible when the ACE inhibitor and/or diuretic is discontinued. The risk of such changes is higher in patients with impaired renal function. In such cases, it may be necessary to reduce the dose and discontinue the diuretic and/or quinapril. In clinical studies of patients with hypertension (arterial hypertension) and unilateral or bilateral renal artery stenosis, an increase in blood urea nitrogen and serum creatinine was observed after therapy with an ACE inhibitor. This increase was almost always reversible when ACE inhibitor and/or diuretic therapy was discontinued. In such cases, it is necessary to monitor the patient's renal function during the first few weeks of therapy. Liver dysfunction. Quinapril in combination with a diuretic should be used with caution in patients with impaired function or progressive liver disease, since small changes in water and electrolyte balance may cause the development of hepatic coma. The metabolism of quinapril to quinaprilat normally occurs under the action of hepatic esterase. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. Hyperkalemia and potassium-sparing diuretics. Both with the use of other ACE inhibitors and with the use of quinapril, the level of potassium ions in the serum may increase. When used concomitantly, quinapril may reduce hypokalemia caused by thiazide diuretics. Studies of the combined use of quinapril and potassium-sparing diuretics have not been conducted. Because there is a risk of increased serum potassium concentrations, it is important that combination therapy in patients receiving potassium-sparing diuretic therapy is initiated cautiously with careful monitoring of serum potassium levels. Hypoglycemia and diabetes. The use of ACE inhibitors may be accompanied by hypoglycemia in diabetic patients who take insulin or oral hypoglycemic agents. Therefore, it is necessary to carefully monitor the condition of such patients. Surgery/anesthesiology. If surgical intervention is necessary, the anesthesiologist should be informed that the patient is taking quinapril, since severe arterial hypotension/collapse may develop. Use in elderly people. Age does not have a significant effect on the effectiveness and safety profile of the drug, therefore the recommended initial dose of Accupro in elderly patients is 10 mg 1 time per day; if necessary, it can be adjusted taking into account the level of blood pressure. Use during pregnancy and lactation When used during pregnancy, ACE inhibitors may cause fetal and neonatal morbidity and mortality. Before using quinapril during pregnancy, its possible adverse effects on the fetus should be considered. If pregnancy occurs while taking quinapril, the drug must be discontinued. Hypotension, renal failure, cranial hypoplasia and/or neonatal death have been reported when taking ACE inhibitors during the second and third trimesters of pregnancy. Oligohydroamnion has also been reported, likely due to decreased fetal renal function; in connection with this, contractures of the limbs, craniofacial deformities, pulmonary hypoplasia and intrauterine growth retardation were noted. If during the first trimester the embryo or fetus was influenced by the drug, the mother should be informed as early as possible about the degree of risk, even if the occurrence of side effects was not diagnosed. Women who used ACE inhibitors during the second and third trimesters of pregnancy should be informed of the potential risk to the fetus; To diagnose oligohydroamnion, frequent ultrasound examinations are necessary. In the case of diagnosis of oligohydroamnion, the use of quinapril must be discontinued; use can only be extended only if it is vital for the mother. Other potential risks to the fetus and newborn when using ACE inhibitors are intrauterine growth retardation, prematurity, and non-closure of the ductus arteriosus; Fetal death may also occur. However, it remains unknown what causes the development of such side effects - the use of the drug or concomitant diseases of the mother. It is also unknown what unfavorable factor acting in the first trimester of pregnancy can cause damage to the fetus. Infants whose mothers received an ACE inhibitor during pregnancy, and therefore the children were exposed to the intrauterine influence of ACE inhibitors, require observation to monitor hypotension, oliguria and hyperkalemia. If oliguria occurs, attention must be paid to maintaining blood pressure and renal perfusion. ACE inhibitors, including quinapril, are excreted in breast milk in limited quantities. Therefore, during treatment with Accupro, it is recommended to stop breastfeeding. Children. The safety and effectiveness of Accupro in pediatric patients have not been studied. The ability to influence the speed of reaction when driving vehicles and working with potentially dangerous mechanisms: The speed of reactions when driving vehicles or working with other mechanisms may be impaired at the beginning of treatment with Accupro.

Accupro tablets 10 mg No. 30

Compound

Active ingredient: 10 mg quinapril hydrochloride,
Excipients: magnesium carbonate, magnesium stearate, lactose, gelatin, crospovidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, titanium dioxide, macrogol 400, candelyl wax, Opadry White OY-S-7331.

Pharmacokinetics

Accupro is an antihypertensive drug, an ACE inhibitor.

Indications for use

Arterial hypertension, chronic heart failure.

Contraindications

• history of angioedema associated with treatment with ACE inhibitors, hereditary and/or idiopathic angioedema,
• children and adolescents up to 18 years of age,
• pregnancy,
• lactation period (breastfeeding),
• lactase deficiency, lactose intolerance and glucose-galactose malabsorption syndrome,
• simultaneous use with aliskiren and aliskiren-containing drugs, with angiotensin II receptor antagonists or with other drugs that inhibit the RAAS (dual blockade of the RAAS), in patients with diabetes mellitus or in patients with diabetes mellitus with target organ damage (diabetic nephropathy), with impaired function kidneys (GFR less than 60 ml/min/1.73 m2), with hyperkalemia (more than 5 mmol/l), with chronic heart failure and arterial hypertension,
• hypersensitivity to any component of the drug.

The drug should be prescribed with caution to patients with symptomatic arterial hypotension, who have previously taken diuretics and are on a diet with limited salt intake, with severe heart failure in patients with a high risk of severe arterial hypotension, with a decrease in the volume of the bcc (including vomiting or diarrhea) , with hyperkalemia, suppression of bone marrow hematopoiesis, with aortic stenosis, hypertrophic obstructive cardiomyopathy, mitral stenosis, with cerebral circulatory failure, coronary artery disease, coronary insufficiency (a sharp decrease in blood pressure during therapy with ACE inhibitors can worsen the course of these diseases), condition after kidney transplantation, with bilateral renal artery stenosis or stenosis of the artery of a single kidney, with impaired renal function, in patients on hemodialysis (creatinine clearance less than 10 ml/min), because There is insufficient data on the use of Accupro in such patients, with severe autoimmune systemic connective tissue diseases (including SLE, scleroderma), with impaired liver function (especially when used simultaneously with a diuretic), with combination therapy with a potassium-sparing diuretic, with diabetes mellitus , extensive surgical interventions and general anesthesia, while taking other antihypertensive drugs, as well as mTOR and DPP-4 enzyme inhibitors.

Directions for use and doses

When conducting monotherapy for arterial hypertension, the recommended initial dose of quinapril in patients not receiving diuretics is 10 mg or 20 mg 1 time / day. Depending on the clinical effect, the dose can be increased to a maintenance dose of 20 mg or 40 mg/day, which is usually prescribed in 1 dose or divided into 2 parts. As a rule, the dose should be changed at intervals of 4 weeks. In most patients, it is possible to achieve adequate blood pressure control during long-term treatment by using the drug once a day. In some patients, the dose of quinapril reached 80 mg/day.

Storage conditions

At a temperature not exceeding 25 C

Best before date

3 years

special instructions

Caution must be exercised when prescribing to patients with reduced blood volume (including as a result of diuretic therapy, limiting NaCl intake, hemodialysis, diarrhea and vomiting) due to the increased risk of developing a sudden decrease in blood pressure after using even the initial dose of ACE. Transient hypotension is not a contraindication for continuing treatment with the drug after stabilization of blood pressure (the dose should be reduced). In case of an excessive decrease in blood pressure, the patient is transferred to a horizontal position with a low head, and, if necessary, saline solution is infused (to increase the volume of the bcc). Before starting treatment, 2-3 days before starting treatment, it is necessary to cancel previous diuretic therapy, except for patients with malignant or difficult-to-treat hypertension. In these patients, the use of quinapril can be started immediately, at a reduced dose, under close medical supervision (within 2 hours after administration and an additional 1 hour until blood pressure stabilizes) and a careful increase in dose. Patients with malignant arterial hypertension or concomitant severe heart failure should begin treatment in a hospital setting. Before starting therapy with ACE inhibitors, it is necessary to count the total number of leukocytes, as well as monitor the leukocyte formula once a month in the first 3-6 months of treatment, and at periodic intervals up to 1 year in patients with an increased risk of neutropenia (with impaired renal function, systemic diseases connective tissue in those receiving high doses, at the first signs of infection). Before and during treatment, monitoring of blood pressure, renal function, K+ content in plasma, control of Hb content in peripheral blood, creatinine, urea, control of the concentration of electrolytes and liver enzymes in the blood is necessary. The use of AN69 dialysis membranes in combination with ACE inhibitors is not recommended (due to the possibility of developing anaphylactoid reactions in patients). It is recommended that neonates exposed in utero to ACE inhibitors be closely monitored for hypotension, oliguria, and hyperkalemia. In oliguria, it is necessary to maintain blood pressure and renal perfusion by administering appropriate fluids and vasoconstrictors. In neonates and infants, the risk of developing oliguria and neurological disorders is associated with a decrease in renal and cerebral blood flow due to the decrease in blood pressure caused by ACE inhibitors, in which case lower initial doses and careful monitoring are recommended. Care must be taken when driving vehicles or performing other work that requires increased attention, because Dizziness is possible, especially after the initial dose of an ACE inhibitor in patients taking diuretics. Caution should be exercised during exercise or hot weather due to the risk of dehydration and hypotension due to decreased fluid volume. Before surgery (including dentistry), the surgeon/anesthesiologist must be warned about the use of ACE inhibitors.

Conditions for dispensing from pharmacies

Available with prescription

Side effects

From the central nervous system and peripheral nervous system: possible dizziness, weakness, headache, rarely - paresthesia, mood and sleep disturbances.

From the cardiovascular system: arterial hypotension is possible, rarely - tachycardia.

From the digestive system: possible dyspeptic symptoms (including dry mouth, loss of appetite), rarely - stomatitis, abdominal pain, pancreatitis, cholestatic jaundice.

Metabolism: possible hyperkalemia, hyponatremia, rarely - proteinuria, increased levels of urea and creatinine in the blood (mainly in patients with impaired renal function).

From the respiratory system: dry cough, bronchitis, rhinitis are possible.

From the hematopoietic system: rarely - neutropenia, agranulocytosis, thrombocytopenia, anemia.

From the urinary system: possible renal dysfunction.

From the reproductive system: rarely - impotence.

Allergic reactions: skin rash, angioedema, and other hypersensitivity reactions are possible.

Dermatological reactions: rarely - alopecia.

Other: rarely - muscle spasms.

Interaction

Antihypertensive, diuretic, opioid analgesics, and general anesthesia agents enhance the hypotensive effect. NSAIDs, table salt - weaken the effect. Potassium supplements, potassium-sparing diuretics (amiloride, spironolactone, triamterene) increase the risk of developing hyperkalemia. Enhances the effect of ethanol, slows down the excretion of Li+. Enhances the hypoglycemic effect of sulfonylurea derivatives and insulin. Increases the risk of developing leukopenia when used simultaneously with allopurinol, cytostatic agents, immunosuppressants, procainamide. Estrogens weaken the hypotensive effect due to fluid retention. Drugs that cause bone marrow suppression increase the risk of neutropenia and/or agranulocytosis, including death.

Overdose

Symptoms: marked decrease in blood pressure, dizziness, weakness, visual impairment.

Treatment is symptomatic. The patient should take a horizontal position; it is advisable to carry out an intravenous infusion using 0.9% sodium chloride solution (to increase the volume of blood volume). Hemodialysis and peritoneal dialysis are not effective.

Interactions of the drug Accupro

Taking tetracycline with quinapril reduces the absorption of tetracycline by approximately 28–37%. The decrease in absorption is due to the presence of magnesium carbonate as a filler in Accupro. Elevated serum lithium levels and symptoms of lithium toxicity have been reported in patients taking lithium and ACE inhibitors concomitantly. The combination of these drugs should be used with caution; Frequent monitoring of serum lithium levels is recommended. Additional use of a diuretic increases the risk of lithium intoxication. No clinically significant pharmacokinetic interactions were observed when quinapril was administered with propranolol, hydrochlorothiazide, digoxin or cimetidine. The anticoagulant effect with a single dose of warfarin (measured by prothrombin time) does not change significantly with simultaneous administration of quinapril 2 times a day. Concomitant therapy with thiazide diuretics and/or beta-adrenergic blockers enhances the antihypertensive effect of quinapril. When quinapril is co-administered with potassium-sparing diuretics (spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes, they should be used with caution and with appropriate monitoring of serum potassium levels. In patients taking quinapril (as well as other ACE inhibitors), serum potassium levels may increase. When used concomitantly, quinapril may reduce hypokalemia caused by thiazide diuretics. Due to the risk of further increases in serum potassium levels, combination therapy with potassium-sparing diuretics should be initiated with caution and regular monitoring of serum potassium levels. Some patients with impaired renal function who are taking NSAIDs may experience further deterioration in renal function after starting ACE inhibitors. This condition is usually reversible. The therapeutic effect of quinapril may be reduced when administered concomitantly with NSAIDs. ACE inhibitors, including quinapril, may increase sensitivity to insulin or oral hypoglycemic agents, which may lead to hypoglycemia in patients with diabetes mellitus. In this case, additional observations are necessary.

Accupro®

Angioedema of the tissues of the head and neck

During treatment with ACE inhibitors, cases of angioedema in the head and neck area have been described, including in 0.1% of patients receiving Accupro®. If a guttural whistle or angioedema of the face, tongue or vocal folds occurs, Accupro® should be discontinued immediately. The patient must be given adequate treatment and observed until symptoms of edema resolve. Antihistamines may be used to reduce symptoms. Angioedema involving the larynx can be fatal. If swelling of the tongue, vocal folds or larynx threatens the development of airway obstruction, adequate emergency therapy is necessary, including subcutaneous administration of a solution of epinephrine (adrenaline) 1:1000 (0.3-0.5 ml).

Patients receiving concomitant therapy with mTOR enzyme inhibitors (eg, temsirolimus) or DPP-4 inhibitors (gliptins) or neutral endopeptidase inhibitors (NEP) or estramustine may be at greater risk of developing angioedema. Caution should be exercised when using these drugs simultaneously with Accupro®.

Angioedema of the intestinal walls

Cases of intestinal angioedema have also been described during treatment with ACE inhibitors. Patients reported abdominal pain (with/without nausea or vomiting); in some cases without previous angioedema of the face and normal C1-esterase activity. Diagnosis was made using abdominal computed tomography, ultrasound, or at the time of surgery. Symptoms disappeared after stopping the ACE inhibitors. Therefore, in patients with abdominal pain taking ACE inhibitors, when establishing a differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine.

Patients with a history of angioedema not associated with an ACE inhibitor may be at increased risk of developing it when treated with drugs of this group.

Anaphylactoid reactions

Patients receiving ACE inhibitors during desensitization therapy with hymenoptera venom may develop life-threatening anaphylactoid reactions. By temporarily stopping the use of ACE inhibitors, these reactions were avoided, but they occurred again with accidental use of these drugs.

Anaphylactoid reactions may also occur with the use of ACE inhibitors in patients undergoing low-density lipoprotein absorption apheresis with dextran sulfate or in patients undergoing hemodialysis using high-flux membranes such as polyacrylonitrile. Therefore, such combinations should be avoided by using either other antihypertensive drugs or alternative hemodialysis membranes.

Arterial hypotension

Symptomatic arterial hypotension rarely occurs during treatment with Accupro in patients with uncomplicated arterial hypertension, but it can develop as a result of therapy with ACE inhibitors in patients with reduced blood volume, for example, when following a diet with limited salt intake, hemodialysis. If symptomatic arterial hypotension occurs, it is necessary to carry out symptomatic therapy (the patient should be laid down, legs elevated and, if necessary, given an intravenous infusion using 0.9% sodium chloride solution). Transient arterial hypotension is not a contraindication to further use of the drug, however, in such cases, its dose should be reduced or the advisability of simultaneous therapy with diuretics should be assessed.

Other causes of decreased blood volume, such as vomiting or diarrhea, can also lead to a pronounced decrease in blood pressure. In such cases, patients should consult a doctor. In patients receiving diuretics, the use of Accupro® may also lead to the development of symptomatic arterial hypotension. It is advisable for such patients to temporarily stop taking the diuretic 2-3 days before starting treatment with Accupro®, except for patients with malignant or difficult-to-treat hypertension. If monotherapy with Accupro® does not provide the required therapeutic effect, then treatment with diuretics should be resumed. If it is impossible to cancel the diuretic, then Accupro® is used in a low initial dose.

In patients with chronic heart failure who are at increased risk of severe hypotension, treatment with Accupro® should be started at the recommended dose under close medical supervision; Patients should be observed during the first two weeks of treatment, as well as in all cases when the dose of Accupro® is increased.

Agranulocytosis

When treated with ACE inhibitors in patients with uncomplicated arterial hypertension, in rare cases, agranulocytosis developed, which was more common in patients with impaired renal function and connective tissue diseases. Agranulocytosis rarely developed during treatment with Accupro®. When using this drug (as well as other AI1P inhibitors) in patients with connective tissue diseases and/or kidney disease, the number of leukocytes in the blood should be monitored.

Renal dysfunction

In susceptible patients, suppression of RAAS activity may lead to renal dysfunction. In patients with severe chronic heart failure, in whom renal function may be dependent on the activity of the RAAS, treatment with ACE inhibitors, including quinapril, may be accompanied by oliguria and/or progressive azotemia, and in rare cases, acute renal failure and/or death.

The use of ARA II, ACE inhibitors or aliskiren can lead to a “double” blockade of RAAS activity. This effect may be manifested by a decrease in blood pressure, hyperkalemia and changes in renal function (including acute renal failure) compared with monotherapy. Blood pressure, renal function and plasma electrolyte levels should be carefully monitored in patients taking Accupro® and other drugs that affect the RAAS. The simultaneous use of RAAS-active agents and quinapril should be avoided. If it is necessary to use this combination, the ratio of the expected benefit to the possible risk of using the combination should be assessed in each individual case and renal function and potassium levels should be regularly monitored.

In patients with chronic heart failure or arterial hypertension with unilateral or bilateral renal artery stenosis, an increase in blood urea nitrogen and serum creatinine was observed in some cases during treatment with ACE inhibitors. These changes were almost always reversible and disappeared after discontinuation of the ACE inhibitor and/or diuretic. In such cases, renal function should be monitored during the first few weeks of treatment.

The half-life of quinaprilat increases with a decrease in CC. In patients with CC less than 60 ml/min, Accupro® should be used at a lower initial dose. In such patients, the dose of the drug should be increased taking into account the therapeutic effect, with regular monitoring of renal function, although in clinical studies no further deterioration of renal function was observed during treatment with the drug.

Liver dysfunction

Accupro® in combination with diuretics should be used with caution in patients with impaired function or progressive liver disease, since small changes in water and electrolyte balance can cause the development of hepatic coma. Hyperkalemia

ACE inhibitors, including quinapril, may increase serum potassium levels.

The use of Accupro® in combination therapy with potassium-sparing diuretics has not been studied. Given the risk of a further increase in serum potassium, combination therapy with potassium-sparing diuretics or other drugs that increase serum potassium should be carried out with caution, under monitoring of serum potassium levels. Accupro® may reduce the hypokalemia caused by thiazide diuretics when used concomitantly.

Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIAD)

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and subsequent hyponatremia have been observed in some patients treated with other ACE inhibitors. It is recommended to regularly monitor serum sodium concentrations in elderly patients, as well as in patients of all age groups, for the risk of hyponatremia.

Hypoglycemia and diabetes mellitus

Patients with diabetes mellitus may require closer monitoring and dosage adjustments of oral hypoglycemic agents and insulin, especially during the first month of ACE inhibitor therapy, including quinapril.

Cough

When treated with ACE inhibitors, including quinapril, the development of cough was noted. Typically, it is nonproductive, persistent, and resolves upon cessation of therapy. In the differential diagnosis of cough, its possible connection with ACE inhibitors should be taken into account.

Patients undergoing surgery and/or anesthesia

Before surgery (including dentistry), the surgeon/anesthesiologist must be warned about the use of ACE inhibitors.

Neutropenia

If any symptoms of infection (eg, acute tonsillitis, fever) appear, the patient should consult a doctor immediately, as they may be a manifestation of neutropenia.

Conditions that impede the outflow of blood from the left ventricle

The use of Accupro® is contraindicated in patients with a condition that impedes the outflow of blood from the left ventricle (aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy).

Kidney transplant

The use of Accupro® is contraindicated in patients after kidney transplantation

Ethnic differences

ACE inhibitors are more likely to cause angioedema in black patients than in Caucasian patients. As with other ACE inhibitors, quinapril may be less effective in lowering blood pressure in black patients.

Elderly patients

Especially at the beginning of treatment, Accupro® should always be used in combination with careful monitoring of blood pressure and/or representative laboratory parameters.