Coaprovel, 12.5 mg+150 mg, film-coated tablets, 28 pcs.

Compound

Pharmacodynamics

Coaprovel® is a combination of an angiotensin II receptor antagonist, irbesartan, and a thiazide diuretic, hydrochlorothiazide.

The combination of these ingredients has an additive antihypertensive effect, lowering blood pressure to a greater extent than each of them alone.

Irbesartan is a selective antagonist of angiotensin II receptors (AT1 type). Irbesartan does not require metabolic activation to acquire pharmacological activity. Angiotensin II is an important component of the RAAS and is involved in the pathogenesis of arterial hypertension, as well as sodium homeostasis. Irbesartan blocks all physiologically significant effects of angiotensin II, regardless of the source or route of its synthesis, incl. its strongly pronounced vasoconstrictor and aldosterone-secreting effects, realized through AT1 type receptors located on the surface of vascular smooth muscle cells and in the adrenal cortex.

It does not have agonistic activity towards AT1 receptors and has a much greater (more than 8500 times) affinity for AT1 receptors than for AT2 receptors (receptors not associated with the regulation of the cardiovascular system).

Irbesartan does not inhibit RAAS enzymes (such as renin, ACE) and does not affect other hormone receptors or ion channels involved in the regulation of blood pressure and sodium homeostasis. Blocking AT1 receptors with irbesartan interrupts the feedback chain in the renin-angiotensin system, which leads to an increase in the concentration of renin and angiotensin II in the blood plasma. After taking irbesartan in recommended doses, the plasma concentration of aldosterone decreases, without having a significant effect on the content of potassium in the blood serum (the average increase is <0.1 mEq/L). Irbesartan does not have a significant effect on serum concentrations of triglycerides, cholesterol and glucose. Irbesartan does not affect the concentration of uric acid in the blood serum or the rate of excretion of uric acid by the kidneys.

Hydrochlorothiazide is a thiazide diuretic with diuretic, natriuretic and antihypertensive effects. The mechanism of antihypertensive action of thiazide diuretics, such as hydrochlorothiazide, is not completely known. Thiazide diuretics affect the tubular mechanisms of reabsorption of electrolytes in the kidneys, increasing the excretion of sodium and chloride in approximately equal amounts. Natriuresis leads to secondary loss of potassium and bicarbonate. Hydrochlorothiazide increases plasma renin activity and aldosterone secretion, and also reduces serum potassium levels. Concomitant use of an angiotensin II receptor antagonist helps reduce potassium losses associated with the action of thiazide diuretics.

The antihypertensive effect of irbesartan in combination with hydrochlorothiazide appears after taking its first dose and becomes significant within 1–2 weeks of administration, its maximum antihypertensive effect is achieved by the 6–8th week of treatment. In long-term clinical studies, the antihypertensive effect of the irbesartan/hydrochlorothiazide combination was observed to persist for more than one year.

The combination of hydrochlorothiazide/irbesartan, when taken in the therapeutic dose range, has a dose-dependent and additive antihypertensive effect. In patients who did not experience a sufficient reduction in blood pressure during monotherapy with irbesartan at a dose of 300 mg, the addition of 12.5 mg of hydrochlorothiazide once a day to monotherapy with irbesartan at a dose of 300 mg once a day led to an additional decrease in dBP at the end of the interdose interval. (i.e. 24 hours after taking the drugs) by 6.1 mm Hg. Art. (compared to adding placebo). There was an overall decrease in sBP/dBP with the combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide (compared to placebo) to -13.6/-11.5 mmHg. Art. A single daily dose of 150 mg of irbesartan and 12.5 mg of hydrochlorothiazide demonstrated (compared to placebo) an average decrease in SBP/DBP at the end of the interdose interval by 12.9/6.9 mmHg. Art. respectively. The maximum antihypertensive effect developed after 3–6 hours. With 24-hour blood pressure monitoring, taking Coaprovel® 12.5/150 mg once a day caused a stable decrease in blood pressure during the day (the average decrease in sBP/dBP was -15.8/-10, respectively .0 mm Hg compared to placebo). Expressed as a percentage, T/P values ​​(the ratio of blood pressure measured at the end of the interdose interval (residual effect) to blood pressure during the maximum effect of irbesartan/hydrochlorothiazide combinations) were at least 68%.

In a clinical study in patients with insufficient blood pressure reduction during hydrochlorothiazide monotherapy at a dose of 25 mg, the addition of irbesartan to hydrochlorothiazide caused an additional mean reduction in sBP/dBP by 11.1/7.2 mm Hg. Art. respectively, compared with hydrochlorothiazide monotherapy.

Blood pressure decreased to the same extent in standing and lying positions. Orthostatic effects have been observed rarely, but may occur in patients with hyponatremia and/or hypovolemia.

The effectiveness of irbesartan/hydrochlorothiazide does not depend on age, race or gender. The overall antihypertensive response to the combination was similar in black patients and patients of other races.

After discontinuation of irbesartan, blood pressure gradually returned to initial values. No withdrawal syndrome was observed for irbesartan and hydrochlorothiazide.

When hydrochlorothiazide is taken orally, the diuretic effect occurs within the first 2 hours, diuresis reaches a maximum after about 4 hours and persists for about 6–12 hours.

Two clinical studies evaluated treatment with Coaprovel® as initial therapy in patients with moderate (initial mean BP 162/98 mmHg) and severe (initial mean BP 172/113 mmHg) hypertension . Both studies showed a significant advantage in the antihypertensive effect of Coaprovel® (in doses from 12.5/150 to 25/300 mg) as initial therapy compared with the use of irbesartan monotherapy (in doses from 150 to 300 mg) as initial therapy. and hydrochlorothiazide (in doses from 12.5 to 25 mg).

Coaprovel, 12.5 mg+150 mg, film-coated tablets, 28 pcs.

Excessive decrease in blood pressure - patients with hypovolemia.

The use of Coaprovel® to date has rarely been accompanied by an excessive decrease in blood pressure in patients with arterial hypertension without other risk factors for the development of an excessive decrease in blood pressure.
An excessive decrease in blood pressure, accompanied by clinical symptoms, may develop in patients with hyponatremia/hypovolemia. Hypovolemia and/or hyponatremia must be corrected before starting Coaprovel®. Thiazide diuretics may potentiate the effect of other antihypertensive drugs (see Precautions
and Dosage and Administration, Interactions).

Impaired kidney and liver function.

The drug Coaprovel® is not recommended for use in patients with severe renal failure (Cl creatinine ≤30 ml/min) (see “Contraindications”). In patients with impaired renal function, an increase in azotemia is possible due to the content of hydrochlorothiazide in the drug. There are no clinical data regarding the use of the drug in patients who have recently undergone a kidney transplant. When Coaprovel® is used in patients with impaired renal function, periodic monitoring of potassium levels, creatinine and uric acid concentrations in the blood serum is recommended.

The drug Coaprovel® should be used with caution in patients with impaired liver function or progressive liver diseases, since even small changes in water and electrolyte balance can trigger the development of hepatic coma.

Water-electrolyte balance and metabolic disorders.

Thiazides, including hydrochlorothiazide, can cause fluid and electrolyte imbalance (hypokalemia, hyponatremia and hypochloremic alkalosis). Although hypokalemia may occur when thiazide diuretics are used alone, especially at high doses, concomitant use of irbesartan may reduce the hypokalemia caused by hydrochlorothiazide. On the contrary, due to irbesartan, which is part of the drug Coaprovel®, hyperkalemia may occur, especially in the presence of renal failure, heart failure, and diabetes mellitus. Regular monitoring of serum potassium levels in patients at risk is recommended.

Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes should be used with caution in combination with Coaprovel® (see "Interactions"). Chloride deficiency is usually minor and usually does not require treatment. Thiazides reduce the excretion of calcium through the kidneys and cause an inconsistent and slight increase in serum calcium. The development of clinically significant hypercalcemia may indicate the possibility of hyperparathyroidism in the patient. Thiazides should be discontinued before testing parathyroid function. Thiazides have been demonstrated to increase renal excretion of magnesium ions, which may lead to the development of hypomagnesemia.

When treated with thiazide diuretics, hyperglycemia and exacerbation of gout may develop in some patients.

When treated with thiazide diuretics, the need for insulin in patients with diabetes mellitus may increase, and latent diabetes mellitus may manifest. Treatment with thiazide diuretics has been associated with an increase in blood cholesterol and triglyceride concentrations, but the 12.5 mg dose contained in Coaprovel® has virtually no effect on blood cholesterol and triglyceride concentrations. When treated with thiazide diuretics, some patients may experience hyperuricemia or exacerbation of gout. Patients at risk for developing fluid and electrolyte imbalances and metabolic disorders may require laboratory monitoring.

Systemic lupus erythematosus.

Exacerbation or worsening of systemic lupus erythematosus has been reported when taking thiazide diuretics.

Acute myopia and secondary acute angle-closure glaucoma.

Sulfonamides or sulfonamide derivatives can cause idiosyncratic reactions leading to the development of transient myopia and acute angle-closure glaucoma. Although hydrochlorothiazide is a sulfonamide derivative, to date only isolated cases of acute angle-closure glaucoma have been reported without establishing a cause-and-effect relationship with its use. Symptoms of acute angle-closure glaucoma include acute loss of visual acuity or eye pain, usually occurring within a few hours to several weeks after starting the drug. Left untreated, acute angle-closure glaucoma can lead to permanent vision loss. If these symptoms occur, you should stop taking the drug as soon as possible. If it is not possible to normalize IOP, then urgent therapeutic or surgical treatment may be required. Risk factors for the development of acute angle-closure glaucoma include a history of allergic reactions to sulfonamides and penicillins.

Double blockade of the RAAS when combining Coaprovel® with ACE inhibitors or aliskiren.

Not recommended because Compared with monotherapy, there is an increased risk of a sharp decrease in blood pressure, the development of hyperkalemia and renal dysfunction.

The use of Coaprovel® in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal failure with GFR <60 ml/min/1.73 m2) (see “Contraindications”, “Interaction”) and is not recommended in other patients.

The use of Coaprovel® in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy (see “Contraindications”, “Interaction”) and is not recommended in other patients.

Patients with renal function dependent on the activity of the RAAS.

As a consequence of RAAS inhibition, deterioration of renal function can be expected in susceptible patients. In patients with renal function dependent on the activity of the RAAS (patients with arterial hypertension and renal artery stenosis of one or both kidneys, patients with NYHA functional class III and IV CHF), treatment with drugs that affect the RAAS was associated with oliguria and /or progressive azotemia and rarely with acute renal failure and/or death. The possibility of a similar effect occurring when using angiotensin II receptor inhibitors, including Coaprovel®, cannot be excluded.

Patients after sympathectomy.

In patients after sympathectomy, the antihypertensive effect of thiazide diuretics may be enhanced.

Aortic stenosis and mitral valve stenosis, hypertrophic obstructive cardiomyopathy.

Particular caution is required when using vasodilators in such patients, including the drug Coaprovel®.

Primary hyperaldosteronism.

The use of the drug Coaprovel® is inappropriate, because such patients usually do not respond to antihypertensive drugs that affect the RAAS.

Anti-doping test.

Hydrochlorothiazide may give a positive result during doping control.

Patients with a history of allergic reactions or bronchial asthma.

The development of allergic reactions to hydrochlorothiazide is more likely in patients with a history of allergic reactions or in patients with bronchial asthma.

Impact on the ability to drive vehicles or engage in other potentially hazardous activities.

Not studied. However, based on its pharmacodynamic properties, the drug Coaprovel® should not affect the ability to drive vehicles and engage in other potentially hazardous activities (work at height, work as an air traffic controller, work with machinery, etc.). When engaging in potentially hazardous activities, caution should be exercised (due to the possibility of developing dizziness, weakness and, therefore, decreased attention and a slowdown in the speed of psychomotor reactions - see “Side effects”).

Pharmacokinetics

Neither irbesartan nor hydrochlorothiazide alters each other's pharmacokinetics.

Absorption. Irbesartan and hydrochlorothiazide are active substances when taken orally and do not require biotransformation to become their active form.

After oral administration of Coaprovel®, the absolute bioavailability of irbesartan is 60–80%, and hydrochlorothiazide is 50–80%. Food intake does not affect the bioavailability of the active substances of the drug. After taking the drug Coaprovel® orally, Tmax in the blood serum is 1.5–2 hours for irbesartan and 1–2.5 hours for hydrochlorothiazide.

Distribution. The binding of irbesartan to plasma proteins is approximately 96%; its binding to cellular components of the blood is negligible. Vd of irbesartan is 53–93 l (0.72–1.24 l/kg). The binding of hydrochlorothiazide to plasma proteins is 68%, and its Vd is 3.6–7.8 l/kg.

Metabolism. After oral or intravenous administration of 14C-irbesartan, 80–85% of the radioactivity circulating in the blood plasma is unchanged irbesartan. Irbesartan is metabolized by the liver by oxidation and conjugation with glucuronic acid. The main metabolite found in the systemic circulation is irbesartan glucuronide (approximately 6%). The oxidation of irbesartan is carried out mainly by the cytochrome P450CYP2C9 isoenzyme; the participation of the CYP3A4 isoenzyme in the metabolism of irbesartan is insignificant. Irbesartan is not metabolized by most isoenzymes that are usually involved in the metabolism of drugs (isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6 or CYP2E1), and does not cause their inhibition or induction. Irbesartan does not induce or inhibit the CYP3A4 isoenzyme.

Excretion. Irbesartan and its metabolites are excreted from the body both through the intestines (with bile) and the kidneys. After oral or intravenous administration of 14C-irbesartan, 20% of the radioactivity is found in the urine, and the rest in the feces. Less than 2% of the administered dose is excreted by the kidneys as unchanged irbesartan. Hydrochlorothiazide is not metabolized and is excreted by the kidneys. The average plasma half-life of hydrochlorothiazide is 5–15 hours. Hydrochlorothiazide crosses the placental barrier and is excreted into breast milk.

The final half-life of irbesartan is 11–15 hours. The total clearance of intravenously administered irbesartan is 157–176 ml/min, and its renal clearance is 3–3.5 ml/min. With a single daily dose of irbesartan, Css is achieved after 3 days, while its limited accumulation in the blood plasma is observed (less than 20%).

Special patient groups

The influence of gender on the pharmacokinetics of irbesartan. Women (compared to men) have slightly higher plasma concentrations of irbesartan. However, gender-related differences in the half-life and accumulation of irbesartan are not detected. No dose adjustment of irbesartan is required in women. No gender-related differences in the effects of irbesartan were observed.

Pharmacokinetics of irbesartan in elderly patients. The AUC and Cmax values ​​of irbesartan in elderly patients (65–80 years) with clinically normal renal and hepatic function were approximately 20–50% higher than in younger patients (18–40 years). Their terminal half-lives were comparable. No age-related differences in the effects of irbesartan were observed.

Pharmacokinetics of irbesartan in liver dysfunction. In patients with mild (functional class A or 5-6 points on the Child-Pugh scale) and moderately severe (functional class B or 7-9 points on the Child-Pugh scale) liver failure due to cirrhosis, the pharmacokinetic parameters of irbesartan do not change significantly.

Pharmacokinetics of irbesartan in renal impairment. In patients with impaired renal function or undergoing hemodialysis, the pharmacokinetics of irbesartan do not change significantly. Irbesartan is not excreted from the body by hemodialysis.

The influence of race on the pharmacokinetics of irbesartan. In volunteers without arterial hypertension, the AUC and T1/2 of irbesartan in blacks were approximately 20–25% higher than in Caucasians; The Cmax of irbesartan was almost the same.

Coaprovel®

Excessive decrease in blood pressure - patients with hypovolemia

The use of Coaprovel® to date has rarely been accompanied by an excessive decrease in blood pressure in patients with arterial hypertension without other risk factors for the development of an excessive decrease in blood pressure. An excessive decrease in blood pressure, accompanied by clinical symptoms, may develop in patients with hyponatremia/hypovolemia. Hypovolemia and/or hyponarthemia must be corrected before starting Coaprovel®. Thiazide diuretics may potentiate the effect of other antihypertensive drugs (see sections “With caution” and “Dosage and administration”, “Interaction with other drugs”). Renal and liver dysfunction

Coaprovel® is not recommended for use in patients with severe renal failure (creatinine clearance <30 ml/min) (see section “Contraindications”). In patients with impaired renal function, an increase in azotemia is possible due to the content of hydrochlorothiazide in the drug. There are no clinical data regarding the use of the drug in patients who have recently undergone a kidney transplant. When Coaprovel® is used in patients with impaired renal function, periodic monitoring of potassium levels, creatinine and uric acid concentrations in the blood serum is recommended.

The drug Coaprovel® should be used with caution in patients with impaired liver function or progressive liver diseases, since even small changes in water and electrolyte balance can trigger the development of hepatic coma.

Electrolyte and metabolic disorders Thiazides, including hydrochlorothiazide, can cause electrolyte imbalance (hypokalemia, hyponatremia and hypochloremic alkalosis). Although hypokalemia may occur when thiazide diuretics are used alone, especially at high doses, concomitant use of irbesartan may reduce the hypokalemia caused by hydrochlorothiazide. On the contrary, due to irbesartan, which is part of the drug Coaprovel®, hyperkalemia may occur, especially in the presence of renal failure, heart failure, and diabetes mellitus. Regular monitoring of serum potassium levels in patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes should be used with caution together with Coaprovel® (see section “Interactions with other medicinal products”). Chloride deficiency is usually minor and usually does not require treatment. Thiazides reduce the excretion of calcium through the kidneys and cause an inconsistent and slight increase in serum calcium. The development of clinically significant hypercalcemia may indicate the possibility of hyperparathyroidism in the patient. Thiazides should be discontinued before testing parathyroid function. Thiazides have been demonstrated to increase renal excretion of magnesium ions, which may lead to the development of hypomagnesemia.

When treated with thiazide diuretics, hyperglycemia and exacerbation of gout may develop in some patients. When treated with thiazide diuretics, the need for insulin in patients with diabetes mellitus may increase, and latent diabetes mellitus may manifest. Treatment with thiazide diuretics has been associated with an increase in blood cholesterol and triglyceride concentrations, but the 12.5 mg dose contained in Coaprovel® has virtually no effect on blood cholesterol and triglyceride concentrations. When treated with thiazide diuretics, some patients may experience hyperuricemia or exacerbation of gout. Patients at risk for developing fluid and electrolyte imbalances and metabolic disorders may require laboratory monitoring.

Systemic lupus erythematosus

Exacerbation or worsening of systemic lupus erythematosus has been reported when taking thiazide diuretics.

Acute myopia and secondary acute angle-closure glaucoma

Sulfonamides or sulfonamide derivatives can cause idiosyncratic reactions leading to the development of transient myopia and acute angle-closure glaucoma. Despite the fact that hydrochlorothiazide is a sulfonamide derivative, to date only isolated cases of acute angle-closure glaucoma have been reported without establishing a cause-and-effect relationship with its use. Symptoms of acute angle-closure glaucoma include acute loss of visual acuity or eye pain, usually occurring within a few hours to several weeks after starting the drug. Left untreated, acute angle-closure glaucoma can lead to permanent vision loss. If these symptoms occur, you should stop taking the drug as soon as possible. If this fails to normalize intraocular pressure, urgent therapeutic or surgical treatment may be required. Risk factors for the development of acute angle-closure glaucoma include a history of allergic reactions to sulfonamides and penicillins.

Double blockade of the RAAS when combining Coaprovel® with ACE inhibitors or aliskiren

Double blockade of the RAAS when using a combination of Coaprovel® with ACE inhibitors or aliskiren is not recommended, since, compared with monotherapy, there is an increased risk of a sharp decrease in blood pressure, the development of hyperkalemia and renal dysfunction.

The use of Coaprovel® in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal failure with GFR < 60 ml/min/1.73 m2 body surface area) (see sections “Contraindications”,

"Interaction with other medicinal products") and is not recommended in other patients.

The use of Coaprovel® in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy (see sections “Contraindications”, “Interaction with other drugs”) and is not recommended in other patients.

Patients with renal function dependent on RAAS activity

As a consequence of RAAS inhibition, deterioration of renal function can be expected in susceptible patients. In patients with renal function dependent on the activity of the RAAS (patients with arterial hypertension and renal artery stenosis of one or both kidneys, patients with chronic heart failure of functional class III and IV [NYHA classification]), treatment with drugs that affect the RAAS, has been associated with oliguria and/or progressive azotemia and, rarely, acute renal failure and/or death. The possibility of a similar effect occurring when using angiotensin II receptor inhibitors, including Coaprovel®, cannot be excluded.

Patients after sympathectomy

In patients after sympathectomy, the antihypertensive effect of thiazide diuretics may be enhanced.

Aortic stenosis and mitral valve stenosis, hypertrophic obstructive cardiomyopathy

Particular caution is required when using vasodilators in such patients, including the drug Coaprovel®.

Primary hyperaldosteronism

The use of Coaprovel® is not advisable, since such patients usually do not respond to antihypertensive drugs that affect the RAAS.

Anti-doping test

Hydrochlorothiazide may give a positive result during doping control.

Patients with a history of allergies or bronchial asthma

The development of allergic reactions to hydrochlorothiazide is more likely in patients with a history of allergic reactions or in patients with bronchial asthma.

Contraindications

hypersensitivity to the active substances of the drug, any of the excipients of the drug Coaprovel® (see “Composition”) or other sulfonamide derivatives (hydrochlorothiazide is a sulfonamide derivative);

hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome;

simultaneous use with drugs containing aliskiren in patients with diabetes mellitus or with moderate to severe renal failure (glomerular filtration rate (GFR) <60 ml/min/1.73 m2);

simultaneous use with ACE inhibitors in patients with diabetic nephropathy;

severe renal failure (Cl creatinine ≤30 ml/min), anuria (due to the presence of hydrochlorothiazide in the drug);

pregnancy (see “Use during pregnancy and lactation”);

period of breastfeeding (see “Use during pregnancy and lactation”);

age under 18 years (efficacy and safety have not been established).

Carefully:

aortic or mitral valve stenosis, or hypertrophic obstructive cardiomyopathy (HOCM);

hypovolemia, hyponatremia, which occurs, for example, during intensive diuretic therapy, hemodialysis, following a diet with limited salt intake, diarrhea, vomiting (danger of excessive reduction in blood pressure, see “Special Instructions”);

patients with renal function dependent on the activity of the RAAS, such as patients with arterial hypertension with bilateral or unilateral renal artery stenosis or with chronic heart failure of functional class III–IV (according to the NYHA classification) (see “Special Instructions”);

coronary heart disease and/or atherosclerotic cerebral vascular disease (the risk of increased myocardial or cerebral ischemia, up to the development of myocardial infarction or stroke with an excessive decrease in blood pressure);

renal failure of mild to moderate severity (Cl creatinine from 60 to 30 ml/min) (risk of increased azotemia, increased concentration of uric acid in the blood, due to the presence of hydrochlorothiazide in the drug, and the development of hyperkalemia, due to the presence of irbesartan);

condition after kidney transplantation (lack of experience in clinical use);

liver failure of all degrees of severity or with progressive liver diseases (due to the presence of hydrochlorothiazide in the drug, since even minor disturbances in the water-electrolyte balance in such patients can provoke hepatic coma);

diabetes mellitus (due to the presence of hydrochlorothiazide in the drug, a decrease in glucose tolerance and an increase in the need for insulin and oral hypoglycemic agents is possible);

gout (due to the presence of hydrochlorothiazide in the drug, an increase in the concentration of uric acid salts in the blood is possible);

hyperkalemia, simultaneous use of potassium-sparing drugs and/or potassium-containing salt substitutes (risk of developing hyperkalemia);

systemic lupus erythematosus (due to the presence of hydrochlorothiazide in the drug, since there are reports of exacerbation or worsening of the course of systemic lupus erythematosus when using thiazide diuretics);

simultaneous use of other antihypertensive drugs (the possibility of potentiating their antihypertensive effect);

sympathectomy (risk of enhancing the antihypertensive effect of hydrochlorothiazide);

use in combination with ACE inhibitors or aliskiren, because compared with monotherapy, with double blockade of the RAAS there is an increased risk of developing an excessive decrease in blood pressure, hyperkalemia and changes in renal function (see “Special Instructions”);

a history of allergic reactions to penicillins and sulfonamides, which are risk factors for the development of an idiosyncratic reaction observed when taking sulfonamides or sulfonamide derivatives, manifested in the form of acute angle-closure glaucoma (see “Special instructions”, Acute myopia and secondary acute angle-closure glaucoma).

Instructions for use COAPROVEL

CoAprovel rarely causes symptomatic hypotension in patients with elevated blood pressure. Symptomatic hypotension is likely in patients with reduced blood volume or low sodium levels due to diuretic therapy, a salt-restricted diet, diarrhea or vomiting. Such conditions should be corrected before starting CoAprovel therapy.

The risk of severe hypotension and renal failure increases in patients with bilateral renal artery stenosis or renal artery stenosis of a solitary kidney when using ACE inhibitors or angiotensin II receptor antagonists. Although there are no such reports with the use of CoAprovel, this effect must be taken into account.

When using CoAprovel in patients with impaired renal function, periodic monitoring of serum potassium, creatinine and uric acid levels is recommended.

There is no experience with the use of CoAprovel in patients after a recent kidney transplant. CoAprovel should not be used in patients with severe renal failure (creatinine clearance <30 ml/min). In patients with impaired renal function, azotemia may increase during therapy with thiazide diuretics.

In patients with vascular tone and renal function dependent primarily on the activity of the RAAS (for example, in patients with severe congestive heart failure or kidney disease, including renal artery stenosis), therapy with ACE inhibitors or angiotensin II receptor antagonists, affecting the RAAS, is accompanied by acute hypotension, azotemia, oliguria and, in rare cases, acute renal failure. As with any antihypertensive drug, an excessive decrease in blood pressure in patients with ischemic cardiopathy or obliterative cardiovascular disease can cause myocardial infarction or stroke.

In patients with impaired liver function or progressive liver disease, thiazide diuretics should be used with caution because small changes in water and electrolyte balance can provoke hepatic coma. There is no clinical experience with the use of CoAprovel in patients with liver failure.

CoAprovel should be prescribed with extreme caution to patients with aortic stenosis and mitral valve stenosis, and obstructive hypertrophic cardiomyopathy.

The use of CoAprovel for primary aldosteronism is not recommended, because such patients usually do not respond to antihypertensive drugs that affect the RAAS.

During therapy with thiazide diuretics, a decrease in glucose tolerance is possible. In patients with diabetes mellitus, dose adjustment of insulin or oral hypoglycemic drugs may be required. Thiazide therapy can cause the manifestation of latent diabetes mellitus.

During therapy with thiazide diuretics, an increase in cholesterol and triglyceride levels is possible, but at a dose of 12.5 mg contained in CoAprovel, minimal or no side effects have been recorded.

During therapy with thiazides, some patients may experience hyperuricemia or exacerbation of gout.

Therapy with thiazide diuretics, including hydrochlorothiazide, may be accompanied by disturbances in water and electrolyte balance (hypokalemia, hyponatremia and hypochloremic alkalosis). Symptoms indicating fluid and electrolyte imbalances include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscle weakness, hypotension, oliguria, tachycardia and gastrointestinal disorders such as nausea or vomit.

Although hypokalemia may occur with the use of thiazide diuretics, concomitant therapy with irbesartan may reduce diuretic-induced hypokalemia. The risk of hypokalemia is greatest in patients with cirrhosis, increased diuresis, inadequate oral electrolyte intake, and concomitant therapy with corticosteroids or ACTH. On the contrary, due to the presence of irbesartan in CoAprovel, the development of hyperkalemia, especially in renal failure and/or heart failure, and diabetes mellitus is possible. Appropriate monitoring of serum potassium levels should be carried out in patients at risk. Potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium should be coadministered with CoAprovel with caution.

There is no evidence that irbesartan is able to reduce or prevent diuretic-induced hyponatremia. Chloride deficiency is usually minor and does not require treatment.

Thiazides can reduce calcium excretion in the urine and cause periodic and slight increases in serum calcium levels, provided there are no disturbances in calcium metabolism. Severe hypercalcemia may be a sign of latent hyperparathyroidism. Thiazides should be discontinued until parathyroid function testing is performed.

Thiazides increase urinary excretion of magnesium, which can lead to hypomagnesemia.

Exacerbation of systemic lupus erythematosus has been observed with the use of thiazide diuretics.

The development of allergic reactions to hydrochlorothiazide is more likely in patients with a history of allergic reactions or in patients with bronchial asthma.

Hydrochlorothiazide may cause a positive result in a drug test.

The tablets of the drug contain lactose, so the drug should not be used in the presence of rare hereditary disorders of galactose tolerance, lactase deficiency and malabsorption syndrome of glucose and galactose.

Impact on the ability to drive vehicles and operate machinery

The effect of CoAprovel on the ability to drive vehicles and operate machinery has not been studied, but based on its pharmacodynamic properties, it is unlikely that CoAprovel affects this ability. When using the drug in patients whose activities involve driving vehicles or working with machinery, it should be taken into account that in rare cases, dizziness and increased fatigue are possible during therapy for high blood pressure.

Use in pediatrics

There is no clinical experience with the use of CoAprovel in children and adolescents.

Experimental results

The oral toxicity of the irbesartan/hydrochlorothiazide combination has been studied in studies of up to 6 months in rats and macaques. No toxicological changes relevant for the therapeutic use of the drug in humans were detected. The changes observed in rats and macaques with oral administration of irbesartan/hydrochlorothiazide at doses of 10/10 mg/kg/day and 90/90 mg/kg/day were also noted when one of the components was used as monotherapy, and/or were side effects of lowering blood pressure (no significant toxicological manifestations of interaction were observed):

• renal changes with a slight increase in serum uric acid and creatinine levels, as well as hyperplasia/hypertrophy of the juxtaglomerular apparatus, which were a direct consequence of the interaction of irbesartan with the RAAS;
• a slight decrease in the content of red blood cells, hemoglobin, hematocrit;
• Loss of gastric coloration, ulcers, and focal necrosis of the gastric mucosa were observed in several rats in a 6-month toxicity study with irbesartan 90 mg/kg/day and hydrochlorothiazide 90 mg/kg/day, and the combination irbesartan/hydrochlorothiazide in dose of 10/10 mg/kg/day (no such pathological changes were observed in macaques);
• decrease in serum potassium due to hydrochlorothiazide (this effect was partially prevented when hydrochlorothiazide was administered in combination with irbesartan).

Most of these effects appear to be the result of the pharmacological action of irbesartan (blockade of angiotensin II-induced inhibition of renin release together with stimulation of renin-secreting cells) and are also observed with ACE inhibitors. These data are not relevant when the combination of irbesartan/hydrochlorothiazide is used in humans at therapeutic doses.

Maternal toxicity and teratogenicity were not observed in rats treated with the irbesartan/hydrochlorothiazide combination. The effect of the combination of irbesartan/hydrochlorothiazide on animal fertility has not been studied, because with monotherapy with irbesartan and hydrochlorothiazide, no evidence of a negative effect on fertility was found in animals or humans.

However, another angiotensin II antagonist affected fertility in animal studies when used as monotherapy and when used at low doses in combination with hydrochlorothiazide.

There is no evidence of mutagenicity or clastogenicity of the irbesartan/hydrochlorothiazide combination. The carcinogenic effect of the irbesartan/hydrochlorothiazide combination has not been studied in preclinical studies.

There are no data indicating pathological systemic or organ toxicity of irbesartan at clinically effective doses. In preclinical studies on the safety of the drug, irbesartan in high doses (rats - > 250 mg/kg/day, macaques - 100 mg/kg/day) caused a decrease in the content of red blood cells, hemoglobin, hematocrit). At very high doses (500 mg/kg/day), irbesartan caused degenerative changes in the kidneys in rats and macaques (including interstitial nephritis, tubular distension, tubular basophilia, increased plasma concentrations of uric acid and creatinine); these changes are considered to be a consequence of a hypotensive effect leading to a decrease in blood supply to the kidneys.

In addition, irbesartan caused hyperplasia/hypertrophy of juxtaglomerular cells (in rats at doses > 90 mg/kg/day, in macaques at doses > 10 mg/kg/day). All these changes were explained by the pharmacological action of irbesartan. When irbesartan is used in therapeutic doses, hyperplasia/hypertrophy of renal juxtaglomerular cells in humans is not significant.

There is no evidence of mutagenicity, clastogenicity or carcinogenicity. Animal studies with irbesartan demonstrated transient toxic effects on the fetus in rats (dilatation of the renal pelvic cavity, hydroureter and subcutaneous edema) that resolved after delivery. Miscarriages and early resorption of rabbit fetuses were observed at doses that caused maternal toxicity (including death). No teratogenic effect was observed in either rats or rabbits.

Although experimental models have shown mixed support for the hepatoxic and carcinogenic effects of hydrochlorothiazide, extensive experience with hydrochlorothiazide in humans does not indicate an association between the drug and an increase in the incidence of neoplasms.

Use during pregnancy and breastfeeding

Pregnancy. There is no experience with the use of Coaprovel® during pregnancy. Taking into account the fact that when pregnant women took ACE inhibitors in the second and third trimesters of pregnancy, damage and death of the developing fetus were observed, the drug Coaprovel®, like any other drug that directly affects the RAAS, cannot be used during pregnancy.

Thiazide diuretics cross the placental barrier and are found in umbilical cord blood. The use of diuretics in pregnant women is not recommended, because the development of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that are observed in adults is possible.

If pregnancy is diagnosed during treatment with Coaprovel®, you should stop taking it as soon as possible.

Breastfeeding period. It is not known whether irbesartan or its metabolites passes into breast milk; hydrochlorothiazide passes into breast milk. Thiazide diuretics, when used in high doses, causing intense diuresis, can suppress lactation. Coaprovel® is contraindicated for use during the entire period of breastfeeding due to the potential risk to the infant. Therefore, after assessing the ratio of the expected benefit of taking the drug for the mother and the potential risk for the child, either breastfeeding or taking Coaprovel® should be stopped.

Side effects

The following adverse events are presented in accordance with the following gradations of the frequency of their occurrence according to the WHO classification: very often (≥1/10); often (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000, including isolated reports); unknown frequency (according to available data, it is not possible to determine the frequency of occurrence of an adverse event).

Irbesartan/hydrochlorothiazide combination

In clinical studies, the safety of the combination of irbesartan and hydrochlorothiazide was assessed in approximately 2750 patients, including 1540 patients with hypertension who received this treatment for 6 months and more than 960 patients who received it for 1 year or more. Adverse events in patients receiving Coaprovel® were usually moderate and transient, and their frequency was not related to the dose taken. The incidence of adverse events was also independent of age, gender and race.

In placebo-controlled studies of 898 patients receiving the irbesartan/hydrochlorothiazide combination (usual treatment duration 2–3 months), treatment discontinuation due to any clinical or laboratory adverse event was significantly less common in patients receiving the irbesartan combination. and hydrochlorothiazide (3.6%) than in patients taking placebo (6.8%).

Adverse events observed with the combination of irbesartan and hydrochlorothiazide in placebo-controlled studies in patients with arterial hypertension

From the nervous system: often - dizziness, headache; infrequently - orthostatic dizziness.

From the heart: infrequently - tachycardia, changes on the ECG.

From the side of blood vessels: infrequently - excessive decrease in blood pressure; peripheral edema, in particular edema of the lower extremities; rushes of blood to the skin of the face, syncope.

From the gastrointestinal tract: often - nausea/vomiting; uncommon - diarrhea, dry oral mucosa, abdominal pain.

From the kidneys and urinary tract: often - change in frequency of urination.

From the genital organs and breast: infrequently - sexual dysfunction (weakened libido, erectile dysfunction).

General disorders and disorders at the injection site: often - increased fatigue; infrequently - weakness.

From the skin and subcutaneous tissues: infrequently - skin rash, itching.

From the musculoskeletal and connective tissue side: infrequently - myalgia, bone pain, weakness in the limbs.

Adverse events observed in placebo-controlled studies using the combination of irbesartan and hydrochlorothiazide as initial treatment in patients with severe to moderate hypertension

Initial treatment with a combination of irbesartan and hydrochlorothiazide. The following adverse events of the combination of irbesartan and hydrochlorothiazide in studies conducted in patients with severe and moderate arterial hypertension were similar to the adverse events described above observed in previously conducted studies in arterial hypertension.

In a clinical study conducted in moderate arterial hypertension (mean sitting DBP 90–110 mmHg), the types and frequency of adverse events observed in patients receiving Coaprovel® as initial therapy were similar to the profile adverse events in patients receiving initial treatment with irbesartan or hydrochlorothiazide monotherapy. There were no cases of syncope reported in the combination therapy group, and one case of syncope was reported in the hydrochlorothiazide monotherapy group.

The frequency of the above-mentioned adverse events during therapy with Coaprovel®, monotherapy with irbesartan and monotherapy with hydrochlorothiazide, respectively, was: 0.9/0/0% - for excessive reduction in blood pressure; 3/3.8/1% - for dizziness; 5.5/3.8/4.8% - for headaches; 1.2/0/1% for hyperkalemia and 0.9/0/0% for hypokalemia.

The rate of treatment discontinuation due to adverse events during therapy with Coaprovel®, irbesartan monotherapy and hydrochlorothiazide monotherapy was 6.7/3.8/4.8%.

In a clinical study conducted in severe arterial hypertension (sitting DBP ≥110 mmHg), the overall pattern of adverse events during 7 weeks of follow-up was similar in patients receiving Coaprovel® as initial therapy and in patients receiving Coaprovel® as initial therapy. who received irbesartan as initial therapy. The frequency of the above-mentioned adverse events for the drug Coaprovel® and irbesartan was respectively: 0 and 0% - for syncope; 0.6 and 0% - for excessive reduction in blood pressure; 3.6 and 4% - for dizziness; 4.3 and 6.6% - for headache; 0.2 and 0% for hyperkalemia and 0.6 and 0.4% for hypokalemia.

The rate of treatment discontinuation due to adverse events when taking Coaprovel® and when taking irbesartan monotherapy was 2.1 and 2.2%, respectively.

Laboratory and instrumental data: clinically significant changes in the results of laboratory tests were not identified during controlled clinical studies of the drug Coaprovel®.

Post-marketing experience

Irbesartan. As with other angiotensin II receptor antagonists, extremely rare cases of hypersensitivity reactions (angioedema, urticaria) were observed with irbesartan monotherapy. In addition, the following adverse reactions were observed with the use of irbesartan after its marketing: vertigo, asthenia, hyperkalemia, jaundice, myalgia, increased liver function tests, hepatitis, tinnitus and impaired renal function, including cases of acute renal failure in patients at-risk groups.

Hydrochlorothiazide. With monotherapy with hydrochlorothiazide, the following adverse events were observed (regardless of their connection with taking hydrochlorothiazide): anorexia, irritation of the gastric mucosa, diarrhea, constipation, jaundice (associated with intrahepatic cholestasis), pancreatitis, sialadenitis, vertigo, paresthesia, xanthopsia, leukopenia, neutropenia /agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, photosensitivity reactions, fever, urticaria, necrotizing angiitis (vasculitis, cutaneous vasculitis), respiratory distress syndrome (including pneumonitis and pulmonary edema), anaphylactic reactions, toxic epidermal necrolysis, hyperglycemia, glycosuria, hyperuricemia, water and electrolyte imbalance (including hyponatremia and hypokalemia), renal dysfunction, interstitial nephritis, muscle spasms, weakness, anxiety, transient visual acuity.

Coaprovel

The risk of developing a pronounced decrease in blood pressure increases against the background of a decrease in blood volume and hyponatremia caused by the use of diuretics, a diet low in Na +, diarrhea, and vomiting, so these conditions must be corrected before starting drug therapy.

In patients with chronic renal failure, azotemia may occur during therapy with thiazide diuretics. Periodic monitoring of serum K+, creatinine and uric acid concentrations is recommended. There is no experience with the use of the drug in patients with recent kidney transplantation.

Therapy with thiazide diuretics can cause mini-festival of latent diabetes mellitus.

diabetes, and also reduce glucose tolerance. In patients with diabetes mellitus, dose adjustment of insulin or oral hypoglycemic drugs may be required.

Therapy with hydrochlorothiazide at a dose of 12.5 mg contained in the drug has virtually no effect on the concentration of cholesterol and triglycerides.

Hyperuricemia or exacerbation of gout may occur during therapy with thiazide diuretics.

Treatment with hydrochlorothiazide can lead to disturbances in water and electrolyte balance (hypokalemia, hyponatremia and hypochloremic alkalosis). Concomitant use of irbesartan may reduce diuretic-induced hypokalemia. The risk of hypokalemia increases with concomitant treatment with corticosteroids or ACTH. Irbesartan may lead to hyperkalemia, especially in the presence of renal failure and/or CHF or diabetes mellitus. During the treatment period, periodic monitoring of K+ concentration in the blood serum is recommended.

There is no evidence that irbesartan can reduce or prevent diuretic-induced hyponatremia. Cl- deficiency is usually mild and does not require treatment.

Thiazide diuretics can cause hypomagnesemia, as well as reduce renal calcium excretion and cause mild hypercalcemia, provided there are no disturbances in Ca2+ metabolism. Hypercalcemia may be a sign of latent hyperparathyroidism; in this case, the drug should be discontinued until a study of the function of the parathyroid glands is carried out.

Hydrochlorothiazide may cause a positive drug test.

In patients in whom vascular tone and renal function depend mainly on

from the activity of the renin-angiotensin-aldosterone system (including CHF, kidney disease, including renal artery stenosis), therapy with angiotensin II receptor antagonists can cause a marked decrease in blood pressure, azotemia, oliguria or, in rare cases, acute renal failure. An excessive decrease in blood pressure due to coronary artery disease or other cardiovascular diseases can lead to myocardial infarction or stroke.

The development of allergic reactions to hydrochlorothiazide is more likely in patients with a history of such reactions.

Exacerbation of SLE has been observed with the use of thiazide diuretics.

It must be taken into account that in rare cases, dizziness and increased fatigue may occur during treatment, so caution should be exercised when engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reaction (including when driving a car).