Coaprovel, 12.5 mg+300 mg, film-coated tablets, 28 pcs.

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.

Directions for use and doses

Coaprovel is taken 1 time/day. regardless of food intake.

Coaprovel is prescribed to patients whose blood pressure is not sufficiently controlled by irbesartan or hydrochlorothiazide in monotherapy.

Coaprovel 150/12.5 mg (tablets containing irbesartan/hydrochlorothiazide 150/12.5 mg, respectively) can be prescribed to patients whose blood pressure is not sufficiently controlled with hydrochlorothiazide (12.5 mg/day) or irbesartan (150 mg/day) in monotherapy.

Coaprovel 300/12.5 mg (tablets containing irbesartan/hydrochlorothiazide 300/12.5 mg, respectively) can be prescribed to patients whose blood pressure is not sufficiently controlled by irbesartan (300 mg) or Coaprovel (150/12.5 mg).

If necessary, use in patients whose blood pressure is not sufficiently controlled with Coaprovel 300 mg/12.5 mg, the dose of the drugs in combination can be increased to 300 mg of irbesartan and 25 mg of hydrochlorothiazide per day: 2 tablets of Coaprovel 150/12.5 mg or 1 tablet of Coaprovel 300/25 mg.

Maximum daily dose: 2 tablets of Coaprovel 150/12.5 mg or 1 tablet of Coaprovel 300/25 mg. If it is impossible to achieve target blood pressure when using Coaprovel 300/25 mg, other antihypertensive drugs (beta-blockers, long-acting calcium channel blockers) can be added to it.

Contraindications for use

• severe renal failure (creatinine clearance less than 30 ml/min), anuria (due to the presence of hydrochlorothiazide in the drug);
• refractory hypokalemia, hypomagnesemia, hypercalcemia (due to the presence of hydrochlorothiazide in the drug);
• severe liver failure (class C /more than 9 points/ on the Child-Pugh scale), biliary cirrhosis of the liver, cholestasis (due to the presence of hydrochlorothiazide in the drug, since minimal disturbances in the water-electrolyte balance in such patients can provoke hepatic coma );
• hereditary galactose intolerance, lactase deficiency or impaired absorption of glucose and galactose;
• pregnancy;
• lactation period;
• age under 18 years (efficacy and safety have not been established);
• hypersensitivity to the components of the drug;
• hypersensitivity to other sulfonamide derivatives (hydrochlorothiazide is a sulfonamide derivative).

Carefully _

the drug should be used:

• with stenosis of the aortic or mitral valve; hypertrophic obstructive cardiomyopathy;
• with dehydration, hyponatremia, diarrhea, vomiting, following a diet with limited salt intake, treatment with diuretics (risk of developing severe arterial hypotension);
• with bilateral or unilateral stenosis of the renal arteries, chronic heart failure of functional class III-IV according to the NYHA classification (as with the use of other drugs affecting the RAAS, the risk of developing arterial hypotension, oliguria and/or azotemia and progressive acute renal failure cannot be excluded) ;
• with ischemic heart disease and/or atherosclerotic damage to the blood vessels of the brain (the risk of increased myocardial or cerebral ischemia up to the development of myocardial infarction or stroke with an excessive decrease in blood pressure);
• with mild to moderate renal failure (creatinine clearance from 60 to 30 ml/min), hemodialysis (risk of increased azotemia due to the presence of hydrochlorothiazide in the drug and the development of hyperkalemia due to the presence of irbesartan in the drug);
• after kidney transplantation (lack of experience in clinical use);
• with liver failure (classes A and B /5-6 points and 7-9 points/ according to the Child-Pugh classification);
• with diabetes mellitus (due to the presence of hydrochlorothiazide in the composition of the drug, a decrease in glucose tolerance is possible);
• with elevated levels of cholesterol and triglycerides in the blood (due to the presence of hydrochlorothiazide in the drug, since thiazide diuretics, especially in high doses, can increase the level of cholesterol and triglycerides in the blood);
• for gout (due to the presence of hydrochlorothiazide in the drug, an increase in the concentration of urate in the blood is possible);
• with hyperkalemia, while taking potassium-sparing drugs and or potassium-containing salt substitutes (risk of hyperkalemia);
• with systemic lupus erythematosus (due to the presence of hydrochlorothiazide in the drug, an exacerbation of this disease is possible);
• while taking other antihypertensive drugs (the possibility of potentiating their hypotensive effect);
• with latent hyperparathyroidism (due to the presence of hydrochlorothiazide in the drug, since thiazide diuretics, especially in high doses, increase the risk of developing or intensifying hypercalcemia);
• after sympathectomy (risk of increased hypotensive effect of hydrochlorothiazide);
• while taking lithium salts (hydrochlorothiazide increases the risk of lithium toxicity).