Coaprovel^® (Tablets) Instructions for Use

ATC Code

C09DA04 (Irbesartan and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Irbesartan (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Combined antihypertensive drug (diuretic + angiotensin II receptor antagonist)

Pharmacotherapeutic Group

Antihypertensive combination agent (angiotensin II receptor antagonist + diuretic)

Pharmacological Action

A combined antihypertensive drug containing the angiotensin II receptor antagonist (ARA II) Irbesartan and the thiazide diuretic Hydrochlorothiazide. The combination of ingredients has an additive antihypertensive effect, reducing blood pressure to a greater extent than each of the components separately.

Irbesartan

Irbesartan is a selective angiotensin II receptor antagonist (type AT₁) that 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 its source or synthesis pathway, including the pronounced vasoconstrictor effect and increased aldosterone secretion, which are mediated through AT₁ receptors located on the surface of vascular smooth muscle cells and in the adrenal cortex. It has no agonistic activity towards AT₁ receptors and has a much greater affinity (more than 8500 times) 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 receptors of other hormones or ion channels involved in the regulation of blood pressure and sodium homeostasis. Blockade of AT₁ receptors by irbesartan interrupts the feedback loop in the renin-angiotensin system, leading to an increase in plasma concentrations of renin and angiotensin II. After administration of irbesartan at recommended doses, the plasma concentration of aldosterone decreases, without significantly affecting serum potassium levels (the mean 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 serum uric acid concentration or the rate of uric acid excretion by the kidneys.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic with diuretic, natriuretic, and antihypertensive action. The mechanism of the antihypertensive action of thiazide diuretics, such as hydrochlorothiazide, is not fully understood. Thiazide diuretics affect the tubular mechanisms of electrolyte reabsorption in the kidneys, increasing the excretion of sodium and chlorides 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. Concurrent use of an angiotensin II receptor antagonist helps to reduce potassium losses associated with the action of thiazide diuretics.

Irbesartan/Hydrochlorothiazide

The antihypertensive effect of irbesartan in combination with hydrochlorothiazide appears after the first dose and becomes significant within 1-2 weeks of use, with the maximum antihypertensive effect achieved by 6-8 weeks of treatment. In long-term clinical studies, the antihypertensive effect of the Irbesartan/Hydrochlorothiazide combination was maintained for more than one year.

The Irbesartan/Hydrochlorothiazide combination, when used in the therapeutic dose range, has a dose-dependent and additive antihypertensive effect. In patients who did not experience sufficient blood pressure reduction with irbesartan monotherapy at a dose of 300 mg, the addition of hydrochlorothiazide at a dose of 12.5 mg once daily to irbesartan monotherapy at a dose of 300 mg once daily led to an additional reduction in diastolic blood pressure at the end of the dosing interval (i.e., 24 hours after drug administration) by 6.1 mm Hg (compared to the addition of placebo). There was an overall reduction in systolic blood pressure (SBP)/diastolic blood pressure (DBP) with the combination of irbesartan 300 mg and hydrochlorothiazide 12.5 mg (compared to placebo) of up to -13.6/-11.5 mm Hg. A single daily dose of irbesartan 150 mg and hydrochlorothiazide 12.5 mg demonstrated (compared to placebo) a mean reduction in SBP/DBP at the end of the dosing interval of 12.9/6.9 mm Hg, respectively. The maximum antihypertensive effect developed within 3-6 hours. With 24-hour blood pressure monitoring, administration of Coaprovel^® at a dose of 12.5 + 150 mg once daily caused a sustained reduction in blood pressure throughout the day (mean reduction in SBP/DBP was -15.8/-10 mm Hg, respectively, compared to placebo). The T/R ratio (the ratio of blood pressure measured at the end of the dosing interval [residual effect] to blood pressure during the maximum effect of the Irbesartan/Hydrochlorothiazide combination), expressed as a percentage, was at least 68%.

In a clinical study of patients with insufficient blood pressure reduction on hydrochlorothiazide monotherapy at a dose of 25 mg, the addition of irbesartan to hydrochlorothiazide caused an additional mean reduction in SBP/DBP of 11.1/7.2 mm Hg, respectively, compared to hydrochlorothiazide monotherapy. Blood pressure decreased equally in the standing and lying positions. Orthostatic effects were rarely observed, but their occurrence is possible in patients with hyponatremia and/or hypovolemia.

The efficacy of the Irbesartan/Hydrochlorothiazide combination does not depend on age, race, or gender. The overall antihypertensive response to the combination in Black patients and patients of other races was similar.

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

After oral administration of hydrochlorothiazide, the diuretic effect occurs within the first 2 hours, diuresis peaks at about 4 hours and lasts for about 6-12 hours.

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

Data from epidemiological studies

In the course of two epidemiological studies based on the Danish National Cancer Registries, a relationship was identified between hydrochlorothiazide use and the risk of non-melanoma skin cancer and lip cancer (basal cell carcinoma and squamous cell carcinoma). In one study, the use of hydrochlorothiazide in high doses (cumulative dose ≥50000 mg) was associated with the development of basal cell carcinoma and squamous cell carcinoma. In another study, a possible association was observed between the risk of lip cancer and hydrochlorothiazide use. A clear dose-response relationship was observed for patients who received at least one dose, for patients who received a high dose (≥25000 mg), and for patients who received the maximum cumulative dose (≥100000 mg).

Pharmacokinetics

Neither Irbesartan nor Hydrochlorothiazide alters the pharmacokinetics of each other.

Absorption

Irbesartan and Hydrochlorothiazide are active substances upon oral administration and do not require biotransformation to convert into an active form.

After oral administration of Coaprovel^®, the absolute bioavailability of irbesartan is 60-80%, and that of hydrochlorothiazide is 50-80%. Food intake does not affect the bioavailability of the active substances of the drug. After oral administration, C_max of irbesartan in plasma is reached in 1.5-2 hours, and that of hydrochlorothiazide in 1-2.5 hours.

Distribution

The binding of irbesartan to plasma proteins is approximately 96%, and binding to cellular components is negligible. The V_d of irbesartan is 53-93 L (0.72-1.24 L/kg). With daily single administration of irbesartan, C_ss is reached in 3 days, with limited accumulation of irbesartan in plasma (less than 20%).

The binding to plasma proteins of hydrochlorothiazide is 68%, V_d is 3.6-7.8 L/kg. Hydrochlorothiazide crosses the placental barrier and is excreted in breast milk.

Metabolism

After oral or intravenous administration of ¹⁴C-irbesartan, 80-85% of the radioactivity circulating in the plasma is accounted for by unchanged Irbesartan. Irbesartan is metabolized in the liver by oxidation and conjugation with glucuronic acid. The main metabolite in the systemic circulation is irbesartan glucuronide (approximately 6%). The oxidation of irbesartan is carried out mainly by the isoenzyme P450 CYP2C9, the participation of the CYP3A4 isoenzyme in the metabolism of irbesartan is insignificant. Irbesartan is not metabolized by most of the isoenzymes that are usually involved in drug metabolism (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6 or CYP2E1), and does not cause their inhibition or induction. Irbesartan does not induce or inhibit the CYP3A4 isoenzyme.

Hydrochlorothiazide is not metabolized.

Excretion

Irbesartan and its metabolites are eliminated from the body both through the intestines (with bile) and by 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. The terminal T_1/2 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.

Hydrochlorothiazide is excreted by the kidneys. The mean plasma T_1/2 values of hydrochlorothiazide are 5-15 hours.

Pharmacokinetics in special patient groups

Women (compared to men) have slightly higher plasma concentrations of irbesartan. However, no gender-related differences in T_1/2 and accumulation of irbesartan are detected. Dose adjustment of irbesartan in women is not required. No gender-related differences in the effects of irbesartan were observed.

The AUC and C_max values of irbesartan in elderly patients (65-80 years) with normal renal and hepatic function were approximately 20-50% higher than in younger patients (18-40 years). Their terminal T_1/2 values were comparable. No age-related differences in the effects of irbesartan were observed.

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

In patients with impaired renal function or patients undergoing hemodialysis, the pharmacokinetic parameters of irbesartan do not change significantly. Irbesartan is not removed from the body by hemodialysis.

In volunteers without arterial hypertension, the AUC and T_1/2 of irbesartan in Black individuals were approximately 20-25% higher than in Caucasian individuals; their C_max of irbesartan was almost the same.

Indications

• Moderate or severe arterial hypertension (treatment of patients for whom combination therapy is indicated).

ICD codes

Dosage Regimen

Tablets

The drug is taken orally, once a day, regardless of meals.

Coaprovel^® is prescribed to patients whose blood pressure is insufficiently controlled by irbesartan or hydrochlorothiazide in monotherapy.

Coaprovel^® 12.5/150 mg (tablets containing Hydrochlorothiazide/Irbesartan 12.5/150 mg respectively) can be prescribed to patients whose blood pressure is insufficiently controlled by hydrochlorothiazide (12.5 mg/day) or irbesartan (150 mg/day) in monotherapy.

Coaprovel^® 12.5/300 mg/ (tablets containing Hydrochlorothiazide/Irbesartan 12.5/300 mg respectively) can be prescribed to patients whose blood pressure is insufficiently controlled by irbesartan (300 mg) or by Coaprovel^® 12.5/150 mg.

Coaprovel^® 25/300 mg (1 tab. containing Hydrochlorothiazide/Irbesartan 25/300 mg respectively or 2 tabs. containing Hydrochlorothiazide/Irbesartan 12.5/150 mg respectively) is recommended for patients whose blood pressure is insufficiently controlled by Coaprovel^® 12.5/300 mg.

The maximum daily dose is 2 tabs. of Coaprovel^® 12.5/150 mg or 1 tab. of Coaprovel^® 12.5/300 mg (Hydrochlorothiazide/Irbesartan 25/300 mg respectively).

If target blood pressure values are not achieved with Coaprovel^®, other antihypertensive drugs (beta-blockers, long-acting calcium channel blockers) can be added to the therapy.

In patients with mild to moderate renal impairment (CrCl >30 ml/min), dose adjustment is not required. In patients with severe renal impairment (CrCl <30 ml/min), the use of Coaprovel^® is contraindicated.

In patients with mild to moderate hepatic impairment (5-9 points on the Child-Pugh scale), dose adjustment is not required. In patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale), caution should be exercised when using the drug.

In elderly patients (over 65 years), dose adjustment is not required.

The use of the drug in children and adolescents under 18 years of age is contraindicated (insufficient clinical data on the safety and efficacy of the drug).

In patients with severe hypovolemia and/or hyponatremia, for example, in patients receiving intensive diuretic therapy, the water-electrolyte balance should be corrected before starting the use of Coaprovel^®.

Adverse Reactions

The frequency of adverse reactions was determined in accordance with the WHO classification: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency unknown (cannot be estimated from the available data).

Hydrochlorothiazide/Irbesartan combination

In clinical studies, the safety of the hydrochlorothiazide and irbesartan combination was assessed in approximately 2750 patients, including 1540 patients with arterial hypertension who received this treatment for 6 months and more than 960 patients who received the drug for one year or more. Adverse events in patients receiving the Hydrochlorothiazide/Irbesartan combination were usually mild and transient, and their frequency was not related to the dose taken. The frequency of adverse events also did not depend on age, gender, or race.

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

Adverse events observed with the use of the Hydrochlorothiazide/Irbesartan combination in placebo-controlled studies in patients with arterial hypertension

Nervous system disorders common – dizziness, headache; uncommon – orthostatic dizziness.

Cardiac and vascular disorders uncommon – tachycardia, ECG changes, excessive decrease in blood pressure, peripheral edema (in particular, lower limb edema), flushing, syncope.

Gastrointestinal disorders common – nausea, vomiting; uncommon – diarrhea, dry mouth, abdominal pain.

Renal and urinary disorders common – change in frequency of urination.

Reproductive system and breast disorders uncommon – erectile dysfunction, decreased libido.

Musculoskeletal and connective tissue disorders uncommon – myalgia, bone pain, limb weakness.

Skin and subcutaneous tissue disorders uncommon – skin rash, pruritus.

General disorders and administration site conditions common – increased fatigue; uncommon – asthenia.

Adverse events observed in placebo-controlled studies with the use of the Hydrochlorothiazide/Irbesartan combination as initial treatment in patients with severe and moderate arterial hypertension

Initial treatment with the Hydrochlorothiazide/Irbesartan combination

The adverse events noted below that developed with the use of the hydrochlorothiazide and irbesartan combination in studies involving patients with severe and moderate arterial hypertension were similar to the adverse events described above observed in previously conducted studies.

In a clinical study involving patients with moderate arterial hypertension (mean sitting DBP 90-110 mm Hg) receiving Coaprovel^® as initial therapy, the types and frequency of adverse events were similar to the adverse event profile in patients receiving initial therapy with irbesartan monotherapy or hydrochlorothiazide monotherapy. There were no cases of syncope in the combination therapy group, and one case of syncope was registered in the hydrochlorothiazide monotherapy group.

The frequency of the above adverse events during therapy with Coaprovel^®, irbesartan monotherapy and hydrochlorothiazide monotherapy, respectively, was: 0.9%, 0% and 0% for excessive decrease in blood pressure; 3.0%, 3.8% and 1.0% for dizziness; 5.5%, 3.8% and 4.8% for headache; 1.2%, 0% and 1.0% for hyperkalemia and 0.9%, 0% and 0% for hypokalemia.

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

In a clinical study conducted in patients with severe arterial hypertension (seated DBP ≥110 mmHg) who received Coaprovel^® as initial therapy, the overall pattern of adverse events over the 7-week observation period was similar to that in patients who received Irbesartan as initial therapy. The frequency of the aforementioned adverse events for Coaprovel^® and irbesartan was, respectively: 0% and 0% for syncope; 0.6% and 0% for excessive blood pressure reduction; 3.6% and 4.0% for dizziness; 4.3% and 6.6% for headache; 0.2% and 0% for hyperkalemia and 0.6% and 0.4% for hypokalemia, respectively.

The frequency of treatment discontinuation due to adverse events during administration of Coaprovel^® and during irbesartan monotherapy was 2.1 and 2.2%, respectively. In a clinical study involving patients with moderate arterial hypertension who received Coaprovel^® as initial therapy (mean seated DBP 90-110 mmHg), the types and frequency of adverse events were similar to the adverse event profile in patients receiving initial treatment with irbesartan or hydrochlorothiazide monotherapy. No cases of syncope were reported in the combination therapy group, while one case of syncope was reported in the hydrochlorothiazide monotherapy group.

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

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

In a clinical study involving patients with severe arterial hypertension (seated DBP ≥110 mmHg) who received Coaprovel^® as initial therapy, the overall pattern of adverse events over the 7-week observation period was similar to that in patients who received Irbesartan as initial therapy. The frequency of the aforementioned adverse events for Coaprovel^® and irbesartan was, respectively: 0% and 0% for syncope; 0.6% and 0% for excessive blood pressure reduction; 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 frequency of treatment discontinuation due to adverse events during administration of Coaprovel^® and during irbesartan monotherapy was 2.1% and 2.2%, respectively.

Laboratory and Instrumental Data

No clinically significant changes in laboratory test results were detected during controlled clinical studies of Coaprovel^®.

Post-Marketing Experience

Irbesartan

As with the use of other angiotensin II receptor antagonists, cases of hypersensitivity reactions (angioedema, urticaria, anaphylactic reactions, including anaphylactic shock) have been observed with irbesartan monotherapy. Furthermore, the following adverse reactions have been observed during the post-marketing use of irbesartan: vertigo, asthenia, hyperkalemia, jaundice, myalgia, increased liver function test results, hepatitis, tinnitus (ringing in the ears), thrombocytopenia (including thrombocytopenic purpura), anemia, psoriasis (including exacerbation of psoriasis), photosensitivity, impaired renal function, including cases of acute renal failure in at-risk patients, hypoglycemia.

Hydrochlorothiazide

The following adverse events have been observed with hydrochlorothiazide monotherapy (regardless of their relationship to hydrochlorothiazide intake): non-melanoma skin cancer and lip cancer (basal cell carcinoma of the skin and squamous cell carcinoma of the skin), anorexia, gastric mucosal irritation, 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-electrolyte balance disorders (including hyponatremia and hypokalemia), impaired renal function, interstitial nephritis, muscle spasms, weakness, restlessness, transient blurred vision, secondary acute angle-closure glaucoma and/or acute myopia, choroidal effusion.

Contraindications

• Hypersensitivity to the active substances or to any of the excipients of the drug;
• Hypersensitivity to other sulfonamide derivatives (since Hydrochlorothiazide is a sulfonamide derivative);
• Severe renal failure (CrCl ≤30 ml/min);
• Anuria (due to the presence of hydrochlorothiazide in the drug);
• Severe hepatic impairment, biliary cirrhosis, cholestasis;
• Refractory hypokalemia, hypercalcemia;
• Concomitant use with drugs containing aliskiren in patients with diabetes mellitus or with moderate or severe renal impairment (GFR <60 ml/min/1.73 m²);
• Concomitant use with ACE inhibitors in patients with diabetic nephropathy;
• Pregnancy;
• Lactation period (breastfeeding);
• Age under 18 years (efficacy and safety have not been established);
• Hereditary galactose intolerance, lactase deficiency or glucose/galactose malabsorption syndrome.

With caution

• Aortic or mitral stenosis;
• Hypertrophic obstructive cardiomyopathy (HOCM);
• Hypovolemia or hyponatremia occurring during intensive diuretic therapy, hemodialysis, adherence to a salt-restricted diet, diarrhea, vomiting (risk of excessive blood pressure reduction);
• Patients with renal function dependent on the activity of the RAAS, including patients with arterial hypertension with bilateral or unilateral renal artery stenosis or patients with chronic heart failure of functional class III-IV (according to the NYHA classification);
• Coronary artery disease and/or atherosclerotic cerebrovascular disease (risk of increased myocardial or cerebral ischemia, up to the development of myocardial infarction or stroke with excessive blood pressure reduction);
• Mild and moderate renal failure (CrCl from 60 to 30 ml/min) (risk of increased azotemia, increased blood uric acid concentration, due to the presence of hydrochlorothiazide in the drug, and development of hyperkalemia, due to the presence of irbesartan in the drug);
• Status after kidney transplantation (no clinical experience);
• Hepatic impairment of any severity or progressive liver disease (due to the presence of hydrochlorothiazide in the drug, since even minor water-electrolyte imbalances in such patients can provoke hepatic coma);
• Diabetes mellitus (due to the presence of hydrochlorothiazide in the drug, a decrease in glucose tolerance, 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;
• Concomitant use of potassium-sparing drugs and/or potassium-containing salt substitutes (risk of hyperkalemia);
• Systemic lupus erythematosus (due to the presence of hydrochlorothiazide in the drug, as there are reports of exacerbation or worsening of systemic lupus erythematosus with the use of thiazide diuretics);
• Concomitant use of other antihypertensive drugs (possibility of potentiating their antihypertensive effect);
• Sympathectomy (risk of increased antihypertensive effect of hydrochlorothiazide);
• Concomitant use of ACE inhibitors or aliskiren, since compared with monotherapy, dual blockade of the RAAS carries an increased risk of excessive blood pressure reduction, hyperkalemia, and changes in renal function;
• History of allergic reaction to penicillins and sulfonamides (a risk factor for the development of an idiosyncratic reaction observed with the use of sulfonamides or sulfonamide derivatives, and manifested as acute angle-closure glaucoma and/or acute myopia);
• Psoriasis (including history) due to possible exacerbation of psoriasis.

Use in Pregnancy and Lactation

Pregnancy

There is no experience with the use of Coaprovel^® during pregnancy. Given that the use of ACE inhibitors by pregnant women in the second and third trimesters of pregnancy has been observed to cause damage and death to the developing fetus, Coaprovel^®, like any other drug that directly affects the RAAS, should not 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, as it may lead to the development of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions observed in adults.

If pregnancy is diagnosed during treatment with Coaprovel^®, the drug should be discontinued as soon as possible.

Breastfeeding period

It is not known whether Irbesartan or its metabolites are excreted in breast milk. Hydrochlorothiazide is excreted in breast milk. Thiazide diuretics, when used in high doses causing intense diuresis, can suppress lactation.

Coaprovel^® is contraindicated for use throughout the entire period of breastfeeding due to the potential risk to the breastfed infant. Therefore, after assessing the ratio of the expected benefit of the drug for the mother and the potential risk for the child, either breastfeeding or the use of Coaprovel^® should be discontinued.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment, biliary cirrhosis, cholestasis.

The drug should be prescribed with caution in hepatic impairment of any severity or progressive liver disease.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal failure (CrCl ≤30 ml/min), anuria.

The drug should be prescribed with caution to patients with renal function dependent on the activity of the RAAS, including patients with arterial hypertension with bilateral or unilateral renal artery stenosis; in mild and moderate renal failure (CrCl from 60 to 30 ml/min); status after kidney transplantation (no clinical experience).

Pediatric Use

The use of the drug is contraindicated under the age of 18 years.

Geriatric Use

In elderly patients (over 65 years of age), dose adjustment of the drug is not required.

Special Precautions

Non-melanoma skin cancer and lip cancer

In two epidemiological studies based on the Danish National Cancer Registries, an increased risk of non-melanoma skin cancer and lip cancer (basal cell carcinoma of the skin and squamous cell carcinoma of the skin) was recorded with increasing cumulative dose of hydrochlorothiazide.

Hydrochlorothiazide has a photosensitizing effect, which may be the cause of non-melanoma skin cancer and lip cancer.

Patients taking Hydrochlorothiazide should be informed about the risk of non-melanoma skin cancer and lip cancer and the need for regular skin examination for any new changes, as well as changes in existing ones. If any suspicious skin lesions are detected, the patient should immediately consult a doctor.

Particular attention should be paid to patients who have known risk factors for skin cancer, including: skin phototypes I and II (pale and light skin), family history of skin cancer, history of skin damage caused by solar or ultraviolet radiation and radiation therapy, smoking and taking drugs with photosensitizing effects. Patients should be advised to take measures to prevent skin cancer, such as limiting time in the sun and under ultraviolet radiation, and using appropriate sun protection while in the sun. Any suspicious skin lesions should be promptly investigated, including histological examination of material obtained by biopsy of the tissue at the site of the lesion. It may also be necessary to reconsider the decision to use hydrochlorothiazide in patients who have previously had non-melanoma skin cancer and lip cancer.

Excessive blood pressure reduction in patients with hypovolemia

The use of Coaprovel^® is rarely accompanied by excessive blood pressure reduction in patients with arterial hypertension without other risk factors for excessive blood pressure reduction. Excessive blood pressure reduction, accompanied by clinical symptoms, may develop in patients with hyponatremia/hypovolemia. Hypovolemia and/or hyponatremia should be corrected before starting Coaprovel^®. Thiazide diuretics may potentiate the effect of other antihypertensive agents.

Renal function disorders

The use of Coaprovel^® is contraindicated in patients with severe renal failure (CrCl ≤30 ml/min). In patients with impaired renal function, an increase in azotemia associated with the hydrochlorothiazide content in the drug is possible. There are no clinical data regarding the use of the drug in patients who have recently undergone kidney transplantation. When taking Coaprovel^® in patients with impaired renal function, periodic monitoring of serum potassium, creatinine and uric acid levels is recommended. If renal failure progresses, discontinuation of diuretic therapy should be considered.

Hepatic function disorders

Coaprovel^® should be used with caution in patients with impaired liver function or progressive liver disease, since even minor changes in water-electrolyte balance can provoke the development of hepatic coma. There is no clinical experience with the use of Coaprovel^® in patients with liver disease.

Water-electrolyte balance disorders and metabolic disorders

Thiazides, including Hydrochlorothiazide, can cause water-electrolyte imbalance (hypokalemia, hyponatremia and hypochloremic alkalosis). Although hypokalemia may develop with the use of thiazide diuretics in monotherapy, especially in high doses, the concomitant administration of irbesartan may reduce the hypokalemia caused by hydrochlorothiazide. Conversely, Irbesartan, which is part of Coaprovel^®, may contribute to the development of hyperkalemia, especially in the presence of renal failure, heart failure, and diabetes mellitus. Regular monitoring of serum potassium levels is recommended in at-risk patients.

Potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes should be used with caution in combination with Coaprovel^®.

Chloride deficiency is usually minor and generally does not require treatment.

Thiazides reduce the renal excretion of calcium and cause a transient and slight increase in serum calcium levels. The development of clinically significant hypercalcemia may indicate the possible presence of hyperparathyroidism in the patient. Thiazide intake should be discontinued before testing parathyroid function.

Thiazides increase the renal excretion of magnesium ions, which can lead to the development of hypomagnesemia.

During treatment with thiazide diuretics, the need for insulin may increase in patients with diabetes mellitus, and latent diabetes mellitus may become manifest.

Treatment with thiazide diuretics is associated with increased blood cholesterol and triglyceride levels; however, the 12.5 mg dose contained in Coaprovel^® has virtually no effect on blood cholesterol and triglyceride levels.

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

Patients at risk of developing water-electrolyte balance disorders and metabolic disorders may require monitoring of laboratory parameters.

Hypoglycemia

Coaprovel^® may cause hypoglycemia, especially in patients receiving drugs for the treatment of diabetes mellitus. Therefore, dose adjustment of drugs for the treatment of diabetes mellitus, such as repaglinide or insulin, may be required.

Systemic lupus erythematosus

Exacerbation or worsening of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

Acute myopia, secondary acute angle-closure glaucoma and choroidal effusion

Sulfonamides or sulfonamide derivatives can cause idiosyncratic reactions leading to the development of secondary acute angle-closure glaucoma, acute myopia and choroidal effusion with visual field defects. Although Hydrochlorothiazide is a sulfonamide derivative, only cases of acute angle-closure glaucoma have been reported to date, the frequency of which and the causal relationship cannot be established based on the available data. Symptoms of acute angle-closure glaucoma include: acute decrease in visual acuity or eye pain, usually occurring within a period of several hours to several weeks after starting the drug. If left untreated, acute angle-closure glaucoma can lead to permanent vision loss. If these symptoms occur, the drug should be discontinued as soon as possible. If intraocular pressure cannot be normalized, urgent medical or surgical treatment may be required. Risk factors for the development of acute angle-closure glaucoma are a history of allergic reactions to sulfonamides and penicillins.

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

Dual blockade of the RAAS with the combination of Coaprovel^® with ACE inhibitors or aliskiren is not recommended, as there is an increased risk of a sharp decrease in blood pressure, the development of hyperkalemia and impaired renal function compared with monotherapy.

The use of Coaprovel^® in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment with GFR <60 ml/min/1.73 m² body surface area and is not recommended in other patients.

Use of the drug Coaprovel^® in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Patients with kidney function dependent on the activity of the RAAS

As a consequence of inhibiting the RAAS, a deterioration in kidney function can be expected in predisposed patients. In patients with kidney function dependent on the activity of the RAAS (patients with arterial hypertension and stenosis of the renal artery of one or both kidneys, patients with chronic heart failure of functional class III and IV [according to the NYHA classification]), treatment with drugs that affect the RAAS was accompanied by oliguria and/or progressive azotemia and rarely by acute renal failure and/or death. The possibility of a similar effect when using ARB II, including the drug Coaprovel^®, cannot be excluded.

Patients after sympathectomy

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

Aortic orifice stenosis and mitral valve stenosis, hypertrophic obstructive cardiomyopathy

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

Primary hyperaldosteronism

The use of the drug 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 in doping control.

Patients with a burdened allergic history or bronchial asthma

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

Effect on laboratory parameters

Due to the presence of hydrochlorothiazide, the drug Coaprovel^® may affect laboratory parameters of parathyroid gland function.

Psoriasis

In patients with psoriasis (including in the medical history), the decision to use the drug should be made only after a thorough assessment of the risk/benefit ratio due to the possible exacerbation of psoriasis.

Photosensitivity

Cases of photosensitivity reactions have been reported with the use of thiazide diuretics. If such reactions occur when using hydrochlorothiazide, it is recommended to discontinue the drug. If repeated diuretic treatment is unavoidable, it is recommended to protect areas exposed to sunlight or artificial ultraviolet radiation.

Excipients

The drug Coaprovel^® contains lactose. Patients with rare hereditary diseases associated with galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Effect on the ability to drive vehicles and mechanisms

The effect of the drug Coaprovel^® on the ability to drive vehicles or engage in other potentially hazardous activities requiring increased attention and high speed of psychomotor reactions has not been 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 (including working at heights, work of an air traffic controller, work with mechanisms). However, caution should be exercised when engaging in potentially hazardous activities (due to the possibility of developing dizziness, weakness and, as a result, decreased attention and slowed speed of psychomotor reactions).

Overdose

There is experience with the use of irbesartan in doses up to 900 mg/day for 8 weeks without the development of toxic effects.

Symptoms The most common symptoms observed in adults with an overdose of hydrochlorothiazide were symptoms caused by disturbances in the electrolyte composition of the blood (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from an excessive diuretic effect. In case of simultaneous use of cardiac glycosides (for example, digoxin) or antiarrhythmic drugs (for example, sotalol), hypokalemia may contribute to the development of arrhythmias. With an overdose of the drug, excessive decrease in blood pressure, development of bradycardia and tachycardia are possible.

Treatment: There is no specific information regarding the treatment of overdose with the drug Coaprovel^®. Constant monitoring of the patient’s condition should be established and, if necessary, symptomatic and supportive therapy should be carried out, including restoration of fluid and electrolyte losses. In case of overdose, it is recommended to induce vomiting and/or perform gastric lavage. Irbesartan is not removed from the body by hemodialysis. The degree of removal of hydrochlorothiazide by hemodialysis has not been established.

Drug Interactions

Irbesartan

Based on in vitro data, no interaction of irbesartan with drugs metabolized by cytochrome P450 isoenzymes (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4) is expected. Irbesartan is mainly metabolized by the CYP2C9 isoenzyme and, to a lesser extent, undergoes glucuronidation. No significant pharmacokinetic and pharmacodynamic interaction was observed with the combined use of irbesartan with warfarin – a drug metabolized by the CYP2C9 isoenzyme.

Irbesartan does not change the pharmacokinetics of digoxin and simvastatin.

With the combined use of irbesartan with hydrochlorothiazide or nifedipine, the pharmacokinetics of irbesartan does not change.

Drugs containing aliskiren

Concomitant use of ARB II, including Irbesartan, with drugs containing aliskiren is contraindicated in patients with diabetes mellitus or with moderate and severe renal impairment (GFR <60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

ACE inhibitors

The use of ARB II, including Irbesartan, simultaneously with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Drugs affecting blood potassium levels

Based on experience with the use of other drugs affecting the RAAS, the simultaneous use of irbesartan with potassium preparations, salt substitutes containing potassium, potassium-sparing diuretics or other drugs that can increase plasma potassium levels (heparin) may lead to an increase in serum potassium levels, which requires careful monitoring of serum potassium levels in patients during treatment. The simultaneous use of hydrochlorothiazide with irbesartan may reduce the frequency of this effect.

NSAIDs, including selective COX-2 inhibitors

In elderly patients, patients with hypovolemia, or patients with impaired renal function, the use of NSAIDs, including COX-2 inhibitors, simultaneously with ARB II, including Irbesartan, may lead to deterioration of renal function, including the possible development of acute renal failure. These effects are usually reversible. Renal function should be periodically monitored in patients taking Irbesartan and NSAIDs simultaneously. With the simultaneous use of ARB II, including Irbesartan, and NSAIDs, including selective COX-2 inhibitors, the antihypertensive effect of ARB II may be weakened.

Repaglinide

Irbesartan may inhibit the OATP1B1 transporter. In a clinical study, it was reported that the use of irbesartan 1 hour before taking repaglinide increased the C_max and AUC of repaglinide (a substrate of the OATP1B1 transporter) by 1.8 and 1.3 times, respectively. In another study, no significant pharmacokinetic interaction was recorded with the combined use of irbesartan and repaglinide. Therefore, a dose adjustment of repaglinide may be required when treating diabetes mellitus in patients with arterial hypertension.

Hydrochlorothiazide

Ethanol, barbiturates or narcotic drugs

An increase in orthostatic hypotension caused by thiazide diuretics may be observed.

Oral hypoglycemic agents and insulin

An increase in the dose of the hypoglycemic agent may be required, since Hydrochlorothiazide may increase blood glucose concentration.

Cardiac glycosides, antiarrhythmic agents

When used in combination with Irbesartan/Hydrochlorothiazide, in case of hypokalemia and hypomagnesemia caused by the thiazide diuretic included in its composition, the danger of developing arrhythmias increases.

Drugs affecting serum potassium levels

It is recommended to monitor serum potassium levels and ECG with the simultaneous use of hydrochlorothiazide with drugs that affect serum potassium levels (for example, cardiac glycosides, antiarrhythmic drugs), as well as with drugs that can cause the development of torsades de pointes ventricular tachycardia (including some antiarrhythmic drugs)

• Class IA antiarrhythmic drugs (for example, quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic drugs (for example, amiodarone, sotalol, dofetilide, ibutilide);
• Some antipsychotic drugs (for example, thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Other drugs (for example, bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vancomycin).

Hypokalemia is a predisposing factor for the development of polymorphic ventricular tachycardia of the “torsades de pointes” type.

Calcium salts

Thiazide diuretics may increase serum calcium levels. If a patient requires the use of calcium preparations or calcium-sparing drugs (for example, vitamin D), it is necessary to monitor serum calcium levels and appropriately adjust the dosage regimen of calcium preparations.

Cholestyramine or colestipol

The absorption of hydrochlorothiazide in the presence of anion exchange resins is reduced. The drug Coaprovel^® should be taken at least 1 hour before or 4 hours after taking these drugs.

Amphotericin B (for parenteral administration) and laxatives affecting intestinal motility

Hydrochlorothiazide may enhance electrolyte imbalance, especially hypokalemia.

Non-depolarizing muscle relaxants (tubocurarine), local anesthetics, general anesthetics and premedication agents for general anesthesia

The effects of non-depolarizing muscle relaxants (for example, tubocurarine), local anesthetics, general anesthetics and premedication agents for general anesthesia may be potentiated by hydrochlorothiazide, and adjustment of their dosage regimen may be required. When combined with hydrochlorothiazide, local anesthetics, general anesthetics and premedication agents for general anesthesia should be used in reduced doses. If possible, hydrochlorothiazide should be discontinued one week before surgery.

Lithium salts

Diuretics reduce the renal clearance of lithium, in turn, Irbesartan increases serum lithium concentrations. All this increases the risk of developing toxic effects of lithium. Caution should be exercised when using the drug Coaprovel^® simultaneously with lithium salts, it is recommended in this case to monitor serum lithium levels.

Amantadine

Thiazides, including Hydrochlorothiazide, may increase the risk of adverse effects of amantadine.

Anti-gout drugs (probenecid, sulfinpyrazone and allopurinol)

When taken simultaneously with drugs used to treat gout (probenecid and sulfinpyrazone), dose adjustment of the latter may be required due to the possibility of increased serum uric acid concentrations when taking hydrochlorothiazide. Simultaneous use of thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol.

Inhibitors of the synthesis of endogenous prostaglandins (for example, NSAIDs)

In some patients, these drugs may reduce the effects of thiazide diuretics.

Methyldopa

There are isolated reports of the development of hemolytic anemia with the simultaneous use of hydrochlorothiazide and methyldopa.

Oral anticoagulants

Thiazides may reduce the effect of oral anticoagulants.

Iodine-containing contrast agents

In case of dehydration caused by taking thiazide diuretics, the risk of developing acute renal failure increases, especially when using iodine-containing contrast agents in high doses.

Other diuretics and antihypertensive agents

Hydrochlorothiazide may potentiate the effects of other antihypertensive agents, especially ganglion blockers and beta-blockers. Hydrochlorothiazide may interact with diazoxide. With their simultaneous use, blood glucose concentration, serum uric acid concentration and blood pressure should be monitored.

Carbamazepine

Simultaneous use of carbamazepine and hydrochlorothiazide may be associated with the risk of developing hyponatremia with clinical manifestations. Blood electrolyte levels should be monitored when these drugs are used simultaneously. If it is necessary to use carbamazepine, it is recommended, if possible, to use diuretics with a different mechanism of action.

Corticosteroids, ACTH

With simultaneous use, an increase in the risk of developing hypokalemia is possible.

Catecholamines (for example, norepinephrine)

The action of catecholamines may be weakened under the influence of thiazide diuretics.

Anticholinergic drugs (for example, atropine, biperiden)

With simultaneous use, an increase in the bioavailability of thiazide diuretics is possible due to slowing of gastrointestinal motility.

Cyclophosphamide, methotrexate

Thiazides may reduce the renal excretion of these cytotoxic agents and enhance their myelosuppressive effects.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 3 years. Do not take the drug after the expiration date indicated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.