Co-router® (Coaprovel®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceHydrochlorothiazide + IrbesartanHydrochlorothiazide + Irbesartan
Dosage form: & nbspFilm-coated tablets.
Composition:

Tablets, film-coated, 12.5 mg + 150 mg

One tablet contains:

active ingredients: hydrochlorothiazide - 12.5 mg; irbesartan - 150 mg;

Excipients: lactose monohydrate 38.5 mg, microcrystalline cellulose 27.0 mg, croscarmellose sodium 12.0 mg, hypromellose 5.0 mg, magnesium stearate 2.5 mg, silicon dioxide 2.5 mg;

film sheath: Opadrai® II pink 32F24503* - 10.0 mg, carnauba wax - less than 0.05 mg.

Film-coated tablets, 12.5 mg + 300 mg

One tablet contains:

active ingredients: hydrochlorothiazide - 12.5 mg; irbesartan - 300 mg;

Excipients: lactose monohydrate - 89.5 mg, microcrystalline cellulose - 54.0 mg, croscarmellose sodium - 24.0 mg, hypromellose - 10.0 mg, magnesium stearate - 5.0 mg, silicon dioxide - 5.0 mg;

film sheath: Opadrai® II pink 32F24503* -20.0 mg, carnauba wax - less than OD mg.

* Opadrai® II pink 32F24503 lactose monohydrate - 36.00%, hypromellose - 28.00%, macrogol-3000 - 10.00%, titanium dioxide (E 171) -25.45%, ferric oxide red oxide (E 172) - 0.24% , iron dye oxide yellow (E 172) -0.31%.

Description:

Tablets, film-coated, 12.5 mg + 150 mg

Oval biconvex tablets, covered with a film shell of orange-pink color, with engraving in the form of a heart on one side and number 2875 on the other.

Film-coated tablets, 12.5 mg + 300 mg

Oval biconvex tablets, covered with a film coat of orange-pink color, with engraving in the form of a heart on one side and number 2876 on the other.

Pharmacotherapeutic group:Hypotensive drug combined (diuretic + angiotensin II receptor antagonist).
ATX: & nbsp

C.09.D.A.04   Irbesartan in combination with diuretics

C.09.D.A   Angiotensin II antagonists in combination with diuretics

Pharmacodynamics:

Coaprove® 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, reducing arterial pressure more than each of them separately.

Irbesartan is a selective angiotensin II receptor antagonist (type ATi). Irbesartan does not require metabolic activation to acquire pharmacological activity. Angiotensin II is an important component of the renin-angiotensin-aldosterone system (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, including its pronounced vasoconstrictor and aldosterone-secreting effects, realized through receptors of the type AT1, located on the surface of the smooth muscle cells of the vessels and in the adrenal cortex. He does not have agonistic activity in relation to AT1 receptors and has a much greater (more than 8500 times) affinity for AT1receptors than to AT1-receptors (receptors, not associated with regulation of the cardiovascular system).

Irbesartan does not inhibit RAAS enzymes (such as renin, angiotensin-converting enzyme [ACE]) and does not affect the receptors of other hormones or ion channels involved in the regulation of blood pressure (BP) and sodium homeostasis. Blocking by irbesartan AT1receptors interrupts the feedback loop in the renin-angiotensin system, which leads to an increase in the concentration of renin and angiotensin II in blood plasma. After taking irbesartan in recommended doses, the plasma concentration of aldosterone decreases without significantly affecting the potassium content in the blood serum (the mean value of its increase is <0.1 mEq / L). Irbesartan has no 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 action. The mechanism of antihypertensive action of thiazide diuretics, for example, hydrochlorothiazide, is not completely known.Thiazide diuretics affect the tubular mechanisms of reabsorption of electrolytes in the kidney, approximately equally increasing the excretion of sodium and chlorides. Sodium sulfur leads to a secondary loss of potassium and bicarbonate. Hydrochlorothiazide increases the activity of renin plasma and the secretion of aldosterone, and also reduces the potassium content in the blood serum. Simultaneous reception of an angiotensin II receptor antagonist helps to reduce potassium losses associated with the action of thiazide diuretics. The antihypertensive effect of irbesartan in combination with hydrochlorothiazide manifests itself after taking its first dose and becomes significant within 1-2 weeks of admission, its maximum antihypertensive effect is achieved by 6-8 weeks of treatment. In long-term clinical trials, the antihypertensive effect of the combination irbesartan / hydrochlorothiazide was observed for more than one year.

The combination of hydrochlorothiazide / irbesartan when administered in the therapeutic dose range has a dose-dependent and additive antihypertensive effect. In patients who did not have a sufficient reduction in blood pressure on the background of monotherapy with irbesartan at a dose of 300 mg,addition to monotherapy with irbesartan at a dose of 300 mg once a day of a single dose of 12.5 mg of hydrochlorothiazide during the day resulted in an additional decrease in diastolic blood pressure at the end of the inter-dose interval (i.e., 24 hours after administration of drugs) by 6.1 mm gt; Art. (compared with the addition of a placebo). There was a general decrease in systolic BP (SBP) / diastolic BP (DBP) with a combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide (compared with placebo) to -13.6 / -11.5 mm Hg. Art. A single administration of 150 mg irbesartan and 12.5 mg hydrochlorothiazide during the course of the day demonstrated (compared with placebo) an average decrease in SBP / DBP at the end of the inter-dose interval by 12.9 / 6.9 mm Hg. art., respectively. The maximum antihypertensive effects developed after 3-6 hours. With daily monitoring of blood pressure, Coaprovel preparation® 12,5 / 150 mg once a day caused a steady decrease in blood pressure during the day (the average decrease in SBP / DBP was, respectively, -15.8 / -10.0 mmHg, compared with placebo). The percentages of T / P (the ratio of blood pressure measured at the end of the inter-dose interval [residual action] to BP during the maximum action of irbesartan / hydrochlorothiazide combinations) was at least 68%.

In a clinical study in patients with insufficient BP reduction on the background of monotherapy with hydrochlorothiazide at a dose of 25 mg, the addition of irbesartan to hydrochlorothiazide caused an additional mean decrease in SBP / DBP by 11.1 / 7.2 mm Hg. respectively, compared with monotherapy with hydrochlorothiazide. The blood pressure was reduced to the same extent in the "standing" and "lying" positions. Orthostatic effects were rarely observed, but their occurrence is possible in patients with hyponatraemia and / or hypovolemia.

The efficacy of irbesartan / hydrochlorothiazide does not depend on the age, race Paccessories or gender. General antihypertensive response to combination of y patients of the Negroid race and patients of other races was similar. After the removal of irbesartan, the blood pressure gradually returned to the initial values. The syndrome of "withdrawal" in irbesartan and hydrochlorothiazide was not observed.

When hydrochlorothiazide was taken orally, the diuretic effect occurred within the first 2 h, diuresis reached a maximum in about 4 hours and lasted about 6-12 hours.

Two clinical trials evaluated Coaprovel® at as initial therapy in patients with moderately expressed (baseline mean the value of AD 162/98 mm Hg. ) and heavy (initial mean value BP 172/113 mm Hg. arterial hypertension. In both studies it was shown a significant advantage of the antihypertensive effect of Coaprovel® (in doses from 12.5 / 150 mg to 25/300 mg) as an initial therapy, compared with the use in as an initial therapy for monotherapy with irbesartan (in doses from 150 mg to 300 mg) and

hydrochlorothiazide (in doses from 12.5 mg to 25 mg).

Pharmacokinetics:

Neither irbesartan, nor hydrochlorothiazide Do not change the pharmacokinetics of each other.

Absorption

Irbesartan and hydrochlorothiazide are active substances when taken orally and do not need biotransformation for their transformation into an active form.

After ingestion of Coaprovel®, the absolute bioavailability of irbesartan is 60-80%, and hydrochlorothiazide is 50-80%. Eating does not affect the bioavailability of the active substances of the drug. After taking Coaprovel®, the maximum concentrations in the blood serum (CmOh) are achieved after 1.5-2 h for irbesartan and after 1-2.5 h for hydrochlorothiazide.

Distribution

The connection of irbesartan with plasma proteins is approximately 96%, its association with the cellular components of the blood is insignificant. The volume of irbesartan distribution is 53-93 l (0.72-1.24 l / kg). The ratio of hydrochlorothiazide to plasma proteins is 68%, and its volume of distribution is 3.6-7.8 l / kg.

Metabolism

After ingestion or intravenous administration 14C-irbesartan 80-85% of the radioactivity circulating in the blood plasma is due to the unchanged irbesartan. Irbesartan metabolized by the liver by oxidation and conjugation with glucuronic acid. The main metabolite in the systemic circulation is irbesartan glucuronide (approximately 6%). Oxidation of irbesartan is carried out, mainly, with the help of cytochrome P450 isoenzyme CYP2C9, isoenzymatic participation CYP3A4 in the metabolism of irbesartan is insignificant. Irbesartan It is not metabolized by most isoenzymes, which 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 isoenzyme CYP3A4.

Excretion

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

The final half-life of irbesartan (T1/2) 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 daily once-daily irbesartan intake, the equilibrium plasma concentration (Css) is achieved after 3 days, while its limited accumulation in blood plasma (less than 20%) is observed.

Special patient groups

Influence of sex on the pharmacokinetics of irbesartan

In women (compared with men), slightly higher plasma concentrations of irbesartan are noted.However, sex-related differences in the half-life and accumulation of irbesartan are not detected. Correction of irbesartan dose in women is not required. There were no gender-related differences in the effects of irbesartan.

The pharmacokinetics of irbesartan in elderly patients

Values AUC (area under the pharmacokinetic curve "concentration-time") and CmOh irbesartan in elderly patients (65-80 years old) with clinically normal renal and hepatic function were approximately 20-50% higher than in younger patients (18-40 years old). The terminal half-lives were comparable. There were no age-related differences in the effects of irbesartan.

The pharmacokinetics of irbesartan in liver function disorder

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

The pharmacokinetics of irbesartan in renal dysfunction

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

Influence of race on the pharmacokinetics of irbesartan

In volunteers without hypertension AUC and T1/2 irbesartan in the Negroid race were approximately 20-25% higher than those of the Caucasoid race; FROMmOh irbesartan they were almost the same.

Indications:
Arterial hypertension of moderate or severe severity (treatment of patients who are shown combined antihypertensive therapy).
Contraindications:
- Hypersensitivity to the active substances of the preparation, to any of the co-agents of Coaprovel® preparation (see the "Composition" section) or to other sulfonamide derivatives (hydrochlorothiazide is a sulfonamide derivative).

- Simultaneous use with medicinal products containing aliskiren, in patients with diabetes mellitus or with moderate and severe renal failure (glomerular filtration rate [GFR] <60 ml / min / 1.73 m "body surface).

- Simultaneous use with ACE inhibitors in patients with diabetic nephropathy.

- Severe renal failure (creatinine clearance (CK) is less than or equal to 30 ml / min), anuria (due to the presence of hydrochlorothiazide in the formulation).

- Pregnancy.

- The period of breastfeeding.

- Age under 18 years (efficiency and safety not established).

- Hereditary intolerance to galactose, deficiency of lactase or syndrome of glucose-galactose malabsorption.
Carefully:
- With stenosis of the aortic or mitral valve, or hypertrophic obstructive cardiomyopathy (GOKMP).

- With hypovolemia, hyponatremia, arising, for example, with intensive diuretic therapy, hemodialysis, adherence to a diet with restricted intake of table salt, diarrhea, vomiting (the risk of excessive blood pressure lowering,

see section "Special instructions"),

- In patients with renal function that is dependent on RAAS activity, such as patients with hypertension with bilateral or unilateral renal artery stenosis or patients with chronic heart failure III-IV functional class (according to the NYHA classification) (see section "Special instructions") .

- In ischemic heart disease and / or atherosclerotic lesions of the cerebral vessels (risk of increased myocardial or cerebral ischemia, up to the development of myocardial infarction or stroke with excessive lowering of blood pressure).

- In renal insufficiency of mild and moderate severity (QC 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 formulation, and the development of hyperkalemia, due to the presence of irbesartan in the formulation).

- After kidney transplantation (lack of clinical experience).

- With hepatic insufficiency of all degrees of severity or with progressive liver diseases (due to the presence of hydrochlorothiazide in the formulation, since even minor violations of the water-electrolyte balance in such patients can provoke a hepatic coma).

- In diabetes (due to the presence of hydrochlorothiazide in the formulation, it is possible to reduce glucose tolerance, increase the need for insulin and oral hypoglycemic agents).

- With gout (in connection with the presence of hydrochlorothiazide in the formulation, it is possible to increase the concentration of uric acid salts in the blood).

- In case of hyperkalemia, simultaneous intake of potassium-sparing drugs and / or potassium-containing salt substitutes (risk of hyperkalemia).

- In systemic lupus erythematosus (due to the presence of hydrochlorothiazide in the formulation, since there are reports of exacerbation or weight gain of systemic lupus erythematosus with the use of thiazide diuretics).

- With simultaneous administration of other antihypertensive drugs (the possibility of potentiating their antihypertensive effect).

- With sympathectomy (risk of strengthening the antihypertensive effect of hydrochlorothiazide).

- When used in combination with ACE inhibitors or aliskiren, as compared with monotherapy, with double blockade of RAAS, there is an increased risk of developing excessive blood pressure lowering, hyperkalemia and changes in kidney function (see section "Special instructions").

- In case of allergic reactions to penicillins and sulfanilamides in anamnesis, which are risk factors for the development of an idiosyncratic response observed with the administration of sulfonamides or sulfonamide derivatives, which manifests itself in the form of acute closed-angle glaucoma (see "Special instructions", subsection "Acute myopia and secondary acute closed angle glaucoma ").
Pregnancy and lactation:Pregnancy
Experience in the use of Coaprovel® in pregnancy is absent. Taking into account the fact that when pregnant women received ACE inhibitors in the second and third trimesters of pregnancy, the developing fetus was damaged and died, the drug Coaprovel®, like any other drug that directly affects RAAS, can not be used during pregnancy. Thiazide diuretics penetrate the placental barrier and are found in the umbilical cord blood. The use of diuretics in pregnant women is not recommended, as fetal or neonatal jaundice, thrombocytopenia and other unwanted reactions that occur in adults are possible.
When diagnosing pregnancy during Coaprovel® treatment, as soon as possible, stop taking it.
Breastfeeding period
It is not known whether the irbesartan or its metabolites into breast milk; hydrochlorothiazide penetrates into breast milk. Thiazide diuretics when used in high doses, causing intense diuresis, can suppress lactation. Coaprove® is contraindicated during breastfeeding because of the potential risk to the infant.Therefore, after evaluating the ratio of the perceived benefit from taking the drug to the mother and the potential risk to the baby, stop breastfeeding or taking Coaprovel®.
Dosing and Administration:
Coaprovel® is taken once a day, regardless of the time of ingestion. Coaprove® should be used in patients whose blood pressure is not adequately controlled by irbesartan or hydrochlorothiazide in monotherapy.

Coaprovel® 12.5 mg + 150 mg (tablets containing hydrochlorothiazide 12.5 mg and irbersantan 150 mg) can be used in patients in whom BP is not adequately controlled by monotherapy with hydrochlorothiazide or irbesartan 150 mg / day.

Coaprovel® 12.5 mg + 300 mg (tablets containing hydrochlorothiazide 12.5 mg and 300 mg of Irbesantan) can be used in patients in whom BP is not adequately controlled by irbesartan at a dose of 300 mg or with Coaprovel® 12.5 mg + 150 mg. When used in patients in whom BP is not adequately controlled by Coaprovel® 12.5 mg + 300 mg, doses of the drugs in combination can be increased to

300 mg of irbesartan and 25 mg of hydrochlorothiazide per day: 2 tablets of Coaprovel preparation® 12.5 mg + 150 mg or one tablet of Coaprovel® 25 mg + 300 mg.The maximum daily dose: 2 tablets of Coaprovel® preparation 12.5 mg + 150 mg or 1 tablet of Coaprovel® 25 mg + 300 mg.

If the target values ​​of blood pressure can not be achieved with Coaprovel® monotherapy, other antihypertensive medications (eg, beta-blockers and slow-acting calcium channel blockers) can be added to receive it.

As an initial therapy in patients who are supposed to be on the basis of the severity of their illness, they will need to perform combined antihypertensive therapy, the treatment is started with Coaprovel preparation® 12,5 mg + 150 mg, taken once a day. If it is necessary to lower the blood pressure more, the dose can be increased after 1-2 weeks of treatment to the maximum dose of hydrochlorothiazide 25 mg and irbesartan 300 mg once a day.

Treatment of individual patient groups Children and adolescents

At the moment, the safety and effectiveness of the drug in patients of childhood and adolescence is not established.

Elderly patients

Usually, elderly patients do not need a dose reduction. In patients who took Coaprovel® in clinical studies, there was generally no difference in efficacy and safety between patients 65 years of age and older and younger patients.

Patients with hepatic insufficiency

Usually, in patients with impaired liver function (light and moderate severity - 5-6 and 7-9 on the Child-Pugh scale, respectively), no dose reduction is required. In view of the presence of hydrochlorothiazide in the formulation, special care should be taken when using the drug in patients with severe hepatic impairment (more than 9 on the Child-Pugh scale).

Patients with renal insufficiency

Usually, in patients with renal insufficiency (mild to moderate severity - creatinine clearance> 30 ml / min), no dose reduction is required. However, due to the presence of hydrochlorothiazide in patients with severe renal insufficiency, the use of Coaprovel preparation® not recommended (creatinine clearance < 30 ml / min) (see section "Special instructions").

Patients with hypovolaemia

In patients with severe hypovolemia and / or hyponatremia, for example, in patients receiving intensive diuretic therapy, hypovolemia and hyponatraemia should be corrected before Coaprovel® is used (seesection "Special instructions").

Side effects:

The following undesirable phenomena are presented in accordance with the following gradations of the frequency of their occurrence according to WHO classification: very often (>1/10); often (>1/100, <1/10); infrequently (>1/1000, <1/100); rarely (>1/10000, <1/1000); very rarely (<1/10000, including individual messages); unknown frequency (according to available data, it is not possible to determine the frequency of occurrence of an undesirable phenomenon).

Combination of irbesartan / hydrochlorothiazide

In clinical trials, the safety of the combination of irbesartan and hydrochlorothiazide was evaluated in approximately 2750 patients, including 1540 patients with hypertension who received this medication for 6 months and more than 960 patients who received it for one year or more. Adverse events in patients receiving Coaprovel® were usually mild and transitory, and their frequency was not related to the dose taken. The incidence of adverse events also did not depend on the age, sex and race of the patients.

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

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

Disturbances from the nervous system

Often: dizziness, headache.

Infrequent: orthostatic dizziness.

Heart Disease

Infrequent: tachycardia, changes in the electrocardiogram.

Vascular disorders

Infrequent: excessive blood pressure lowering; peripheral edema, in particular, swelling of the lower extremities; "tides" of blood to the skin of the face, syncopal conditions.

Disorders from the gastrointestinal tract

Often: nausea / vomiting.

Infrequent: diarrhea, dryness of the oral mucosa, abdominal pain.

Disorders from the kidneys and urinary tract

Often: change in frequency of urination.

Violations of the genitals and mammary gland

Infrequent: sexual dysfunction (weakening of libido, erectile dysfunction).

General disorders and disorders at the site of administration

Often: increased fatigue.

Infrequently: weakness.

Disturbances from the skin and subcutaneous tissues

Infrequent: skin rash, itching.

Disturbances from musculoskeletal and connective tissue

Infrequently: myalgia, pain in the bones, weakness in the extremities.

The adverse events observed in placebo-controlled studies with the combination of irbesartan and hydrochlorothiazide as initial treatment in patients with severe and moderate arterial hypertension

Initial treatment with a combination of irbesartan and hydrochlorothiazide

The following undesirable effects of the combination of irbesartan and hydrochlorothiazide in studies conducted in patients with severe and moderate arterial hypertension were similar to those described above in adverse events observed in previous studies with hypertension.

In a clinical study conducted with moderate arterial hypertension (mean DBP, in the "sitting" position 90-110 mm Hg.The types and frequency of adverse events observed in patients who received Coaprovel® as an initial therapy were similar to the profile of adverse events in patients who received initial treatment as monotherapy with irbesartan or hydrochlorothiazide. There were no cases of syncopal conditions in the combination therapy group, and in the monotherapy group with hydrochlorothiazide, one case of syncope was recorded.

The frequency of the above-mentioned adverse events with Coaprovel®, monotherapy with irbesartan and hydrochlorothiazide monotherapy, respectively, was 0.9%, 0%, and 0% for excessive reduction 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 cancellation of treatment due to adverse events with Coaprovel® therapy, irbesartan monotherapy and hydrochlorothiazide monotherapy was 6.7%, 3.8%, and 4.8%, respectively.

In a clinical study conducted with severe arterial hypertension (DBP in the "sitting" > 110 mm Hg.), the overall picture of adverse events during 7 weeks of follow-up was similar in patients receiving Coaprovel® as an initial therapy, and in patients receiving initial therapy irbesartan. The frequency of the above undesirable phenomena for the preparation Coaprovel® and irbesartan was, respectively: 0% and 0% for the syncopal condition; 0.6% and 0% for excessive lowering of blood pressure; 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 cancellation of treatment due to adverse events with Coaprovel® and monotherapy with irbesartan was 2.1% and 2.2%, respectively.

Laboratory and instrumental data

Clinically significant changes in the results of laboratory studies during controlled clinical trials of Coaprovel® were not detected.

Experience of postmarketing application

Irbesartan

As with other angiotensin II receptor antagonists, extremely rare cases of development of hypersensitivity reactions (angioedema, urticaria) have been observed with monotherapy with irbesartan.In addition, the application of irbesartan after its release on the market observed the following adverse reactions: vertigo, asthenia, hyperkalemia, jaundice, myalgia, increasing functional "liver" trial, hepatitis, tinnitus and impaired renal function including cases of acute renal failure in patients at risk.

Hydrochlorothiazide

In monotherapy with hydrochlorothiazide, the following adverse events were observed (regardless of their relationship to hydrochlorothiazide): 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 vasculitis (vasculitis, cutaneous vasculitis), respiratory distres -sindrom (including pneumonitis and pulmonary edema), anaphylactic reactions, toxic epidermal necrolysis, hyperglycemia, glycosuria, hyperuricemia, disorders of water and electrolyte balance (including hyponatremia and hypokalemia)impaired renal function, interstitial nephritis, muscle spasms, weakness, anxiety, transient visual impairment.

Overdose:

Symptoms

The most common symptoms observed in adults with an overdose of hydrochlorothiazide were symptoms caused by impaired electrolyte blood composition (hypokalemia, hypochloraemia, hyponatremia) and dehydration resulting from excessive diuretic effect. In the case of simultaneous reception of cardiac glycosides (eg, digoxin) or antiarrhythmics (for example, sotalol), hypokalemia may contribute to the development of rhythm disturbances. When an overdose of the drug, excessive reduction in blood pressure, the development of bradycardia and tachycardia.

There is an experience of taking irbesartan in doses up to 900 mg / day for 8 weeks without

development of toxic effects.

Treatment

There is no specific information on the treatment of overdose with Coaprovel®. It is necessary to establish constant monitoring of the patient's condition and, if necessary, to carry out symptomatic and supportive therapy,including recovery of fluid and electrolyte losses. In case of overdose, it is recommended to induce vomiting and / or gastric lavage. Irbesartan is not excreted from the body by hemodialysis. The degree of excretion of hydrochlorothiazide by hemodialysis is not established.

Interaction:
Based on data from the in vitro study. no interaction of irbesartan with drugs metabolized by isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2E1 or CYP3A4 is expected. Irbesartan, is mainly metabolized with the isoenzyme of CYP2C9 and, to a lesser extent, undergoes glucuronation. There were no significant pharmacokinetic and pharmacodynamic interactions in the joint use of irbesartan with warfarin, drug,

metabolized by isoenzyme CYP2C9. Irbesartan does not change the pharmacokinetics of digoxin and simvastatin. With the combined use of irbesartan with hydrochlorothiazide or nifedipine, the pharmacokinetics of irbesartan do not change.

With medications containing aliskiren

The combination of Coaprovel® with medicines containing aliskiren, is contraindicated in patients with diabetes mellitus or with moderate and severe renal failure (GFR <60 mL / min / 1.73 m2 body surface) and is not recommended in other patients (see the sections "Contraindications", "With caution", "Special instructions").

FROM with ACE inhibitors

The use of Coaprovel® in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see "Contraindications", "With caution", "Special instructions").

With drugs that affect the content of potassium in the blood

Based on the experience gained with the use of other drugs that affect RAAS, the simultaneous use of irbesartan with potassium preparations; substitutes for salt containing potassium; potassium-sparing diuretics or others capable of increasing the potassium content of blood plasma with drugs (heparin), can sometimes significantly increase the serum potassium concentration, which requires careful monitoring of the potassium levels of blood plasma in patients during treatment. Simultaneous with irbesartan hydrochlorothiazide intake can reduce the frequency of this effect.

With non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2) In elderly patients, patients with hypovolemia or patients with impaired renal function, the use of NSAIDs. including COX-2 inhibitors, concomitantly with angiotensin II receptor antagonists, including irbesartan, can lead to impaired renal function, including the possible development of acute renal failure. These effects are usually reversible. Should

periodically monitor kidney function in patients who simultaneously take irbesartan and NSAIDs. With simultaneous use of angiotensin II receptor antagonists, including irbesartan, and NSAIDs, including selective COX-2 inhibitors, the attenuation of the antihypertensive effect of inhibitors of angiotensin II receptors is possible.

With ethanol, barbiturates or narcotic drugs There may be an increase in orthostatic hypotension caused by thiazide diuretics.

With oral hypoglycemic agents and insulin

As hydrochlorothiazide may increase the concentration of glucose in the blood, may require an increase in the dose hypoglycemic agent.

With antidotal drugs

With the simultaneous use of Coaprovel® and antidotal drugs, dosage adjustments for antidotal drugs may be required because of the possibility of increasing serum uric acid concentrations when taking hydrochlorothiazide.

With cardiac glycosides, antiarrhythmic agents

When they are used together with the drug Coaprovel®, in the case of hypokalemia and hypomagnesemia caused by the thiazide diuretic entering into it, the risk of arrhythmias increases.

With calcium salts

Thiazide diuretics can increase the serum calcium level. If the patient requires the use of calcium or calcium-saving drugs (for example, vitamin D), it is necessary to monitor the calcium content in the blood serum and to carry out appropriate correction of the dosing regimen of calcium preparations.

With colestyramine resin or colestipol

The absorption of hydrochlorothiazide in the presence of anion-exchange resins is reduced. It should be divided by the time of taking Coaprovel® and these drugs for at least 4 hours.

With lithium salts

Diuretics reduce renal clearance of lithium.in its turn irbesartan increases serum lithium concentrations. All this increases the risk of developing toxic effects of lithium. Caution should be exercised while using Coaprovel® with lithium salts, it is recommended in this case to control the lithium content in the blood serum.

FROM inhibitors of the synthesis of endogenous prostaglandins (for example, CPAP)

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

With other diuretics and antihypertensives

Hydrochlorothiazide, which is part of the drug Coaprovel®, can potentiate the effects of other antihypertensive agents, especially ganglion blockers and beta-adrenoreceptor blockers. Hydrochlorothiazide can react with diazoxide; when combined, monitor blood glucose, serum uric acid and blood pressure.

With nondepolarizing muscle relaxants (tubocurarine). means for local anesthesia, means for general anesthesia and means for premedication before general anesthesia

Effects of nondepolarizing muscle relaxants (eg tubocurarine), local anesthetic agents, general anesthetics and premedication means before general anesthesia may be potentiated with hydrochlorothiazide, and their dosage regimen may need to be adjusted. When combined with hydrochlorothiazide, local anesthetics, general anesthetics and premedication before general anesthesia should be used in reduced doses. If possible, hydrochlorothiazide should be discontinued one week prior to surgery.

With carbamazepine

The simultaneous use of carbamazepine and hydrochlorothiazide may be associated with the risk of developing hyponatremia with clinical manifestations. The content of electrolytes in the blood should be monitored during the combined use of these drugs. If it is necessary to use carbamazepine, diuretics with a different mechanism of action are recommended, if possible.

With glucocorticosteroids, adrenocorticotropic hormone

Increased risk of hypokalemia.

With catecholamines (for example, with norepinephrine)

The effect of catecholamines may be weakened by the influence of thiazide diuretics.

With anticholinergic drugs (for example, with atropine, biperidenum)

Increased bioavailability of thiazide diuretics due to slowing down the motility of the gastrointestinal tract.

With cyclophosphamide, methotrexate Thiazides can reduce the secretion of these cytotoxic agents by the kidneys and enhance their myelosuppressive effects.


Special instructions:

Excessive reduction in blood pressure - patients with hypovolaemia

The use of Coaprovel® has so far rarely been accompanied by an excessive decrease in blood pressure in patients with hypertension without other risk factors for the development of excessive BP reduction. Excessive reduction in blood pressure, accompanied by clinical symptoms, may develop in patients with hyponatremia / hypovolemia. Hypovolemia and / or hyponotism should be corrected before taking Coaprovel®. Thiazide diuretics can potentiate the action of other antihypertensive agents (see the sections "With caution" and "Method of administration and dose", "Interaction with other drugs").

Impaired kidney and liver function

Coaprovel® is not recommended for patients with severe renal failure (creatinine clearance < 30 ml / min) (see the section "Contraindications"). In patients with impaired renal function, an increase in azotemia may be associated with the content of hydrochlorothiazide in the formulation. There are no clinical data on 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, creatinine and serum uric acid concentrations is recommended.

Coaprove® should be used with caution in patients with impaired liver function or progressive liver disease, because even small changes in the water-electrolyte balance can trigger the development of the hepatic coma.

Violations of the water-electrolyte balance and metabolic disturbances

Thiazides, including hydrochlorothiazide, can cause a violation of the water-electrolyte balance (hypokalemia, hyponatremia and hypochloraemic alkalosis).Although the use of thiazide diuretics in monotherapy, especially in high doses, may lead to hypokalemia, simultaneous administration of irbesartan may reduce hypokalemia caused by hydrochlorothiazide. On the contrary, due to irbesartan, which is part of the drug Coaprovel®, there may be hyperkalemia, especially in the presence of kidney failure, heart failure, diabetes mellitus. Regular monitoring of serum potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes should be used with caution when taken with Coaprovel® (see section "Interactions with other drugs"). Deficiency of chlorides usually is insignificant and, as a rule, does not require treatment. Thiazides reduce the excretion of calcium through the kidneys and cause a fickle and insignificant increase in serum calcium. The development of clinically significant hypercalcemia may indicate the possibility of the patient having hyperparathyroidism. Admission of thiazides should be discontinued before the study of parathyroid function.It has been demonstrated that thiazides increase the excretion of magnesium ions by the kidneys, which can lead to the development of hypomagnesemia.

In the treatment of thiazide diuretics, hyperglycemia and exacerbation of gout in some patients may develop. In the treatment of thiazide diuretics, the need for insulin in patients with diabetes mellitus may increase, and the manifestation of latent diabetes mellitus is possible. Treatment with thiazide diuretics was associated with an increase in the concentration of cholesterol and triglycerides in the blood, but the dose of 12.5 mg contained in the drug Coaprovel® has virtually no effect on the concentration of cholesterol and triglycerides in the blood. With thiazide diuretics, hyperuricemia or exacerbation of the gout current may occur in some patients. Patients at risk of developing water-electrolyte imbalance and metabolic disorders may need to monitor laboratory indicators.

Systemic lupus erythematosus

It has been reported that the course of systemic lupus erythematosus is exacerbated or worsened with thiazide diuretics.

Acute myopia and secondary acute closed-angle glaucoma

Sulfanilamides or sulfonamide derivatives can cause idiosyncratic reactions leading to the development of transient myopia and acute closed-angle glaucoma. Although hydrochlorothiazide is a derivative of sulfonamide, so far only cases of development of acute closed-angle glaucoma have been reported without establishing a causal relationship with its

reception. Symptoms of acute closed-angle glaucoma are: acute reduction in visual acuity or eye pain, usually occurring within a period of several hours to several weeks after the start of the drug. Left with no treatment acute acute angle glaucoma can lead to persistent loss of vision. If these symptoms occur, stop taking the drug as soon as possible. If it does not manage to normalize intraocular pressure, then urgent therapeutic or surgical treatment may be required. Risk factors for the development of acute angle-closure glaucoma are the indication of anamnesis for allergic reactions to sulfonamides and penicillins.

Double blockade of RAAS with a combination of Coaprovel® with ACE inhibitors or with aliskiren

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

Application of Coaprovel preparation® in combination with aliskiren is contraindicated in

patients with diabetes mellitus or renal insufficiency with

GFR <60 ml / min / 1.73 m2 surface of the body) (see sections "Contraindications",

"Interaction with other drugs") and is not recommended in others

patients.

Application of Coaprovel preparation® in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy (see the sections "Contraindications", "Interaction with other drugs") and is not recommended in other patients.

Patients with renal function, depending on the activity of RAAS

As a consequence of inhibition of RAAS, impairment of renal function in patients susceptible to this can be expected. In patients with renal function, depending on the activity of RAAS (patients with arterial hypertension and stenosis of the renal artery of one or both kidneys,patients with chronic cardiac insufficiency III and IV of the functional class [by classification NYHA]), treatment with drugs that affect RAAS was associated with oliguria and / or progressive azotemia and, rarely, with acute renal failure and / or death. It can not be ruled out that such an effect can occur with the use of angiotensin II receptor inhibitors, including Coaprovel®.

Patients after sympathectomy

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

Stenosis of the aortic aorta and stenosis of the mitral valve, hypertrophic obstructive cardiomyopathy

Special caution is required when using such vasodilators in patients, including Coaprovel®.

Primary hyperaldosteronism

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

Anti-doping test

Hydrochlorothiazide can give a positive result in doping control.

Patients with a history of allergic anamnesis or bronchial asthma

Development of allergic reactions to hydrochlorothiazide more likely in patients with a history of allergic anamnesis or patients with bronchial asthma.

Effect on the ability to drive transp. cf. and fur:The effect of 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, Coaprovel® should not affect the ability to drive vehicles and engage in other potentially hazardous activities (work at altitude, work as an air traffic controller, work with mechanisms, etc.). However, when dealing with potentially dangerous activities, care should be taken (due to the possibility of developing dizziness, weakness and, in this connection, reducing attention and slowing the speed of psychomotor reactions, see the "Side effect" section).
Form release / dosage:
Tablets, film-coated, 12.5 mg + 150 mg and 12.5 mg + 300 mg.
Packaging:
For 14 tablets in the blister PVC / PVDC / Aluminum.

For 1, 2, 4 or 7 blisters together with instructions for use in a cardboard box.
Storage conditions:Store at a temperature not exceeding 30 ° C. Keep out of the reach of children.
Shelf life:
3 years.

Do not take the drug after the expiry date indicated on the package.
Terms of leave from pharmacies:On prescription
Registration number:LP-001027
Date of registration:18.10.2011
Date of cancellation:2016-10-18
Manufacturer: & nbsp
Representation: & nbspSanofi Aventis GroupSanofi Aventis Group
Information update date: & nbsp26.12.2015
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