Cardosal Plus tablets 12.5 mg + 20 mg, 28 pcs. (Hydrochlorothiazide, Olmesartan Medoxomil)

Release form

Film-coated tablets.

Packing

28 pcs.

Pharmacological action of

Pharmacodynamics of

Cardosal® Plus is a combination drug which contains an angiotensin II receptor antagonist (olmesartan medoxomil) and a thiazide diuretic (hydrochlorothiazide). The combination of two active substances has a combined antihypertensive effect, as a result of which blood pressure decreases to a greater extent than when each of them is taken separately. When taking the drug once a day, an effective and uniform decrease in blood pressure is achieved within 24 hours.

Olmesartan medoxomil is a specific angiotensin II receptor antagonist (type AT1). Angiotensin II is the primary vasoactive component of the renin-angiotensin-aldosterone system (RAAS) and plays a significant role in the pathophysiology of arterial hypertension by affecting AT1 receptors. Olmesartan medoxomil is believed to block all the effects of angiotensin P mediated by AT1 receptors, regardless of the source and route of synthesis of angiotensin II.

In arterial hypertension, olmesartan medoxomil causes a dose-dependent, prolonged decrease in blood pressure. There is no data on the development of arterial hypotension after taking the first dose of the drug and on the development of the “withdrawal” syndrome (a sharp increase in blood pressure after drug withdrawal).

Taking olmesartan medoxomil once a day provides an effective and mild decrease in blood pressure within 24 hours. The hypotensive effect of olmesartan medoxomil occurs, as a rule, after 2 weeks, and the maximum effect develops after about 8 weeks. after starting therapy.

Hydrochlorothiazide - a thiazide diuretic - disrupts the reabsorption of sodium, chlorine and water ions in the renal tubules. It increases the excretion of potassium, magnesium, bicarbonate ions, retains calcium ions in the body. The diuretic effect occurs 2 hours after ingestion of hydrochlorothiazide, reaches a maximum after 4 hours and lasts up to 12 hours. It helps to reduce high blood pressure. With the combined use of olmesartan medoxomil and hydrochlorothiazide, there is a decrease in the loss of potassium ions caused by the action of a diuretic. The result of the combination therapy of olmesartan with medoxomil and hydrochlorothiazide is the potentiation of the hypotensive effect, which depends on the dose of each component of the drug. Combination therapy is well tolerated by patients. With prolonged treatment, the effectiveness of combination therapy (olmesartan medoxomil / hydrochlorothiazide) is maintained, the development of the "withdrawal" syndrome is not observed.

Pharmacokinetics

Absorption and distribution of

Olmesartan medoxomil is a prodrug. It quickly turns into a pharmacologically active metabolite olmesartan under the action of enzymes in the intestinal mucosa and peripheral blood during absorption from the gastrointestinal tract and circulates in the blood as a metabolite (olmesartan). The bioavailability of olmesartan averages 25.6%.

Cmax of olmesartan in plasma is achieved on average 2 hours after ingestion and increases approximately linearly with a single dose increase to 80 mg.

Eating does not significantly affect the bioavailability of olmesartan medoxomil, therefore olmesartan medoxomil can be taken without regard to meals.

Clinically significant differences in the pharmacokinetic parameters of olmesargan medoxomil depending on gender were not detected.

Olmesargan has a high degree of binding to plasma proteins (99.7%). With the simultaneous use of olmesartan medoxomil with other drugs, characterized by a high degree of binding to blood plasma proteins, there are no significant changes in this value (confirmation of this is the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The relationship of olmesartan with blood cells is negligible.

After oral administration of olmesartan medoxomil in combination with hydrochlorothiazide, the average time to reach Cmax hydrochlorothiazide is 1.5–2 hours.

Hydrochlorothiazide binds to plasma proteins by 68%. The systemic bioavailability of hydrochlorothiazide while the use of medoxomil with olmesartan is reduced by about 20%, but this slight decrease is not clinically significant. The simultaneous administration of hydrochlorothiazide, for its part, does not significantly affect the kinetics of olmesartan medoxomil. In controlled clinical trials, a pronounced anti-hypertensive effect of this combination was revealed, which exceeded the effect of each component separately, as well as the placebo effect.

Metabolism and excretion

The total plasma clearance of olmesartan is usually 1.3 l / h (coefficient of variation - 19%) and is relatively low compared with hepatic blood flow (approximately 90 l / h). Renal excretion of olmesartan is approximately 40%, with bile through the intestine - about 60% extrahepatic circulation - is minimal. Since most of olmesartan medoxomil is metabolized in the liver, its use in patients with bile duct obstruction is contraindicated.

The half-life of olmesartan is 10-15 hours. A stable effect of therapy is achieved during the first 14 days of daily intake of olmesartan medoxomil. Renal clearance is approximately 0.5-0.7 l / h and is not dose dependent.

Hydrochlorothiazide in the body is not metabolized and is almost completely unchanged excreted by the kidneys. After oral administration, about 60% of the accepted dose of hydrochlorothiazide is excreted unchanged within 48 hours. The renal clearance of hydrochlorothiazide is about 250-300 ml / min. T1 / 2 of the final phase is 10-15 hours.

Pharmacokinetics in various categories of patients

In patients aged 65-75 years with arterial hypertension, the area under the concentration-time curve (AUC) for olmesartan in the saturation stage increases compared to the group patients younger than 65 years of age by approximately 35%, patients older than 75 years of age by approximately 44%. Available data allow us to conclude that the systemic clearance of hydrochlorothiazide in both healthy elderly volunteers and elderly patients with arterial hypertension is reduced compared to volunteers of a younger age. In patients with impaired renal function (CC = 30-60 ml / min.), The saturation AUC for olmesartan is increased by approximately 62, 82 and 179% in case of mild, moderate and severe renal impairment, respectively, compared with healthy volunteers . For this category of patients, an increase in T1 / 2 of hydrochlorothiazide is possible.

In patients with impaired liver function of mild to moderate severity after a single oral administration, the AUC values ​​for olmesartan were 6 and 65% higher, respectively, compared with healthy volunteers. The unbound olmesartan fraction 2 hours after taking the dose in healthy volunteers, in patients with mild to moderate hepatic impairment, was 0.26 0.34 and 0.41%, respectively. The effect of impaired liver function on the pharmacokinetics of hydrochlorothiazide is negligible.

For patients with severe hepatic impairment (more than 9 Child-Pugh scores), pharmacokinetics of olmesartan medoxomil are not available.

Indications

Essential arterial hypertension (with the ineffectiveness of monotherapy with olmesartan medoxomil).

Contraindications

Hypersensitivity to olmesartan medoxomil, hydrochlorothiazide or other sulfonamide derivatives or to any of the excipients that make up the drug.

hereditary lactose intolerance, lack of lactase in the body, or glucose and lactose malabsorption syndrome

severe liver dysfunction (more than 9 points on the Child-Pugh scale) (risk of hepatic coma), biliary obstruction and cholestasis

severe renal dysfunction (C less 30 ml / min.)

refractory hypokalemia, hyponatremia, hypercalcemia and symptomatic hyperuricemia

pregnancy and lactation

age up to 18 years (the effectiveness and safety of the drug have not been studied).

Precautions: bronchial asthma, coronary heart disease (CHD), chronic heart failure in the decompensation stage, severe cerebrovascular disorders of aortic or mitral valve stenosis hypertrophic obstructive cardiomyopathy mild and moderate liver function impairment (less than 9 Child-Pugh score) renal impairment ( CC more than 30 ml / min, but less than 60 ml / min.) Bilateral renal artery stenosis or single kidney artery stenosis condition after recently transplanted Points (experience with no drug) primary aldosteronism diabetes, gout, disorders of water and electrolyte balance, dehydration of connective tissue disease, including systemic lupus erythematosus, in patients on a salt-restricted diet or on hemodialysis with inhibition of bone marrow hematopoiesis, accompanied by a decrease in circulating blood volume (BCC), including diarrhea, vomiting, or previous diuretic therapy.

Use during pregnancy and lactation

There is no experience with the use of olmesartan medoxomil in pregnant women. However, in view of the reports of severe teratogenic effects of drugs acting on RAAS, like any drug of this class, Cardosal® plus is contraindicated in pregnancy.

If you plan or have a pregnancy during therapy with Cardosal® plus, you must cancel the drug as soon as possible.

It is not known whether olmesartan medoxomil is excreted in breast milk, but thiazides are excreted in breast milk and can inhibit lactation, so if you need to use the cardosal® plus drug during lactation, you should stop breast-feeding during the period of its administration.

Special instructions

Symptomatic arterial hypotension, especially after taking the first dose of the drug, can occur in patients with reduced BCC and / or reduced sodium concentration due to intensive diuretic therapy, dietary salt restriction, and diarrhea or vomiting. Relevant factors should be eliminated before starting the use of CardosalВ® plus.

thiazide diuretics, including hydrochlorothiazide, can cause a violation of the BCC or water-electrolyte balance of blood serum (including hypokalemia, hyponatremia and hypochloremic alkalosis). Symptoms of the precursors are: dry oral mucosa, thirst, weakness, drowsiness, anxiety, myalgia or cramps, muscle weakness, hypotension, oliguria, tachycardia, nausea and vomiting (see section Adverse effects).

The highest risk of hypokalemia is in patients with cirrhosis, in patients with forced diuresis, and in patients who take glucocorticosteroids or ACTT at the same time (see Interaction with Other Medicines). And, on the contrary, due to the antagonism of the medoxomil contained in the drug CardosalВ® plus olmesartan, manifested with respect to angiotensin II (AT1) receptors, hyperkalemia may occur - primarily in patients with impaired renal function and / or chronic heart failure, as well as patients with diabetes mellitus. In patients with risk factors, regular monitoring of serum potassium concentrations is recommended.

There is no data on whether olmesartan medoxomil can reduce hyponatremia caused by diuretics or inhibit its development. In hot weather, dilated hyponatremia may occur in patients prone to edema.

The decrease in chloride concentration is generally negligible and usually does not require treatment. Thiazides can reduce the excretion of calcium ions by the kidneys and also lead to a transient insignificant increase in the concentration of calcium in the blood serum in the absence of a history of metabolic disturbances. Hyperkalygemia may indicate latent hyperparathyroidism. Before examining the function of the parathyroid glands, thiazides should be discontinued.

It has been proven that thiazide diuretics increase the excretion of magnesium ions by the kidneys, which can lead to hypomagnesemia.

In patients whose vascular tone and renal function are highly dependent on RAAS activity (for example, in patients with severe chronic heart failure or impaired renal function, including renal artery stenosis), treatment with other agents that affect RAAS is associated with the possibility the development of acute arterial hypotension, azotemia, oliguria, or, in rare cases, acute renal failure. The possibility of a similar effect cannot be excluded with the use of angiotensin P. receptor antagonists.

There is an increased risk of developing severe arterial hypotension and renal failure if a patient with bilateral renal artery stenosis or arterial stenosis of a single functioning kidney receives therapy with drugs that affect RAAS . When using CardosalВ® plus in patients with impaired renal function, it is recommended to periodically monitor the concentration of potassium, creatinine and uric acid in the blood serum. There is no experience with olmesartan medoxomil in patients with a recent kidney transplant or in patents with a late stage renal impairment.

In patients with impaired renal function, thiazide diuretics may be accompanied by azotemia. With obvious progression of renal failure, it is necessary to review the therapy and decide on the abolition of diuretics.

As with any antihypertensive drug, an excessive decrease in blood pressure in patients with coronary artery disease or with cerebrovascular insufficiency can lead to myocardial infarction or stroke.

Thiazide diuretics can cause impaired glucose tolerance, as well as an increase in serum cholesterol, triglycerides and uric acid. In patients with diabetes mellitus, it may be necessary to adjust the dose of insulin or a hypoglycemic agent for oral administration (see the Interaction with Other Medicines section). When treated with thiazide diuretics, latent diabetes mellitus can manifest.

There are reports that thiazide diuretics can contribute to the development of an attack of gout and cause an exacerbation of systemic lupus erythematosus. Hypersensitivity reactions to hydrochlorothiazide may be more likely to occur in patients with a history of allergic history or bronchial asthma (history).

The effect on the ability to drive vehicles and other mechanisms that require an increased concentration of attention

The effect of the drug CardosalВ® plus on the ability to drive vehicles and drive mechanisms has not been specifically studied, therefore, during the treatment with CardosalВ® plus, caution should be exercised when driving vehicles and engaging in potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Composition

1 tablet contains:

Active ingredients:

hydrochlorothiazide 12.5 mg

olmesartan medoxomil 20 mg.

Dosage and administration

Cardosal® Plus tablets are taken orally regardless of food intake. Before prescribing the combined drug Cardosal® Plus, a preliminary selection of the dose of each of the active ingredients separately (i.e., olmesartan medoxomil and hydrochlorothiazide) is recommended.

Recommended dose:

Daily, 1 tablet of Cardosal® Plus, containing 20 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide,jus containing 20 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide daily 1 tablet.

The maximum dose of Cardosal® Plus is 20 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide once a day.

Elderly patients (65 years of age) with normal renal function (CC more than 90 ml / min) and patients with impaired renal function (CC = 30-60 ml / min.) do not require dose adjustment.

Drug interactions

Olmesartan medoxomil

Not recommended for combined use with potassium-sparing diuretics, potassium preparations, salt substitutes containing potassium, or other drugs that can increase the concentration of potassium in the blood serum (for example, blood serum potassium concentration may increase) .

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid at doses greater than 3 g / day, as well as cyclooxygenase-2 inhibitors (COX-2), and angiotensin II receptor antagonists can act synergistically, reducing glomerular filtration. With the simultaneous use of NSAIDs and angiotensin II receptor antagonists, there may be a risk of developing acute renal failure, therefore it is recommended to monitor renal function at the beginning of treatment, as well as regular intake of a sufficient amount of fluid. However, simultaneous treatment can reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to a partial loss of their therapeutic effectiveness.

With simultaneous use with antacids (magnesium and aluminum hydroxides), a moderate decrease in the bioavailability of olmesartan medoxomil is possible. There are reports of a reversible increase in serum lithium concentration and toxicity during the simultaneous use of lithium preparations with angiotensin converting enzyme (ACE) inhibitors and with angiotensin II receptor antagonists, therefore, the use of olmesartan medoxomil in combination with lithium preparations is not recommended.

If appropriate combination therapy is necessary, regular monitoring of serum lithium concentration is recommended. In rare cases, ACE inhibitors can enhance the hypoglycemic effect of insulin and hypoglycemic agents for oral administration (for example, sulfonylurea derivatives) in patients with diabetes mellitus. In these cases, with the simultaneous use of ACE inhibitors, it may be necessary to reduce the dose of a hypoglycemic agent for oral administration and insulin.

Hydrochlorothiazide

Glucocorticosteroids, adrenocorticotropic hormone (ACTH), amphotericin B (parenteral), carbenoxolone, penicillin G sodium salt, salicylic acid derivatives: while taking them with hydrochlorothiazide, there may be an increase in electrolyte losses, in particular, the development of hypokalemia.

Concomitant use of ion exchange drugs (cholesterol, colestepol) reduces the absorption of hydrochlorothiazide.

With the simultaneous use of hydrochlorothiazide with calcium salts, an increase in the concentration of calcium in the blood serum is possible due to a decrease in its excretion. If necessary, the appointment of calcium preparations should monitor its concentration in the blood serum and adjust its dose accordingly.

With the simultaneous use of hydrochlorothiazide with cardiac glycosides, arrhythmias may occur.

Medicines that can cause pirouette type arrhythmias (torsades des pointes) (a special form of polymorphic ventricular tachycardia with wave, screw-or spindle-shaped configuration of ventricular complexes in combination with an increase or decrease in the amplitude of the teeth of the QRS complex, which can lead to fibrillation of the ventricles or asystole): due to the risk of hypokalemia, caution is required when using hydrochlorothiazide with some antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide , amiodarone, sotalol, dofetilide, ibutilide), antipsychotics (thioridazine, chlorpromazine, levomepromazine, trifluoperazin, cyamemazine, sulpiride, sultopride, am sulpride, tiapride, pimozide, haloperidol, droperidol) and others (bepridal, cisapride, diphemanil methyl sulfate, erythromycin for intravenous administration, halofantrine, misolastine, nentamidine, sparfloxacin, terfenadine, for which type of intravenous administration is known) "pirouette".

With the combined use of hydrochlorothiazide with non-depolarizing muscle relaxants (including tubocurarine chloride) - increased effect of muscle relaxants.

Thiazides may increase the risk of side effects of amantadine. Treatment with thiazide diuretics may impair glucose tolerance. With the simultaneous use of M-anticholinergics (atropine) and thiazides, due to decreased motility of the gastrointestinal tract, the bioavailability of thiazide diuretics may increase.

A dose reduction of hypoglycemic agents for oral and insulin administration may be required.

Anti-gout agents (probenecid, sulfinpyrazone, allopurinol): it may be necessary to adjust the dose of a hypouricemic agent (increase in the dose of probenecid or sulfinpyrazone), since hydrochlorothiazide can increase the concentration of uric acid in blood serum. The simultaneous use with thiazide diuretics can increase the frequency of development of hypersensitivity reactions to allopurinol. The action of sympathomimetics while taking thiazide diuretics may be weakened.

Thiazide diuretics can reduce renal excretion of cytotoxic drugs and enhance their myelosuppressive effect.

When taking salicylates in high doses, hydrochlorothiazide can enhance their toxic effect on the central nervous system.

There are reports of isolated cases of hemolytic anemia while taking methyldopa with hydrochlorothiazide.

Concomitant use of cyclosporine with hydrochlorothiazide may increase the risk of hyperuricemia and exacerbation of gout.

The simultaneous use of tetracyclines with thiazide diuretics increases the risk of an increase in urea concentration due to tetracyclines. This interaction does not apply to doxycycline.

Olmesartan medoxomil / hydrochlorothiazide in combination

The simultaneous use of lithium preparations with thiazide diuretics can increase the already increased risk of lithium intoxication due to ACE inhibitors, therefore, the combined use of the drug Cardosal® plus lithium preparations is not recommended. If such a combination is nevertheless necessary, careful monitoring of the serum lithium concentration is also necessary.

With the simultaneous use of the drug Cardosal * plus with baclofen and amifostine, an increase in the antihypertensive effect is possible.

With the simultaneous use of other antihypertensive drugs, the hypotensive effect of Cardosal® plus may increase. Ethanol, barbiturates, narcotic analgesics or antidepressants when used with Cardosal® plus can aggravate orthostatic hypotension.

Storage conditions

Do not store above 30 ° C.

Keep out of the reach and sight of children.

Shelf life

3 years.

Deystvuyushtee substance

Gidrohlorotiazid, olmesartan medoxomil

Prescription drugstore

prescription

Possible product names

CARDOSAL PLUS 0.0125 + 0.02 N28 TABLE P / FILM / SHELL

CARDOSAL PLUS TAB. P.P.O. 12.5MG + 20MG No. 28

CARDOSAL PLUS TAB. P / O CAPTURE. 12.5 MG + 20 MG No. 28

Cardosal Plus tablets 12.5 mg + 20 mg, 28 pcs.

Berlin-Hemi AG, Germany



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