Cardosal®

Brand Berlin-Chemie / Menarini

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Available since: 2019-09-19

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Clinical Pharmacology

Cardosal Plus is a combination drug that contains the angiotensin II receptor antagonist (olmesartan medoxomil) and thiazide diuretic (hydrochlorothiazide). The combination of the two active substances has a combined anti-hypertensive effect, as a result of which the blood pressure is reduced to a greater extent than when taking each of them 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 influencing AT₁receptors. It is assumed that olmesartan medoxomil blocks all effects of angiotensin II mediated by AT₁receptors, regardless of the source and route of synthesis of angiotensin II.

In case of arterial hypertension of 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 "withdrawal" syndrome (a sharp increase in blood pressure after discontinuation of the drug).

Taking olmesartan medoxomil once a day provides an effective and mild decrease in blood pressure for 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 initiation of therapy.

Hydrochlorothiazide - thiazide diuretic - violates the reabsorption of sodium ions, chlorine and water in the renal tubules. Increases the excretion of potassium, magnesium, bicarbonate ions, retains calcium ions in the body. The diuretic effect occurs 2 hours after taking hydrochlorothiazide inside, reaches a maximum after 4 hours and lasts up to 12 hours. Helps 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 with olmesartan 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 long-term treatment, the effectiveness of combination therapy (olmesartan medoxomil / hydrochlorothiazide) remains, the development of the syndrome of "cancellation" is not observed.

Pharmacokinetics

Absorption and distribution

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

C_max Olmesartan in plasma is on average 2 hours after ingestion and increases approximately linearly with an increase in a single dose to 80 mg.

Eating does not have a significant effect on the bioavailability of olmesartan medoxomil, so olmesartan medoxomil can be taken regardless of the meal.

There were no clinically significant differences in the pharmacokinetic parameters of olmesargan medoxomil depending on gender.

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 plasma proteins, there is no significant change of this magnitude (this is confirmed by the absence of clinically significant interaction between olmesartan medoxomil and warfarin). Communication olmesartan with blood cells is negligible.

After oral administration of olmesartan medoxomil in combination with hydrochloride and azide, the average time to reach C_max hydrochlorothiazide is 1.5-2 hours.

Hydrochlorothiazide binds to plasma proteins by 68%. The systemic bioavailability of hydrochlorothiazide with simultaneous use with olmesartan medoxomil is reduced by about 20%, but this small decrease is not significant in clinical terms. The simultaneous appointment of hydrochlorothiazide, for its part, does not significantly affect the kinetics of olmesartan medoxomil. In controlled clinical trials, a pronounced antihypertensive effect of this combination was identified, which exceeded the effect of each of the components separately, as well as the placebo effect.

Metabolism and excretion

Total plasma clearance 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 obstruction of the biliary tract is contraindicated.

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

Hydrochlorothiazide it is not metabolized in the body and is almost completely excreted unchanged by the kidneys. After ingestion, 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; T_1/2 The final phase is 10-15 hours.

Pharmacokinetics in various categories of patients

In patients aged 65-75 years with arterial perfusion, the area under the concentration-time curve (AUC) for olmesartan in the saturation stage increases by about 35% compared with the group of patients younger than 65 years, in patients older than 75 years - 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 with volunteers of younger age. In patients with impaired renal function (CC = 30-60 ml / min.) The AUC for olmesartan in the saturation stage increases by approximately 62, 82 and 179% in the case of mild, moderate and severe renal dysfunction, respectively, compared with healthy volunteers. For this category of patients may increase T_1/2 hydrochlorothiazide.

In patients with mild and moderately impaired liver function after a single oral administration, the AUC values for olmesartan were 6% and 65% higher, respectively, compared with healthy volunteers. The unbound fraction of olmesartan 2 h after administration of the drug in healthy volunteers, in patients with mild and moderate degrees of liver dysfunction was 0.26; 0.34 and 0.41%, respectively. The effect of impaired liver function on the pharmacokinetics of hydrochlorothiazide is negligible.

In a relationship patients with severe liver dysfunction (more than 9 points on the Child-Pugh scale) data on the pharmacokinetics of olmesartan medoxomil are not available.

Indications

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

Composition

1 tablet contains:

Active substances: hydrochlorothiazide 12.5 mg; olmesartan medoxomil 20 mg.

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Dosage and Administration

pills Cardosal® plus is taken orally, regardless of the meal. Prior to the appointment of the combined drug Kardosal Plus, it is recommended to pre-select the dose of each of the active ingredients separately (ie, olmesartan medoxomil and hydrochlorothiazide).

Recommended Dose:

Every day, 1 tablet of Cardosal® Plus, containing 20 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide, in the absence of adequate blood pressure control against the background of monotherapy with olmesartan medoxomil at a dose of 20 mg;

In the absence of adequate blood pressure control in patients receiving Cardosal® Plus, containing 20 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide, use of Cardosal® Plus, containing 20 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide, is possible daily with 1 tablet.

The maximum dose of Cardosal® Plus is 20 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide 1 time per day.

Older patients (over 65) with normal renal function (CC more than 90 ml / min) and patients with impaired renal function (CC = 30-60 ml / min) dose adjustment of the drug is not required.

Adverse reactions

Possible side effects are listed below in descending frequency of occurrence:

often (> 1/100, <1/10);
infrequently (> 1/1000, <1/100);
rarely (> 1/10000, <1/1000);
very rarely (<1/10000), including individual messages.

Combination of olmesartan medoxomil and hydrochlorothiazide

From the side of the central nervous system: often - dizziness; infrequently - syncope.

Since the cardiovascular system: infrequently - palpitations, marked reduction in blood pressure, orthostatic hypotension.

On the part of the skin: infrequently - skin rash, eczema.

Metabolism: infrequently, hyper- or hypokalemia, hypercalcemia, hypertriglyceridemia, hyperuricemia, elevated blood lipid concentration.

From the laboratory indicators: very rarely - a slight increase in serum creatinine, uric acid and urea nitrogen, a slight decrease in hemoglobin and hematocrit.

Olmesartan Medoxomil (monotherapy)

From the hemopoietic system: very rarely - thrombocytopenia.

From the side of the central nervous system: very rarely - dizziness, headache.

Since the cardiovascular system: rarely - marked reduction in blood pressure; Infrequently - angina.

On the part of the respiratory system: often - bronchitis, pharyngitis, rhinitis; very rarely - cough.

From the digestive tract: often - diarrhea, dyspepsia, gastroenteritis; very rarely - abdominal pain, nausea, vomiting.

From the urinary system: often - hematuria, urinary tract infection; very rarely, acute renal failure.

From the musculoskeletal system: often - arthritis, back pain; very rarely - muscle cramps, myalgia.

On the part of the skin: very rarely - pruritus, rash, angioedema, allergic dermatitis, urticaria.

Metabolism: often - increased activity of creatine phosphokinase, hypertriglyceridemia, hyperuricemia; rarely - hyperkalemia.

From the laboratory indicators: very rarely, an increase in serum creatinine and urea concentrations; often - increased activity of liver transaminases.

Other violations: often - chest pain, flu-like symptoms, peripheral edema; very rarely - weakness, fatigue, drowsiness, malaise.

Hydrochlorothiazide (monotherapy)

From the hemopoietic system: rarely - leukopenia, neutropenia, agranulocytosis, thrombocytopenia, and plastic anemia, hemolytic anemia, inhibition of bone marrow hematopoiesis.

From the central and peripheral nervous system: often - dizziness, weakness, headache, fatigue; rarely - anxiety, sleep disturbance, confusion, apathy, depression, obnubilation, paresthesia, convulsions.

On the part of the organ of vision: rarely - xantopsia, transient disturbance of accommodation, reduction of the formation of tear fluid.

Since the cardiovascular system: infrequently - orthostatic hypotension; rarely - arrhythmias, thrombosis, embolism.

On the part of the respiratory system: rarely, dyspnea (including interstitial pneumonia and pulmonary edema).

From the digestive tract: infrequently - anorexia, abdominal pain, nausea, vomiting, diarrhea, constipation, flatulence, inflammation of the salivary glands; rarely - pancreatitis, acute cholecystitis, intrahepatic cholestatic jaundice; very rarely - paralytic intestinal obstruction.

From the genitourinary system: rarely - impaired renal function, interstitial nephritis, acute renal failure, impaired potency.

From the musculoskeletal system: rarely - muscle cramps, muscle weakness, paresis.

On the part of the skin: infrequently - photosensitivity, skin rash, urticaria; rarely: lupus-like syndrome (fever, arthralgia, myalgia, serositis, vasculitis, increased erythrocyte sedimentation rate (ESR), leukocytosis, eosinophilia), activation of the skin form of systemic lupus erythematosus, anaphylactic reactions, toxic epidermal necrolysis.

From the laboratory indicators: often - hyperglycemia, glucosuria, hyperuricemia, increased serum creatinine concentration, impaired water-electrolyte balance (including hyponatremia, hypomagneemia, hypochloremia, hypokalemia and hypercalcemia), increased cholesterol and triglycerides in the blood.

Other violations: rarely fever.

Carefully: bronchial asthma; ischemic heart disease (CHD); chronic heart failure in the stage of decompensation; severe cerebrovascular disorders; stenosis of the aortic or mitral valve; hypertrophic obstructive cardiomyopathy; liver dysfunction mild to moderate (less than 9 points on the Child-Pugh scale); renal dysfunction (CC more than 30 ml / min, but less than 60 ml / min.); bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney; condition after a recent transplantation of the kidney (no experience with the drug); primary aldosteronism; diabetes, gout; violations of water and electrolyte balance, dehydration; connective tissue diseases, including systemic lupus erythematosus; patients on a salt-restricted diet or on hemodialysis; in the suppression of bone marrow hematopoiesis; conditions accompanied by a decrease in circulating blood volume; (Bcc) including diarrhea, vomiting, or previous diuretic therapy.

Drug interactions

Olmesartan Medoxomil

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 (eg, heparin) is not recommended - it is possible to increase the concentration of potassium in the blood serum.

Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid in doses of more than 3 g / day, as well as cyclooxygenase-2 inhibitors (COX-2), and angiotensin II receptor antagonists can act synergistically, reducing glomerular filtration. With simultaneous use of NSAIDs and angiotensin II receptor antagonists, there may be a risk of developing acute renal failure, therefore, monitoring renal function at the beginning of treatment is recommended, 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 efficacy. 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 manifestation of toxicity during simultaneous use of lithium preparations with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists, therefore the use of olmesartan medoxomil in combination with lithium preparations is not recommended. If necessary, the use of appropriate combination therapy is recommended to regularly monitor the concentration of lithium in the serum.In rare cases, ACE inhibitors may enhance the hypoglycemic effect of insulin and hypoglycemic oral agents (for example, sulfonylurea derivatives) in diabetic patients. In these cases, with the simultaneous use of ACE inhibitors, it may be necessary to reduce the dose of the hypoglycemic agent for oral and insulin.

Hydrochlorothiazide

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

The simultaneous intake of ion-exchange drugs (colesteramine, colestepol) reduces the absorption of hydrochlorothiazide.

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

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

Drugs that can cause arrhythmia type "pirouette" ("torsades des pointes") (a special form of polymorphic ventricular tachycardia with wave, screw or spindle 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 ventricular disease or asystole): due to the risk of hypokalemia, caution is required with the simultaneous use of hydrochlorothiazide with some antiarrhythmic agents (quinidine, hydroquinidine, disopyramide, amiodarone, with alof, dof, mizolastine, nentamidine, sparfloxacin, terfenadine, vincamine for intravenous administration), which are known to cause arrhythmia of the "pirouette" type.

When combined use of hydrochlorothiazide with non-depolarizing muscle relaxants (including tubocurarine chloride) - increased action 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, the bioavailability of thiazide diuretics may increase due to reduced motility of the gastrointestinal tract.

You may need to reduce the dose of hypoglycemic agents for oral and insulin.

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

Thiazide diuretics can reduce the excretion of cytotoxic drugs by the kidneys and enhance their myelosuppressive effect.

When taking salicylates in high doses, hydrochlorothiazide may increase their toxic effects on the central nervous system.

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

The simultaneous 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 increasing the concentration of urea caused by 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 caused by ACE inhibitors, so the combined use of Cardosal® plus and lithium preparations is not recommended. If such a combination is still necessary, then careful control of the concentration of lithium in the blood serum is also necessary.

With simultaneous use of the drug Cardosal * plus with baclofen and amifostine, the antihypertensive effect can be enhanced.

With the simultaneous use of other antihypertensive agents, the hypotensive effect of the drug Cardosal® Plus may increase. Ethanol, barbiturates, narcotic analgesics or antidepressants when used with Cardosal® Plus can lead to aggravation of orthostatic hypotension.

Pregnancy and Lactation

Experience with olmesartan medoxomil in pregnant women is absent. However, due to the reports of severe teratogenic effects of drugs acting on the RAAS, like any drug of this class, Cardosal® plus is contraindicated for use in pregnancy. In the case of planning or the occurrence of pregnancy during therapy with Cardosal® plus the drug must be canceled 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 suppress lactation, therefore, if necessary, use Cardosal® plus during lactation to stop breastfeeding.

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, restriction of salt intake with food in the diet, and also due to diarrhea or vomiting. Relevant factors should be eliminated before using Cardosal® Plus.

Thiazide diuretics, including hydrochlorothiazide, may be the cause of impaired BCC or water-electrolyte balance in blood serum (including hypokalemia, hyponatremia, and hypochloraemic alkalosis). Symptoms of precursors are: dryness of the oral mucosa, thirst, weakness, drowsiness, anxiety, myalgia or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, nausea and vomiting (see the Side Effects section).

The highest risk of developing hypokalemia is in patients with cirrhosis of the liver, in patients during forced diuresis, and in those patients who are also taking glucocorticosteroids or ACTT (see the section on Interaction with Other Drugs). Conversely, due to the antagonism of Cardosal® plus olmesartan medoxomil contained in the preparation for angiotensin II receptors (AT₁), hyperkalemia may occur - primarily in patients with reduced kidney function and / or chronic heart failure, as well as patients with diabetes. 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 interfere with its development. In hot weather patients with prone to edema may be diluted hyponatremia. The decrease in chloride concentration is generally expressed slightly and usually does not require treatment.Thiazides can reduce the excretion of calcium ions by the kidneys and also lead to a transient slight increase in serum calcium concentration in the absence of a history of metabolic disturbances. Hypercalihemia may indicate latent hyperparathyroidism. Before examining the function of the parathyroid glands, thiazides should be abolished.

Thiazide diuretics have been proven to increase the excretion of magnesium ions by the kidneys, which can lead to hypomagnesemia.

In patients whose vascular tone and kidney function depend to a large extent on the activity of the RAAS (for example, in patients with severe chronic heart failure or impaired renal function, including renal artery stenosis), treatment with other drugs that affect the RAAS is associated with the possibility of acute hypotension, azotemia, oliguria, or, in rare cases, acute renal failure. The possibility of a similar action cannot be excluded when using 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 the only functioning kidney is receiving therapy with drugs that affect the RAAS. When using the drug Cardosal 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. The experience of using olmesartan medoxomil in patients with recently performed kidney transplantation or in patents with the last stage of renal impairment is absent.

In patients with impaired renal function, thiazide diuretic may be associated with azotemia. With the apparent progression of renal failure, it is necessary to review the therapy and decide on the cancellation of diuretics.

As in the case of 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 levels of 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 section Interaction with other drugs). When treating 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. Reactions of hypersensitivity to hydrochlorothiazide can take place with greater probability in patients with aggravated allergic history or bronchial asthma (in anamnesis).

Impact on the ability to drive vehicles and other mechanisms that require high concentration of attention

The effect of Kardosal® plus on the ability to drive vehicles and control mechanisms has not been specifically studied, therefore, during treatment with Kardosal® plus, care should be taken when driving vehicles and practicing potentially hazardous activities that require increased concentration and psychomotor speed.

Overdosage

Symptoms: with an overdose of olmesartan medoxomil, the most pronounced decrease in blood pressure, as well as tachycardia, bradycardia, nausea, drowsiness are most likely; in case of hydrochlorothiazide overdose, symptoms of electrolyte deficiency (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis.

Treatment: recommended gastric lavage and / or reception of activated carbon; therapy aimed at correcting dehydration and impaired water and electrolyte balance. With a marked decrease in blood pressure, it is recommended to lay the patient in a horizontal position, raising his legs, and to conduct therapy aimed at replenishing the BCC. Hemodialysis is not effective.