Cardosal® Plus (Cardosal® Plus)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceHydrochlorothiazide + Olmesartan medoxomilHydrochlorothiazide + Olmesartan medoxomil
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  • Cardosal® Plus
    pills inwards 
    BERLIN-PHARMA, CJSC     Russia
    • Dosage form: & nbsp

    tablets, film-coated.

    Composition:

    Composition per one tablet:

    Tablets 12.5 mg + 20 mg

    Core:

    Active substances:

    Olmesartan medoxomil - 20.00 mg,

    Hydrochlorothiazide - 12.50 mg.

    Excipients: microcrystalline cellulose - 20.00 mg, giprolose (with a low degree of substitution) - 40.00 mg, lactose monohydrate - 110.70 mg, giprolose - 5.00 mg, magnesium stearate - 1.80 mg;

    Shell:

    Opadrai 02A22352 - 8.00 mg [hypromellose, 2910 - 72.00%; talcum powder - 14.00%; titanium dioxide (E 171) - 13.15%; coloring agent iron oxide yellow (E 172) - 0.75%; ferric dye oxide red (E 172) - 0.10%].

    Tablets 25 mg + 20 mg

    Core:

    Active substances:

    Olmesartan medoxomil - 20.00 mg,

    Hydrochlorothiazide - 25.00 mg.

    Excipients: microcrystalline cellulose - 20.00 mg, giprolose (with a low degree of substitution) - 40.00 mg, lactose monohydrate - 98.20 mg, giprolose - 5.00 mg, magnesium stearate - 1.80 g.

    Shell:

    Opadrai 02A24576 - 8.00 mg [hypromellose, 2910 - 72.00%; talcum powder - 14.00%; titanium dioxide (E 171) - 13.5%; iron dye oxide yellow (E 172) - 0.25%; iron dye red oxide (E 172) - 0.25%].

    Description:

    Tablets 12.5 mg + 20 mg: round tablets covered with a film shell, peach color with a print "C22" on one side, with a characteristic smell.View of the fracture: white.

    Tablets 25 mg + 20 mg: round tablets covered with a film coating, light pink with an impression "C24" on one side, with a characteristic odor.

    View of the fracture: white.

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

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

    C.09.D.A.08   Olmesartan medoxomil in combination with diuretics

    Pharmacodynamics:

    Cardosal® plus is a combined preparation that contains an angiotensin II receptor antagonist (olmesartan medoxomil) and thiazide diuretic (hydrochlorothiazide). The combination of the two active substances has a combined antihypertensive effect, so that the blood pressure (BP) decreases more than with the reception of 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 potent specific antagonist of angiotensin II receptor (type AT). Angiotensin II is a primary vasoactivecomponent of the renin-angiotensin-aldosterone system (RAAS) and plays a significant role in the pathophysiology of hypertension by affecting AT] -receptors. It is assumed that olmesartan medoxomil blocks all the effects of angiotensin II, mediated by AT] -receptors, regardless of the source and route of synthesis of angiotensin II.

    The specific antagonism of olmesartan in relation to ATGregs leads to an increase in the concentration of renin, angiotensin I and II in blood plasma, and also helps to reduce the plasma concentration of aldosterone.

    With arterial hypertension olmesartan medoxomil causes a dose-dependent long-term decline in blood pressure. There is no data on the development of arterial hypotension after taking the first dose of the drug, about tachyphylaxis during long-term treatment or about the "withdrawal" syndrome (a sharp increase in BP after drug withdrawal).

    The use of olmesartan medoxomil once a day provides an effective and gentle 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 approximately in 8 weeks. after the start of therapy.

    Hydrochlorothiazide - Thiazide diuretic - reduces the reabsorption of sodium, chlorine and water ions in the renal tubules.

    Increases the excretion of potassium, magnesium, hydrocarbonates, reduces the excretion of calcium ions. Diuretic effect occurs 2 hours after taking hydrochlorothiazide inwards, reaches a maximum after 4 hours and lasts up to 12 hours. It helps to decrease high blood pressure.

    With the simultaneous use of olmesartan medoxomil and hydrochlorothiazide, there is a decrease in the loss of potassium ions caused by the action of the diuretic.

    The result combination therapy Olmesartan medoxomil and hydrochlorothiazide is potentiation of the hypotensive effect, which depends on the dose of each component of the drug. In controlled clinical trials, the pronounced antihypertensive effect of this combination was found, which exceeded the effect of each of the components separately, as well as the placebo effect. Combination therapy is well tolerated by patients. With long-term treatment, the effectiveness of combination therapy (olmesartan medoxomil / hydrochlorothiazide) remains, the development of the "withdrawal" syndrome with discontinuation of the drug is not observed.

    Age and sex of patients had no clinically significant effect on the efficacy of combined therapy with olmesartan medoxomil and hydrochlorothiazide.

    Pharmacokinetics:

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

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

    The ingestion of food does not significantly affect the bioavailability of olmesartan medoxomil, therefore olmesartan medoxomil can be taken regardless of drinking.

    Clinically significant differences in pharmacokinetic parameters of olmesartan medoxomil, depending on sex, were not revealed.

    Olmesartan 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 is no significant change in this value (which is confirmed by the absence of a clinically significant interaction between olmesartan medoxomil and warfarin). The association of olmesartan with blood cells is negligible. The average volume of distribution after intravenous administration is low (16-29 L).

    Hydrochlorothiazide binds to plasma proteins by 68%, and its apparent volume of distribution is 0.83-1.14 l / kg. Systemic bioavailability of hydrochlorothiazide with simultaneous use with olmesartan medoxomil decreases by about 20%, but this small decrease in clinical terms is not significant. After oral administration of olmesartan medoxomil in combination with hydrochlorothiazide, the mean time to achieve Cmax hydrochlorothiazide is 1.5-2 hours.

    The simultaneous use of hydrochlorothiazide, for its part, does not significantly affect the kinetics of olmesartan medoxomil.

    Metabolism and excretionThe total plasma clearance of olmesartan is usually 1.3 l / h (the coefficient of variation is 19%) and is relatively low in comparison with the hepatic blood flow (about 90 l / h).

    Elimination of olmesartan is carried out in two ways, approximately 40% is excreted through the kidneys, about 60% - with bile. It is excreted in the form of olmesartan, other metabolites are not found. The intestinal and hepatic recirculation of olmesartan is minimal. Since most of the olmesartan medoxomil is metabolized in the liver, its use in patients with bile duct obstruction is contraindicated (see Contraindications section).

    The half-life of olmesartan is 10-15 hours. The equilibrium state is achieved after taking several first doses of the drug, and after 14 days of repeated application no further cumulation is observed. Kidney clearance is approximately 0.5-0.7 l / h and is not dose-dependent. Hydrochlorothiazide in the body is not metabolized and almost completely unchanged is excreted by the kidneys. After oral administration, about 60% of the dose of hydrochlorothiazide taken unchanged is withdrawn within 48 hours.Renal clearance of hydrochlorothiazide is about 250-300 ml / min .; half-life (T1/2) of the final phase is 10-15 h.

    Pharmacokinetics in elderly patients (65 years and older)

    In elderly patients (65-75 years) and senile (75 years and older) with arterial hypertension, the area under the concentration-time curve (AUC) for olmesartan in the equilibrium state was greater by 35% and by approximately 44% respectively, compared with younger patients, which may be partly due to the age-related decline in kidney function.

    Systemic clearance of hydrochlorothiazide in both healthy elderly volunteers and in elderly patients with hypertension is reduced compared to volunteers of a younger age.

    Pharmacokinetics in patients with renal insufficiency In patients with mild, moderate and severe severe renal failure, the equilibrium AUC in olmesartan increases approximately 62%, 82%, and 179%, respectively, compared to healthy volunteers.

    For this category of patients is characterized by an increase T1/2 hydrochlorothiazide.

    Pharmacokinetics in patients with hepatic impairment

    In patients with hepatic insufficiency of mild and moderate severity after single ingestion, the values ​​of AUC for olmesartan were 6% and 65% higher, respectively, compared to healthy volunteers. Unrelated fraction of olmesartan 2 hours after taking the dose of the drug in healthy volunteers, in patients with hepatic insufficiency of mild and moderate severity were 0.26%, 0.34% and 0.41%, respectively.

    When administered multiple times, the AUC for olmesartan in patients with moderate hepatic impairment was 65% higher than in healthy volunteers in the control group. Mean values Cmax Olmesartan in patients with hepatic insufficiency and healthy volunteers were similar. The pharmacokinetics of olmesartan medoximil in patients with severe hepatic insufficiency (more than 9 on the Child-Pugh scale) has not been studied.

    The presence of hepatic insufficiency does not have a significant effect on the pharmacokinetics of hydrochlorothiazide.

    Indications:Essential arterial hypertension (with inefficiency of olmesartan monotherapy with medoxomil).
    Contraindications:

    - Hypersensitivity to olmesartan medoxomil, hydrochlorothiazide or other derivatives of sulfonamides or to any of the excipients that make up the formulation;

    - renal failure of severe severity (creatinine clearance less than 30 ml / min), condition after kidney transplantation (no experience of clinical use);

    - hepatic insufficiency of severe severity (more than 9 on the Child-Pugh scale) (risk of hepatic coma development), bile duct obstruction and cholestasis;

    -refractory hypokalemia, hyponatremia, hypercalcemia and symptomatic hyperuricemia;

    - Hereditary intolerance to galactose, deficiency of lactase and syndrome of malabsorption of glucose and galactose;

    - simultaneous use with aliskiren and aliskirenoderzhaschimi drugs in patients with diabetes mellitus and / or renal failure (glomerular filtration rate less than 60 ml / min / m);

    -pregnancy;

    -period of breastfeeding;

    Primary aldosteronism;

    -About 18 years of age (efficacy and safety not established).

    Carefully:

    - Bronchial asthma;

    - Ischemic heart disease (CHD);

    - Chronic heart failure;

    - cerebrovascular diseases;

    - or aortic stenosis, mitral valve; mgipertroficheskaya obstructive cardiomyopathy;

    - hepatic insufficiency of mild and moderate severity (less than 9 on the Child-Pugh scale);

    - renal insufficiency of mild and moderate severity (QC more than 30 ml / min, but less than 60 ml / min);

    - vasorenal hypertension (bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney); diabetes mellitus, gout;

    - Violations of the water-electrolyte balance, dehydration; connective tissue diseases, including systemic lupus erythematosus; patients who follow a diet with salt restriction or who are on hemodialysis;

    - with oppression of bone marrow hematopoiesis;

    - conditions, accompanied by a decrease in the volume of circulating blood (BCC), incl. diarrhea, vomiting, or previous therapy with diuretics; with simultaneous use with lithium preparations.

    Pregnancy and lactation:

    The experience of using olmesartan medoxomil in pregnant women is absent. However, in view of the available reports of severe teratogenic effects of drugs acting on RAAS, Cardosal® plus is contraindicated in pregnancy.In the case of planning or the onset of pregnancy during therapy with Cardosal® plus, the drug should be discontinued as soon as possible.

    Patients who plan pregnancy are recommended to be transferred to anti-hypertensive drugs of other groups, the safety of which is proven in pregnancy, except for the cases when the drug Kardosal® Plus is used for vital indications.

    Given the mechanism of action of hydrochlorothiazide, its use in the second and third trimesters of pregnancy can cause a violation of the fetoplacental blood flow and have an adverse effect on the fetus and the newborn, causing jaundice, electrolyte disorders and thrombocytopenia.

    Hydrochlorothiazide is not intended for the treatment of dropsy in pregnant women, hypertension in pregnant women or preeclampsia, since it can cause a decrease in plasma volume and hypoperfusion of the placenta.

    At the present time, it is not known whether olmesartan medoxomil in breast milk. Hydrochlorothiazide penetrates into breast milk, so the use of Cardosal plus in the period of breastfeeding is contraindicated.If it is necessary to prescribe the drug, breast-feeding should be discontinued.

    Dosing and Administration:

    Tablets coated with a film coat of Cardosal® Plus are taken orally at the same time, regardless of food intake, once a day, without chewing, squeezed with enough liquid (for example, a glass of water).

    Prior to the appointment of the combined drug Cardosal® plus, it is recommended that the dose of each of the active substances be separately selected (ie, olmesartan medoxomil and hydrochlorothiazide).

    In the presence of clinical indications, a patient can be transferred from olmesartan monotherapy to medoxomil in a dose of 20 mg once per combination preparation; however, one should take into account the fact that the maximum hypotensive effect of olmesartan medoxomil is achieved 8 weeks after the start of treatment.

    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 olmesartan monotherapy with medoxomil at a dose of 20 mg.

    In the absence of adequate control of blood pressure when taking Cardosal plus, containing 20 mg of olmesartan medoxomil and 12.5 mg hydrochlorothiazide,It is possible to use Cardosal plus, containing 20 mg of olmesartan medoxomil and 25 mg hydrochlorothiazide daily for 1 tablet.

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

    Use in elderly patients (over 65 years).

    In elderly patients (over 65 years) with normal renal function (CC greater than 90 ml / min), dose adjustment is not required. When using the drug in elderly patients, it is necessary to carry out a thorough control of blood pressure.

    Use in patients with renal insufficiency

    If Cardosal® plus is used in patients with mild and moderate renal insufficiency (creatinine clearance 30-60 ml / min), it is recommended to monitor renal function. In patients with severe renal insufficiency (creatinine clearance <30 ml / min), the use of Cardosal® plus is contraindicated.

    Use in patients with hepatic impairment

    In patients with mild to moderate hepatic insufficiency, Cardosal® plus should be used with caution.

    In the case of hepatic insufficiency of moderate severity, the initial dose of olmesartan medoxomil is 10 mg once daily. The maximum daily dose is 20 mg once a day.

    When used simultaneously with diuretics and / or other antihypertensive drugs in patients with hepatic insufficiency, careful monitoring of blood pressure and kidney function is recommended.

    The use of Cardosal plus is contraindicated in patients with hepatic insufficiency of severe severity, and in patients with bile duct obstruction and cholestasis.

    Side effects:

    Possible side effects are listed below in descending frequency of occurrence: very often (> 1/10), often (> 1/100 <1/10) infrequently (> 1/1000 <1/100), rare (> 1 / 10000, <1/1000), very rarely, including individual messages (<1/10000).

    The combination of olmesartan medoxomil and hydrochlorothiazide

    Impaired nervous system:

    Often: dizziness, headache.

    Infrequently: postural dizziness, drowsiness, syncope.

    Rarely: disorders of consciousness.

    Disorders from the cardiovascular system:

    Infrequent: palpitation, marked decrease in blood pressure, orthostatic hypotension.

    Disturbances from the respiratory system, chest and mediastinal organs:

    Infrequently: cough.

    Hearing disorders and labyrinthine disturbances:

    Infrequently: vertigo.

    Disorders from the gastrointestinal tract:

    Infrequent: abdominal pain, diarrhea, indigestion, nausea, vomiting.

    Disturbances from the skin and subcutaneous tissues:

    Infrequent: skin rash, eczema.

    Rarely: angioedema, hives.

    Disturbances from the skeletal musculature and connective tissue:

    Infrequently: arthralgia, back pain, muscle cramps, myalgia, pain in the extremities.

    Disorders from the kidneys and urinary tract:

    Infrequently: hematuria.

    Rarely: acute renal failure.

    Violations of the genitals and mammary glands:

    Infrequent: erectile dysfunction.

    Disorders from the metabolism:

    Infrequent: increased concentration of triglycerides, cholesterol, uric acid in the blood plasma.

    Common violations:

    Often: asthenia, pain in the chest, fatigue, peripheral edema.

    Infrequently: weakness.

    Rarely: malaise.

    Violations from laboratory indicators:

    Infrequently: increased activity of alanine aminotransferase, aspartate aminotransferase and gamma glutamyl transferase; increasing the concentration of calcium in the blood plasma, increasing the concentration of creatinine, urea, glucose in the blood plasma, increasing / lowering the concentration of potassium in the blood plasma

    Rarely: a decrease in the concentration of hemoglobin and hematocrit.

    OLMESARTANA MEDOXOMIL (monotherapy)

    Violations from the blood and lymphatic system:

    Infrequent: thrombocytopenia.

    Impaired nervous system:

    Often: dizziness, headache.

    Hearing disorders and labyrinthine disturbances:

    Infrequently: vertigo.

    Disturbances from the respiratory system, chest and mediastinal organs:

    Often: pharyngitis, rhinitis, bronchitis, cough.

    Disturbances from the digestive system:

    Often: diarrhea, indigestion, gastroenteritis, abdominal pain, nausea.

    Infrequently: vomiting.

    Disturbances from the skin and subcutaneous tissues:

    Infrequently: exanthema, allergic dermatitis, urticaria, rash, itchy skin.

    Rarely: angioedema.

    Disorders from the musculoskeletal system:

    Often: back pain, bone pain, arthritis.

    Infrequently: myalgia.

    Rarely: muscle cramps.

    Disorders from the kidneys and urinary tract:

    Often: hematuria, urinary tract infection.

    Rarely: acute renal failure, renal failure.

    Disorders from the cardiovascular system:

    Infrequently: angina.

    Rarely: excessive decrease in blood pressure.

    Disorders from the metabolism and nutrition:

    Often: increased concentration of triglycerides, uric acid in the blood plasma.

    Rarely: an increase in the concentration of potassium in the blood plasma.

    Immune system disorders:

    Infrequently: anaphylactic reactions.

    Common violations:

    Often: chest pain, peripheral edema, flu-like symptoms, fatigue.

    Infrequent: swelling of the face, asthenia, malaise.

    Rarely: drowsy.

    Other violations:

    Often: increased urea concentration in blood plasma, increased activity of liver enzymes, increased concentration of creatine phosphokinase

    Rarely: an increase in the concentration of creatinine in the blood plasma.

    There have also been reports of single cases of rhabdomyolysis, which, in terms of developmental time, was associated with the use of ATP receptor blockers.

    HYDROCHLOROTHAZIDE (monotherapy)

    Violations from the blood and lymphatic system:

    Rarely: leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, oppression of bone marrow hematopoiesis.

    Infections and infestations:

    Rarely: sialadenitis (inflammation of the salivary glands).

    Immune system disorders:

    Rarely: anaphylactic reactions.

    Disorders from the metabolism and nutrition:

    Very often: an increase in the concentration of cholesterol, uric acid and triglycerides in the blood plasma.

    Often: increasing the concentration of glucose in the urine, increasing the concentration of glucose in the blood plasma, increasing the concentration of calcium ions in the blood plasma, reducing the concentration of chloride, potassium, magnesium and sodium ions in the blood plasma, increasing the concentration of amylase in the blood plasma.

    Infrequently: anorexia.

    Very rarely: hypochloraemic alkalosis.

    Disorders from the psyche:

    Rarely: apathy, depression, anxiety, sleep disturbance.

    Disorders from the central and peripheral nervous system:

    Often: dizziness, confusion.

    Infrequently: loss of appetite.

    Rarely: headache, paresthesia, convulsions.

    Disorders from the side of the organ of vision:

    Infrequent: progression of myopia.

    Rarely: xantopsy, transient disruption of accommodation, reducing the formation of tear fluid.

    Disorders from the cardiovascular system:

    Infrequent: orthostatic hypotension.

    Rarely: arrhythmias, thrombosis, embolism, necrotizing vasculitis.

    Hearing disorders and labyrinthine disturbances:

    Rarely: vertigo.

    Disturbances from the respiratory system, chest and mediastinal organs:

    Infrequent: respiratory distress.

    Rarely: dyspnea, interstitial pneumonia, pulmonary edema.

    Disturbances from the digestive tract:

    Often: abdominal pain, nausea, vomiting, diarrhea, constipation, flatulence, irritation of the gastric mucosa.

    Rarely: pancreatitis.

    Very rarely: paralytic intestinal obstruction.

    Disorders from the liver and hepatobiliary tract:

    Rarely: acute cholecystitis, intrahepatic cholestatic jaundice.

    Disorders from the kidneys and urinary tract:

    Rarely: renal dysfunction, interstitial nephritis.

    Violations of the genitals and mammary glands:

    Infrequent: erectile dysfunction.

    Disturbances from the skin and subcutaneous tissues:

    Infrequently: photosensitization, skin itch, skin rash, purpura, erythema, urticaria.

    Rarely: cutaneous anaphylactic reactions, the development of lupus-like syndrome (fever, arthralgia, myalgia, serositis, vasculitis,increased erythrocyte sedimentation rate (ESR), leukocytosis, eosinophilia), activation of cutaneous systemic lupus erythematosus, anaphylactic reactions, toxic epidermal necrolysis.

    Disorders from the musculoskeletal system:

    Rarely: muscle weakness, paresis.

    Common violations:

    Rarely: fever.

    Violations from laboratory indicators:

    Often: increase in the concentration of creatinine and urea in the blood plasma.

    Overdose:

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

    Treatment: recommended gastric lavage and / or reception of activated charcoal; therapy aimed at correcting dehydration and disturbances in the water-electrolyte balance. At a marked decrease in blood pressure, it is recommended to put the patient in a horizontal position, lifting his legs, and to conduct therapy aimed at replenishing the BCC. Data on excretion of olmesartan in hemodialysis are absent.

    Interaction:

    Olmesartan medoxomil

    It is not recommended simultaneous use with potassium-sparing diuretics, potassium preparations, salt substitutes containing potassium, or other drugs that increase the concentration of potassium in the blood plasma (for example, heparin, ACE inhibitors) - it is possible to increase the concentration of potassium in the blood plasma.

    When used simultaneously with antacids (magnesium and aluminum hydroxide), there is a moderate decrease in the bioavailability of olmesartan.

    With simultaneous application olmesartan medoxomil does not have a clinically significant effect on the pharmacokinetics and pharmacodynamics of warfarin, digoxin, hydrochlorothiazide, pravastatin and antacids (magnesium and aluminum hydroxide).

    There have been reports of a reversible increase in lithium plasma concentration and toxicity during simultaneous use of lithium drugs with angiotensin converting enzyme (ACE) inhibitors and with angiotensin II receptor antagonists, so the use of olmesartan medoxomil in combination with lithium preparations is not recommended. If it is necessary to use the appropriate combination therapy, regular monitoring of the concentration of lithium in the blood plasma is recommended.

    Clinical studies show that the double blockade of the renin-angiotensin-aldosterone system (RAAS), while using ACE inhibitors, angiotensin II receptor antagonists or aliskiren, is associated with a higher incidence of side effects such as hypotension, hyperkalemia, and decreased renal function including, the development of acute renal failure) than with the use of only one drug that affects RAAS. Thus, simultaneous use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended.

    Simultaneous use of olmesartan medoxomil and preparations containing aliskiren, is contraindicated in patients with diabetes mellitus and renal insufficiency (at a glomerular filtration rate <60 ml / min / m).

    Patients with diabetic nephropathy should not simultaneously use ACE inhibitors and angiotensin II receptor antagonists.

    In the case when the simultaneous use of two agents that affect the RAAS is necessary, their application should be carried out under the supervision of a physician and with regular monitoring of renal function, blood pressure and electrolyte concentration in the blood plasma.

    The clinically significant inhibitory effect of olmesartan on the isoenzymes 1A1 / 2, 2A6, 2C8 / 9, 2C19, 2D6, 2E1 and ZA4 of human cytochrome P450 was not detected in vitro; a minimum or zero inducing effect was noted for rat cytochrome P450, suggesting the absence of clinically significant interactions with the simultaneous use of olmesartan medoxomil and drugs metabolized with the abovementioned cytochrome P450 isoenzymes.

    Hydrochlorothiazide

    Glucocorticosteroids, potassium-diuretic diuretics, adrenocorticotropic hormone (ACTH), amphotericin B (parenteral), carbenoxolone, penicillin G sodium salt, amphotericin, salicylic acid derivatives, laxatives, while taking them with hydrochlorothiazide, there may be an increase in electrolyte losses, especially the development of hypokalemia. The simultaneous use of hydrochlorothiazide with these drugs is not recommended.

    Simultaneous reception of anion-exchange drugs (colestramine, colestipol) reduces the absorption of hydrochlorothiazide.

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

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

    Medicines that can cause torsades des pointes (a special form of polymorphic ventricular tachycardia with a wave, screw or spindle configuration of the ventricular complexes in combination with an increase or decrease in the amplitude of the teeth of the QRS complex, which can lead to fibrillation ventricles or asystole): due to the risk of developing hypokalemia, caution is required when hydrochlorothiazide is used together with certain antiarrhythmics (quinidine, hydroquinidine, disopyramide, amiodarone, sotalol, dofetilide, ibutilide), neuroleptics (thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol) and other drugs (bepridil, cisapride, difemanyl methyl sulfate, erythromycin for intravenous administration, halofantrine, misolastine, pentamidine, sparfloxacin, terfenadine, wincamine for intravenous administration), of which it is known that they can cause arrhythmia of the "pirouette" type.

    With the combined use of hydrochlorothiazide with nondepolarizing muscle relaxants (including tubocurarine chloride) - increased action of muscle relaxants.

    Thiazides may increase the risk of side effects of amantadine.

    Treatment with thiazide diuretics can impair glucose tolerance. It may be necessary to reduce the dose of hypoglycemic agents for ingestion and insulin.

    Metformin should be used with caution because of the risk of developing lactic acidosis caused by functional renal failure, which sometimes occurs when hydrochlorothiazide is used.

    The hyperglycemic efficacy of beta-blockers and diazoxide can be enhanced by the action of thiazides.

    With the simultaneous use of M-holinoblokatorov (atropine) and thiazides due to a decrease in the motility of the gastrointestinal tract, the bioavailability of thiazide diuretics can increase.

    Antifungal agents (probenecid, sulfinpyrazone, allopurinol): there may be a need for correction of the dose of the hypo-uricemic agent (an increase in the dose of probenecid or sulfinpyrazone), since hydrochlorothiazide can increase the concentration of uric acid in the blood plasma. Simultaneous use with thiazide diuretics can increase the frequency of development of hypersensitivity reactions to allopurinol. The effect of sympathomimetics with simultaneous administration of thiazide diuretics may be weakened.

    Thiazide diuretics can reduce the excretion of cytotoxic agents by the kidneys (for example, cyclophosphamide, methotrexate) 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 single cases of hemolytic anemia with concomitant administration of methyldopa with hydrochlorothiazide.

    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 an increase in urea concentration due to tetracyclines.This interaction does not apply to doxycycline.

    Olmesartan medoxomil / hydrochlorothiazide in combination

    Simultaneous use of lithium preparations with thiazide diuretics may increase the already high risk of lithium intoxication caused by ACE inhibitors (rarely with angiotensin II receptor blockers), so the combined use of Cardosal plus and lithium preparations is not recommended. If such a combination is still necessary, then careful monitoring of the concentration of lithium in blood plasma is also necessary.

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

    With the simultaneous use of other antihypertensive drugs, the hypotensive effect of Cardosal® Plus can increase.

    Ethanol, barbiturates, narcotic analgesics or antidepressants when used with the drug Cardosal plus may lead to aggravation of orthostatic hypotension.

    Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid in doses greater than 3 g / day, as well as inhibitors of cyclooxygenase-2 (COX-2), can reduce the hypotensive effect of thiazide diuretics and angiotensin II receptor blockers.

    NSAIDs 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, so it is recommended that kidney function be monitored at the beginning of treatment and that a sufficient amount of fluid is taken regularly. However, simultaneous use can reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to a partial loss of their therapeutic efficacy.

    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 therapy with diuretics, dietary restriction of dietary intake, and also due to diarrhea or vomiting. Corresponding factors should be eliminated before starting the use of Cardosal® plus.

    Thiazide diuretics, including hydrochlorothiazide, can cause a violation of bcc or water-electrolyte balance of blood plasma (including hypokalemia, hyponatremia and hypochloraemic alkalosis).Symptoms-forerunners are: dryness of the oral mucosa, thirst, weakness, drowsiness, anxiety, myalgia or convulsions, muscle weakness, arterial hypotension, oliguria, tachycardia, nausea and vomiting (see Side effect).

    The highest risk of hypokalemia exists in patients with cirrhosis of the liver, in patients with forced diuresis and in patients who simultaneously take glucocorticosteroids or ACTH (see Interactions with Other Drugs). Conversely, because of the antagonism of Cardosal® plus olmesartan medoxomil displayed for angiotensin II receptor (AT1), hyperkalemia can occur, primarily in patients with impaired renal function and / or chronic heart failure, as well as patients with diabetes mellitus. Patients with risk factors are recommended to regularly monitor the concentration of potassium in the blood plasma.

    Data on whether olmesartan medoxomil To reduce hyponatremia, caused by diuretics or to prevent its development, no.In hot weather, diluted hyponatremia may occur in patients prone to edema. Reduction of the chloride concentration in general is not very pronounced 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 the calcium concentration in the blood plasma in the absence of an anamnesis of metabolic disturbances. Hypercalcemia may indicate latent hyperparathyroidism. Before the study of the function of parathyroid glands, thiazides should be discontinued.

    It is proved that thiazide diuretics increase the excretion of magnesium ions by the kidneys, which can lead to hypomagnesemia.

    In patients who have vascular tone and kidney function depending to a large extent on the activity of RAAS (for example, in patients with severe chronic heart failure or renal dysfunction, including renal artery stenosis), treatment with other agents that affect RAAS is associated with the possibility of developing acute arterial hypotension, azotemia, oliguria, or, in rare cases, acute renal failure. The possibility of a similar effect can not be ruled out with the use of angiotensin II receptor antagonists.

    Before prescribing simultaneously with the drug Cardosal® plus other drugs that affect RAAS, the benefit / risk ratio of this combination should be carefully assessed and other options should be considered (see Interactions with Other Drugs).

    There is an increased risk of severe arterial hypotension and kidney failure if a patient with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney receives therapy with drugs that affect RAAS.

    When using Cardosal plus in patients with impaired renal function, it is recommended that periodic monitoring of the concentration of potassium, creatinine and uric acid ions in the blood plasma is recommended. The experience of using olmesartan medoxomil in patients with recent kidney transplantation or in patients with the last stage of renal impairment is absent.

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

    As with any antihypertensive drug, an excessive reduction in blood pressure in patients with ischemic heart disease or with cerebrovascular insufficiency can lead to myocardial infarction or stroke.

    Thiazide diuretics can cause a violation of glucose tolerance, as well as an increase in the concentration of cholesterol, triglycerides and uric acid in the blood plasma. In patients with diabetes mellitus, it may be necessary to adjust the dose of insulin or hypoglycemic agent for oral administration (see Interactions with other drugs). In the treatment of 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 in patients with a history of allergic history or bronchial asthma.

    Effect on the ability to drive transp. cf. and fur:Cardosal® plus has little or moderate influence on the ability to drive vehicles and other mechanisms.Because during the treatment with Cardosal plus, in some cases, the development of side effects such as drowsiness, weakness and dizziness, caution should be exercised when driving vehicles or other mechanisms and engaging in potentially dangerous activities requiring increased attention and speed of psychomotor reactions.
    Form release / dosage:Film-coated tablets are 12.5 mg + 20 mg and 25 mg + 20 mg.
    Packaging:

    For 14 tablets in a contour squeeze box (blister) made of laminated film (polyamide / aluminum / PVC) and aluminum foil.

    For 1, 2, 4 or 7 blisters together with the instructions for use are placed in a cardboard box.

    Storage conditions:

    Store at a temperature not exceeding 25 ° C.

    Keep the medicine out of the reach of children!

    Shelf life:

    5 years.

    Do not use after the expiration date stated on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-007457/10
    Date of registration:30.07.2010 / 04.10.2013
    Expiration Date:Unlimited
    The owner of the registration certificate:BERLIN-PHARMA, CJSC BERLIN-PHARMA, CJSC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp12.12.2017
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