Ordiss N 12,5 + 16mg pills №30

Mechanism of action

Angiotensin II is the main hormone of the RAAS, which plays an important role in the pathogenesis of hypertension, heart failure and other cardiovascular diseases. The main physiological effects of angiotensin II are vasoconstriction, stimulation of aldosterone production, regulation of the water-electrolyte state, and stimulation of cell growth. The effects are mediated by the interaction of angiotensin II with type 1 angiotensin receptors (AT₁receptors).

Candesartan - selective antagonist AT₁- angiotensin II receptors, does not inhibit ACE, converts angiotensin I to angiotensin II, destroys bradykinin, does not lead to the accumulation of bradykinin or substance P. As a result of blocking AT₁of angiotensin II receptors, a dose-dependent increase in renin, angiotensin I, angiotensin II and a decrease in plasma aldosterone concentration occurs.

When comparing Candesartan with ACE inhibitors, cough development was less common in patients who received candesartan.

Candesartan does not bind to receptors of other hormones and does not block the ion channels involved in regulating the functions of the cardiovascular system.

Hydrochlorothiazide - thiazide diuretic, inhibits the active reabsorption of sodium, mainly in the distal renal tubules and enhances the release of sodium ions, chlorine and water.The excretion of potassium and Magnesium by the kidneys increases with the dose, while Calcium begins to be reabsorbed in larger quantities than before.

Hydrochlorothiazide reduces the volume of blood plasma and extracellular fluid, reduces the intensity of blood transport by the heart, reduces blood pressure. During long-term treatment, the hypotensive effect develops due to the expansion of arterioles. With prolonged use of hydrochlorothiazide decreases the risk of cardiovascular diseases and mortality.

Candesartan and hydrochlorothiazide have a cumulative hypotensive effect. In patients with arterial hypertension, the use of candesartan / hydrochlorothiazide causes an effective and prolonged decrease in blood pressure without an increase in heart rate. Orthostatic hypotension at the first dose of the drug is not observed, after the end of treatment arterial hypertension does not increase.

After a single dose of candesartan / hydrochlorothiazide, the main hypotensive effect develops within 2 hours. The use of the drug 1 time / day effectively and gently reduces blood pressure within 24 hours with a slight difference between the maximum and average effect of the action. With prolonged treatment, a steady decrease in blood pressure occurs within 4 weeks after the start of the drug and can be maintained with a long course of treatment.

In clinical studies, the incidence of side effects, especially cough, was less common with candesartan / hydrochlorothiazide than with a combination of ACE inhibitors and hydrochlorothiazide.

Currently, there are no data on the use of candesartan / hydrochlorothiazide in patients with renal failure, nephropathy, reduced left ventricular function, acute heart failure, and after myocardial infarction.

The effectiveness of candesartan / hydrochlorothiazide is independent of gender and age.

Pharmacokinetics

Suction and distribution

Candesartan. When absorbed from the gastrointestinal tract, candesartan cilexityl is rapidly converted into active substance, candesartan, by means of ether hydrolysis, and is firmly bound to AT₁-receptors and slowly dissociates, does not have the properties of an agonist. The absolute bioavailability of candesartan after oral administration is about 40%. The relative bioavailability of the pill form compared to the oral solution is approximately 34%. Thus, the calculated absolute bioavailability of the pill form of the drug is 14%. Eating does not have a significant effect on the AUC, i.e. food does not significantly affect the bioavailability of the drug.

C_maxin blood plasma is achieved 3-4 hours after taking the pill form of the drug. With increasing doses in the recommended limits, the concentration of candesartan increases linearly. Binding of candesartan to plasma proteins - more than 99%. Plasma v_dcandesartan is 0.1 l / kg.

The pharmacokinetic parameters of candesartan do not depend on the sex of the patient.

Hydrochlorothiazide.Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract. Bioavailability is approximately 70%.Concomitant food intake increases absorption by approximately 15%. Bioavailability can be reduced in patients with heart failure and severe edema.

Plasma protein binding is approximately 60%. Visible V_d is approximately 0.8 l / kg.

Metabolism and excretion

Candesartan. Candesartan is mainly excreted by the kidneys and through the intestine with bile in an unchanged form and is only slightly metabolized in the liver. T_1/2 approximately 9 hours. There is no cumulation of candesartan in the body.

The total clearance of candesartan is about 0.37 ml / min / kg, while the renal clearance is about 0.19 ml / min / kg. Renal excretion of candesartan is carried out by glomerular filtration and active tubular secretion.

When radioactively labeled candesartan is ingested, about 26% of the injected amount is excreted in the urine as candesartan and 7% as an inactive metabolite, whereas 56% of the injected amount is detected in the feces as candesartan and 10% as an inactive metabolite.

Hydrochlorothiazide. Hydrochlorothiazide is not metabolized and is almost completely excreted in the form of the active form of the drug by glomerular filtration and active tubular secretion in the proximal nephron. T_1/2 is about 8 hours and does not change when taken together with candesartan. Approximately 70% of the dose taken orally is excreted by the kidneys within 48 hours. When using a combination of drugs, no additional accumulation of hydrochlorothiazide was found in comparison with monotherapy.

Pharmacokinetics in special clinical situations

Candesartan. In patients older than 65 years C_max and AUC of candesartan are increased by 50% and 80%, respectively, compared with young patients. However, the hypotensive effect and the incidence of side effects with candesartan / hydrochlorothiazide do not depend on the age of the patients.

In patients with mild to moderate renal impairment C_max and AUC of candesartan increased by 50% and 70% respectively, while T_1/2 unchanged compared with patients with normal renal function.

In patients with severe renal impairment and / or those on hemodialysis C_max and AUC of candesartan increased by 50% and 110% respectively, and T_1/2 increased by 2 times.

In patients with mild and moderately impaired liver function, an increase in AUC of candesartan was noted by 23%.

Hydrochlorothiazide. T_1/2 more prolonged in patients with renal insufficiency.

Indications

- treatment of arterial hypertension in patients for whom combination therapy is indicated.

Dosage and administration

Order N^® should be taken orally 1 time / day, regardless of the meal.

The recommended dose - 1 pill 1 time / day.

Candesartan dose titration is recommended before transferring a patient from hydrochlorothiazide monotherapy to therapy with Ordiss N^®. If necessary, patients are transferred from the monotherapy with the drug Order^® on drug therapy Order H^®.

The main hypotensive effect is achieved, as a rule, in the first 4 weeks after the start of treatment.

Haveelderly patients dose adjustment is not required.

Havepatients with mild or moderate renal dysfunction (CC 30-80 ml / min / 1.73 m² body surface area)dose titration is recommended. Drug Ordiss N^®contraindicated in patients withsevere renal failure (CC <30 ml / min / 1.73 m²surface area of ​​the body).

Havepatients with impaired liver function mild or moderate severitydose titration is recommended. Drug Ordiss N^® contraindicated in patients withsevere abnormal liver function and / or cholestasis .

Patients with reduced BCC: for patients at risk of arterial hypotension, for example, for patients with reduced BCC, candesartan dose titration is recommended (through monotherapy with Ordiss^®) starting at 4 mg.

Safety and efficacy of the use of the drug Order H^® atchildren and adolescents under the age of 18 not installed.

Side effect

Determination of the incidence of side effects according to the recommendations of the WHO: very often - at least 10%; often not less than 1%, but less than 10%; infrequently - not less than 0.1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely (including individual messages) - less than 0.01%.

Candesartan

From the hemopoietic system: very rarely - leukopenia, neutropenia, agranulocytosis.

Metabolism: very rarely - hyperkalemia, hyponatremia.

From the nervous system: often - dizziness; very rarely - headache.

From the digestive system:very rarely - nausea.

Liver and biliary tract: very rarely - increased activity of hepatic transaminases, abnormal liver function, hepatitis.

On the part of the respiratory system:very rarely - cough.

Skin and Subcutaneous Tissues: very rarely - skin rash, pruritus, urticaria, angioedema.

From the musculoskeletal system: very rarely - back pain, arthralgia, myalgia.

From the kidneys and urinary tract: very seldom - renal failure (see the section "Special Instructions").

Hydrochlorothiazide

From the blood system: rarely - leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, inhibition of bone marrow function, hemolytic anemia, decrease in hemoglobin.

On the part of the immune system: rarely an anaphylactic reaction.

Metabolism: often - hyperglycemia, hyperuricemia, hyponatremia, hypokalemia.

From the nervous system: often - dizziness, vergigo; rarely - sleep disorders, anxiety, depression, paresthesia.

On the part of the organ of vision: rarely - blurred vision, acute myopia, acute angle-closure glaucoma.

Since the cardiovascular system: infrequently - postural hypotension; rarely - arrhythmia, vasculitis.

On the part of the respiratory system: rarely - respiratory distress syndrome, pneumonitis, pulmonary edema.

From the digestive system: infrequently - anorexia, loss of appetite, constipation, diarrhea, irritation of the gastric mucosa; rarely - pancreatitis.

Liver and biliary tract: rarely, intrahepatic cholestatic jaundice.

Skin and Subcutaneous Tissues: infrequently - rash, urticaria, photosensitization reaction; rarely, toxic epidermal necrolysis, erythematosus-like reactions, recurrence of cutaneous erythematosus.

From the musculoskeletal system: rarely, muscle spasm.

From the urinary system: often - glycosuria; rarely - impaired renal function, interstitial nephritis.

Other: often - weakness, increased concentration of cholesterol, triglycerides in the blood plasma; rarely - fever, increased concentration of creatinine, urea in the blood plasma.

Contraindications

- hypersensitivity to candesartan, hydrochlorothiazide and other components of the drug;

- hypersensitivity to other sulfonamide derivatives;

- primary hyper aldosteronism;

- gout;

- severe renal impairment (GFR <30 ml / min / 1.73 m²);

- severe liver dysfunction;

- cholestasis;

- refractory hypokalemia;

- hypercalcemia;

- condition after kidney transplantation;

- pregnancy;

- breastfeeding period;

- children's and teenage age up to 18 years;

- simultaneous use with aliskiren or aliskiren-containing drugs in patients with diabetes and / or renal dysfunction (GFR <60 ml / min / 1.73 m²);

- lactose intolerance ;

- Lactase deficiency;

- syndrome of glucose-galactose malabsorption.

Carefully:simultaneous use with other antihypertensive drugs,potassium-sparing diuretics, amphotericin, carbenoxolone, penicillin G sodium preparations, salicylic acid derivatives, cardiac glycosides, antiarrhythmic drugs, lithium preparations, NSAIDs , whets