Ordiss N, tablets 16 mg+12, 5 mg 30 pcs

Pharmacological group: hypertensive combined agent (diuretic + angiotensin II receptor antagonist)

ATX code: C09DA06

Pharmacological properties.

Pharmacodynamics

Angiotensin II is the major hormone of the renin-angiotensin-aldosterone system (RAAS), which plays an important role in the pathogenesis of arterial hypertension, heart failure and other cardiovascular diseases. The main physiological effects of angiotensin II are vasoconstriction, stimulation of aldosterone production, regulation of water-electrolyte balance and stimulation of cell growth. The effects are mediated by the interaction of angiotensin II with angiotensin type 1 receptors (AT₁ receptors).

Candesartan is a selective antagonist of AT₁-receptor angiotensin II, does not inhibit angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II, destroys bradykinin, does not lead to the accumulation of bradykinin or substance P. Blocking of AT₁ receptors of angiotensin II results in a dose-dependent increase in the concentration of renin, angiotensin I, angiotensin II and a decrease in plasma aldosterone concentration.

When comparing candesartan with ACE inhibitors, the development of cough was less frequent in patients receiving candesartan.

Candesartan does not bind to other hormone receptors and does not block ion channels involved in the regulation of cardiovascular function.

Hydrochlorothiazide, a thiazide-like diuretic, inhibits active sodium reabsorption, mainly in the distal renal tubules and increases the excretion of sodium, chloride and water ions. Renal excretion of potassium and magnesium increases in a dose-dependent manner, while calcium begins to be reabsorbed in larger amounts than before.

Hydrochlorothiazide reduces plasma and extracellular fluid volume, decreases the intensity of blood transport by the heart, and lowers blood pressure (BP). During long-term treatment, the hypotensive effect is developed by dilating the arterioles. Long-term use of hydrochlorothiazide reduces the risk of cardiovascular disease and mortality.

Candesartan and hydrochlorothiazide have a combined hypotensive effect. In patients with arterial hypertension, the use of candesartan/hydrochlorothiazide causes effective and prolonged reduction of BP without an increase in heart rate (HR). Orthostatic arterial hypotension is not observed with the first administration of the drug, and arterial hypertension does not increase after the end of treatment.

After a single dose of candesartan/hydrochlorothiazide, the main hypotensive effect develops within 2 hours. Administration of the drug once daily effectively and gently reduces BP within 24 hours with little difference between the maximum and average effect of action. With long-term treatment, a stable BP decrease occurs within 4 weeks after the beginning of the drug administration and may be maintained with a long-term course of treatment.

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

There are currently no data on the use of candesartan/hydrochlorothiazide in patients with renal impairment, nephropathy, reduced left ventricular function, acute heart failure and who have had a myocardial infarction.

The efficacy of candesartan/hydrochlorothiazide is independent of patient gender and age.

Pharmacokinetics

. Absorption and distribution

Candesartan. On absorption from the gastrointestinal tract (GIT), candesartan cilexetyl is rapidly converted to the active substance, candesartan, by ester hydrolysis, binds firmly to AT₁ receptors and dissociates slowly, has no agonist properties. The absolute bioavailability of candesartan after oral administration is about 40%. The relative bioavailability of the tablet form compared to the oral solution is approximately 34%. Thus, the estimated absolute bioavailability of the tablet form of the drug is 14%. Food intake has no significant effect on the area under the curve “concentration-time” (AUC), i.e. food has no significant effect on the bioavailability of the drug.

The maximum plasma concentration (C_max) is reached 3-4 hours after taking the tablet form of the drug. When increasing the drug dose within the recommended limits, the concentration of candesartan increases linearly. Binding of candesartan to plasma proteins is more than 99%. Plasma volume of distribution (V_d) of candesartan is 0.1 l/kg.

Pharmacokinetic parameters of candesartan are independent of patient gender.

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

The binding to plasma proteins is approximately 60%. The apparent V_d is approximately 0.8 l/kg.

Metabolism and excretion

Candesartan. Candesartan is primarily excreted unchanged by the kidneys and through the intestine with the bile and only to a minor extent is metabolized in the liver.

The half-life (T_1/2) of candesartan is approximately 9 hours.

The total clearance of candesartan is approximately 0.37 ml/min/kg, with renal clearance of approximately 0.19 ml/min/kg. Renal excretion of candesartan is by glomerular filtration and active tubular secretion.

In oral administration of radioactively labeled candesartan, approximately 26% of the administered amount is excreted in the urine as candesartan and 7% as an inactive metabolite, while 56% of the administered amount is found in the feces as candesartan and 10% as an inactive metabolite.

Hydrochlorothiazide. Hydrochlorothiazide is not metabolized and is excreted almost entirely as the active form of the drug by glomerular filtration and active tubular secretion in the proximal nephron. T_1/2 is about 8 h and does not change with concomitant use with candesartan. Approximately 70% of the oral dose is excreted by the kidneys within 48 hours. No additional accumulation of hydrochlorothiazide was detected when using a combination of drugs compared to monotherapy.

Pharmacokinetics in special clinical cases

Candesartan. In patients older than 65 years, the C_max and AUC of candesartan are increased by 50% and 80%, respectively, compared with younger patients. However, the hypotensive effect and the incidence of side effects with candesartan/hydrochlorothiazide are independent of patient age.

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

In patients with severe renal impairment and/or undergoing hemodialysis, C_max and AUC of candesartan increased by 50% and 110%, respectively, while T_1/2 drug was 2-fold increased.

In patients with mild to moderate hepatic impairment, there was a 23% increase in the AUC of candesartan.

Hydrochlorothiazide. T_1/2 is longer in patients with renal impairment.

Indications

Active ingredient

Composition

How to take, the dosage

The drug Ordiss N® should be taken once a day regardless of meals.

Dosage

The recommended dose is 1 tablet once daily.

The titration of a dose of candesartan is recommended before converting a patient from hydrochlorothiazide monotherapy to therapy with Ordiss H®. If necessary, patients are transferred from Ordiss® monotherapy to Ordiss H® therapy.

The main hypotensive effect is usually achieved within the first 4 weeks of treatment initiation.

Elderly patients

Dose adjustment is not necessary in elderly patients.

In patients with impaired renal function

In patients with mild to moderate impaired renal function (creatinine clearance 30-80 ml/min/1.73 m2 body surface area) dose titration is recommended.

The drug Ordiss N® is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min/1.73 m2 body surface area).

Hepatic dysfunction

In patients with mild to moderate hepatic dysfunction, dose titration is recommended.

The drug Ordiss N® is contraindicated in patients with severe hepatic impairment and/or cholestasis.

Patients with reduced circulating blood volume

. For patients at risk of arterial hypotension, such as those with reduced circulating blood volume, titration of the dose of candesartan (through monotherapy with Ordiss®) is recommended, starting at 4 mg.

Application in children and adolescents

The safety and effectiveness of Ordiss H® in children and adolescents (under 18 years of age) has not been established.

Interaction

The concomitant use of candesartan/hydrochlorothiazide with hydrochlorothiazide, warfarin, digoxin, oral contraceptives (ethinylestradiol/levonorgestrel), glibenclamide, nifedipine and enalapril has been studied in pharmacokinetic studies. No clinically significant drug interactions have been identified.

Candesartan is slightly metabolized in the liver with participation of CYP2C9 isoenzyme. The conducted studies on interaction showed no effect of the drug on CYP2C9 and CYP3A4 isoenzymes; the effect on other isoenzymes of cytochrome P450 system has not been studied.

The simultaneous use of angiotensin II receptor antagonists and NSAIDs, including cyclooxygenase-2 inhibitors and non-selective NSAIDs such as acetylsalicylic acid over 3 g per day, may decrease the hypotensive effect of candesartan.

The concomitant use of candesartan/hydrochlorothiazide with other antihypertensive agents increases the hypotensive effect.

Double RAAS blockade with angiotensin II receptor antagonists (ARA II), ACE inhibitors or aliskiren (renin inhibitor) may be associated with an increased risk of hypotension, syncope, hyperkalemia and renal function disorders (including acute renal failure) compared to monotherapy. Regular monitoring of BP, renal function, and blood electrolytes is necessary in patients concomitantly taking candesartan/hydrochlorothiazide and other drugs that affect the RAAS.

Candesartan/hydrochlorothiazide is contraindicated concomitantly with aliskiren or aliskiren-containing drugs in patients with diabetes and/or moderate to severe renal function impairment (FFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

The concomitant use of angiotensin II receptor antagonists with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

The simultaneous use of ACE inhibitors and dipeptidyl peptidase type 4 inhibitors (e.g., vildagliptin) may increase the risk of Quincke’s edema.

The potassium-loss effect of hydrochlorothiazide may be enhanced by other drugs leading to potassium loss and hypokalemia (e.g., diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid derivatives).

The experience with other drugs acting on the RAAS shows that concomitant therapy with potassium-saving diuretics, potassium preparations, table salt substitutes containing potassium, and other agents that increase serum potassium (e.g., heparin) may lead to the development of hyperkalemia.

Hypokalemia and hypomagnesemia caused by taking diuretics predispose to the development of cardiotoxic effects of cardiac glycosides and antiarrhythmic drugs. When taking candesartan/hydrochlorothiazide concomitantly with such drugs, monitoring of plasma potassium is required.

When concomitant use of lithium preparations with ACE inhibitors a reversible increase in lithium concentration in blood serum and development of toxic reactions occurs. Similar reactions may also occur with angiotensin II receptor antagonists, and therefore it is recommended that serum lithium levels be monitored.

The diuretic, natriuretic and hypotensive effects of hydrochlorothiazide are impaired with concomitant use of NSAIDs.

The absorption of hydrochlorothiazide is impaired when using colestipol, colestyramine.

The effect of nondepolarizing myorelaxants (e.g., tubocurarine) may be enhanced by hydrochlorothiazide.

Thiazide diuretics may increase plasma calcium levels due to decreased calcium excretion. If it is necessary to use calcium-containing food supplements or vitamin D, plasma calcium levels should be monitored and the dose should be adjusted if necessary.

Thiazide-like diuretics increase the hyperglycemic effect of beta-adrenoblockers and diazoxide.

The anticholinergic agents (e.g., atropine, biperiden) may increase bioavailability of thiazide diuretics due to decreased gastrointestinal motility.

Thiazide-like diuretics may increase the risk of adverse effects of amantadine.

Thiazide-like diuretics may slow the excretion of cytostatic drugs (such as cyclophosphamide, methotrexate) from the body and increase their myeloprotective effect.

The risk of hypokalemia may be increased if glucocorticosteroids (GCS) or adrenocorticotropic hormone (ACTH) are taken at the same time.

The incidence of orthostatic arterial hypotension when using ethanol, barbiturates, or general anesthetics may increase with the use of Ordiss N®.

The treatment with thiazide diuretics may decrease glucose tolerance and may require adjusting the dose of hypoglycemic drugs (including insulin).

Hydrochlorothiazide may reduce the effect of vasoconstrictor amines (e.g., epinephrine).

Hydrochlorothiazide may increase the risk of acute renal failure, especially in combination with high doses of iodinated filler.

No significant interaction of hydrochlorothiazide with food has been found.

Special Instructions

Double RAAS blockade

Concomitant use of ACE inhibitors, ARA II or aliskiren increases the risk of arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure). Dual RAAS blockade with concomitant use of ACE inhibitors, ARA II or aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal dysfunction (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients (see section “Interaction with other medicinal products”).

If dual RAAS blockade is considered absolutely necessary, the treatment should only be performed under medical supervision and should be accompanied by regular monitoring of renal function, electrolytes and blood pressure. The use of ACE inhibitors and ARA II simultaneously in patients with diabetic nephropathy is contraindicated and not recommended in other patients.

Renal insufficiency/kidney transplantation

In patients with renal insufficiency, the use of “loop” diuretics is preferable to thiazide diuretics. In patients with renal failure, regular monitoring of potassium, creatinine and uric acid concentrations is recommended during therapy with Ordiss H®.

There are no data on use of Ordiss N® in patients who have recently had a kidney transplant.

Renal artery stenosis

. Drugs that affect the RAAS (e.g., ACE inhibitors) may result in increased blood urea and serum creatinine concentrations in patients with bilateral renal artery stenosis or renal artery stenosis of the sole kidney. A similar effect should be expected from angiotensin II receptor antagonists.

Decrease of the RBC volume

In patients with RBC and/or sodium deficiency, symptomatic arterial hypotension may develop, therefore it is not recommended to use Ordiss N® until these symptoms disappear.

Anesthesia and surgery

Patients receiving angiotensin II receptor antagonists during general anesthesia and surgical interventions may develop arterial hypotension as a result of RAAS blockade. Very rarely there may be cases of severe arterial hypotension requiring IV fluid and/or vasoconstrictors.

Hepatic disorders

Patients with impaired liver function or advanced liver disease should use thiazide diuretics with caution because slight fluctuations in fluid volume and water-electrolyte balance may cause hepatic coma.

There are no data on the use of Ordiss N® in patients with severe hepatic impairment.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)

When Ordiss N® is prescribed patients with hypertrophic obstructive cardiomyopathy or hemodynamically significant aortic or mitral valve stenosis, caution should be exercised.

Primary hyperaldosteronism

. Patients with primary hyperaldosteronism are usually resistant to therapy with antihypertensive agents affecting the RAAS, so the use of Ordiss N® is not recommended in these patients.

Electrolyte balance disorder

As in all cases of diuretic drugs, plasma electrolyte levels should be monitored.

Thiazide-based diuretics can decrease renal calcium excretion and may cause discontinuous changes and slight increases in plasma calcium levels.

The thiazides, including hydrochlorothiazide, may cause electrolyte-water balance disorders (hypercalcemia, hypokalemia, hyponatremia, hypomagnesemia and hypochloremic alkalosis).

Hypercalcemia may be a sign of hidden hyperparathyroidism.

The use of thiazide diuretics should be discontinued until the results of parathyroid gland tests are available.

Hydrochlorothiazide dose-dependently increases potassium excretion, which may cause hypokalemia. This effect of hydrochlorothiazide is less pronounced if used concomitantly with candesartan. The risk of hypokalemia is increased in patients with cirrhosis, increased diuresis, patients taking low-salinity fluids, concomitant treatment with GCS or ACTH.

Based on experience with agents affecting the RAAS, the simultaneous use of Ordiss H® and diuretics that increase potassium excretion can be compensated by the use of potassium supplements or other drugs that can increase plasma potassium levels.

The use of Ordiss H® may cause hypokalemia, especially in patients with cardiac or renal insufficiency (these cases have not been documented).

Thiazide diuretics increase magnesium excretion, which may cause hypomagnesemia.

Metabolic and endocrine effects

The use of thiazide diuretics may change the blood glucose concentration up to the appearance of latent diabetes mellitus. Correction of the dose of hypoglycemic agents, including insulin, may be required.

The use of thiazide diuretics is associated with an increase in plasma cholesterol and triglyceride concentrations. However, minimal or no such effects have been observed with Ordiss H®.

Thiazide diuretics increase plasma concentrations of uric acid and may contribute to the development of gout symptoms in predisposed patients.

Chorioidal effusion, acute myopia, and secondary closed-angle glaucoma

. Sulfonamides or their derivatives (including hydrochlorothiazide) may cause an idiosyncratic reaction leading to chorioidal effusion, development of acute myopia, and secondary closed-angle glaucoma. Symptoms include: sudden decrease in vision or eye pain, which usually manifests within hours or weeks of initiation of hydrochlorothiazide therapy. Left untreated, acute closed-angle glaucoma can lead to permanent loss of vision. Treatment is to discontinue hydrochlorothiazide as soon as possible. If intraocular pressure remains uncontrolled, emergency medication or surgery may be needed. A history of allergic reaction to sulfonamides or benzylpenicillins are risk factors for acute closed angle glaucoma.

Nemelanoma skin cancer

. Two pharmacoepidemiologic studies using data from the Danish National Cancer Registry demonstrated an association between increasing hydrochlorothiazide intake and an increased risk of nonmelanoma skin cancer (NSCLC) – basal cell carcinoma and squamous cell carcinoma. The risk of developing NSCLC increased with increasing total (cumulative) dose of hydrochlorothiazide. A possible mechanism for the development of NSCLC is the photosensitizing effect of hydrochlorothiazide.

Patients taking hydrochlorothiazide as monotherapy or in combination with other medications should be aware of the risk of NMRK. These patients are advised to have their skin examined for any new suspicious lesions, as well as changes to existing skin lesions.

All suspicious skin changes should be promptly reported to the physician. Suspicious skin areas should be examined by a specialist. Histological examination of skin biopsy specimens may be necessary to confirm the diagnosis.

Patients should be advised to use preventive measures such as limiting exposure to sunlight and UV rays and appropriate protective equipment to minimize the risk of developing SLE.

In patients with a history of nonmelanoma skin cancer, it is recommended to reconsider the appropriateness of hydrochlorothiazide.

General

Patients in whom vascular tone and renal function are predominantly dependent on RAAS activity (e.g., patients with severe chronic heart failure, renal disease, including renal artery stenosis) are particularly sensitive to drugs acting on RAAS. Prescription of such drugs is accompanied by severe arterial hypotension, azotemia, oliguria and, rarely, acute renal failure in these patients. The possibility of these effects is not excluded by the use of angiotensin II receptor antagonists. Sharp decrease of BP in patients with ischemic cardiopathy, cerebrovascular diseases of ischemic genesis while using any antihypertensive agents may lead to myocardial infarction or stroke.

The manifestation of hypersensitivity reactions to hydrochlorothiazide is most likely in patients with bronchial asthma, history of allergic reactions, which does not exclude allergic symptoms in other patients.

When using thiazide diuretics, there have been cases of exacerbation or appearance of symptoms of congestive seborrhea.

When using thiazide diuretics there have been cases of worsening of the course of systemic lupus erythematosus.

The drug contains lactose, so it should not be taken in patients with rare hereditary diseases manifested by lactose intolerance, lactase deficiency, or impaired glucose and galactose absorption.

Hydrochlorothiazide in Ordiss H® may be positive in doping controls.

Pediatric use

The safety and effectiveness of Ordiss N® in children under 18 years of age has not been established.

Influence on driving and operating ability

In case of adverse effects of the CNS during treatment with Ordiss N® Additional effects of the drug are observed.sup>® Care should be taken when performing activities requiring increased concentration and quick psychomotor reactions.

Synopsis

Tablets 12.5 mg+16 mg. Double convex capsule-shaped pale pink tablets with a groove on both sides. One side is engraved “C” to the left and “16” to the right of the risk.

Tablets 12.5 mg+32 mg. Biconvex capsule-shaped tablets white or nearly white with a rib on both sides. One side is engraved “C” to the left and “32” to the right of the risk.

Contraindications

Side effects

The incidence of side effects is classified according to World Health Organization guidelines: very common, at least 10%; common, at least 1% but less than 10%; infrequent, at least 0.1% but less than 1%; rare, at least 0.01% but less than 0.1%; very rare (including individual reports), less than 0.01%.

Candesartan

Infections and invasions

Often: Respiratory tract infection.

Disorders of the blood and lymphatic system

Very rare: leukopenia, neutropenia and agranulocytosis.

Metabolic and nutritional disorders

Very rare: hyperkalemia, hyponatremia.

Nervous system disorders

Often: dizziness/systemic dizziness, headache.

Disorders of the respiratory system, chest and mediastinum organs

Very rare: cough.

Gastrointestinal tract disorders

Very rare: nausea.

Prevalence unknown: diarrhea.

Hepatic and biliary tract disorders

Very rare: increased activity of “hepatic” transaminases, impaired liver function or hepatitis.

Dermatological and subcutaneous tissue disorders

Very rare: angioedema, skin rash, urticaria, itching.

Muscular, skeletal and connective tissue disorders

Very rare: back pain, arthralgia, myalgia.

Renal and urinary tract disorders

Very rare: renal dysfunction, including renal failure in predisposed patients (see section “Special Precautions”).

Hydrochlorothiazide

The following adverse reactions have been noted with hydrochlorothiazide monotherapy, usually at a dose of 25 mg or more:

Blood and lymphatic system disorders

Rarely: leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anemia, depressed bone marrow function, hemolytic anemia.

Disorders of the immune system

Rarely: anaphylactic reactions.

Metabolic and nutritional disorders

Often: hyperglycemia, hyperuricemia, electrolyte disorders (including hyponatremia and hypokalemia).

Mental disorders

Rarely: sleep disorders, depression, anxiety.

Nervous system disorders

Often: preconsciousness, systemic dizziness.

Rarely: paresthesia.

Visual disorders

Rarely: transient blurred vision, acute myopia, acute closed-angle glaucoma.

Prevalence unknown: chorioidal effusion.

Cardiac disorders

Rarely: arrhythmia.

Vascular disorders

Infrequent: postural arterial hypotension.

Rarely: necrotizing angiitis (vasculitis, subcutaneous vasculitis).

Disorders of the respiratory system, thorax and mediastinum

Rarely: difficulty in breathing (including pneumonitis and pulmonary edema).

Gastrointestinal tract disorders

Infrequent: anorexia, loss of appetite, gastric mucosal irritation, diarrhea, constipation.

Rarely: pancreatitis.

Liver and biliary tract disorders

Rarely: jaundice (intrahepatic cholestatic jaundice).

Skin and subcutaneous tissue disorders

Infrequent: skin rash, urticaria, photosensitivity reaction.

Rarely: toxic epidermal necrolysis, erythematosis-like reactions, recurrence of cutaneous erythematosis.

Muscle, skeletal and connective tissue disorders

Rarely: muscle spasm.

Disorders of the kidneys and urinary tract

Often: glucosuria.

Rarely: impaired renal function, interstitial nephritis.

General disorders and reactions at the site of administration

Often: weakness.

Rarely: fever.

Laboratory and instrumental findings

Often: increased plasma cholesterol and triglyceride concentrations.

Rarely: increased concentration of urea and creatinine in plasma.

Overdose

Pregnancy use