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

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

Pharmacological effect

Pharmacological group: combined antihypertensive drug (diuretic + angiotensin II receptor antagonist)

ATX code: C09DA06

Pharmacological properties

Pharmacodynamics

Angiotensin II is the main 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 and 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 the AT1 receptors of angiotensin II, does not inhibit the angiotensin-converting enzyme (ACE), which converts angiotensin I into angiotensin II, which destroys bradykinin, and does not lead to the accumulation of bradykinin or substance P. As a result of blocking the AT1 receptors of angiotensin II, a dose-dependent increase in renin concentration occurs, angiotensin I, angiotensin II and a decrease in the concentration of aldosterone in the blood plasma.

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

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

Hydrochlorothiazide is a thiazide-like diuretic that inhibits active sodium reabsorption, mainly in the distal renal tubules and increases the excretion of sodium, chlorine and water ions. The excretion of potassium and magnesium by the kidneys increases in a dose-dependent manner, while calcium begins to be reabsorbed in greater quantities than before.

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

Candesartan and hydrochlorothiazide have a cumulative hypotensive effect. In patients with arterial hypertension, the use of candesartan/hydrochlorothiazide causes an effective and lasting reduction in blood pressure without an increase in heart rate (HR). Orthostatic arterial hypotension is not observed when taking the drug for the first time; after 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 once a day effectively and gently reduces blood pressure within 24 hours with a slight difference between the maximum and average effect of action. With long-term treatment, a stable decrease in blood pressure occurs within 4 weeks after starting the drug and can be maintained with a long course of treatment.

In clinical studies, the incidence of side effects, especially cough, was lower 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 failure, nephropathy, reduced left ventricular function, acute heart failure and myocardial infarction.

The effectiveness of candesartan/hydrochlorothiazide does not depend on the gender and age of the patient.

Pharmacokinetics

Suction and distribution

Candesartan. When candesartan cilexetil is absorbed from the gastrointestinal tract (GIT), it quickly turns into the active substance, candesartan, through ether hydrolysis, binds strongly to AT1 receptors and slowly dissociates, and 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 calculated absolute bioavailability of the tablet form of the drug is 14%. Food intake does not have a significant effect on the area under the concentration-time curve (AUC), i.e. food does not significantly affect the bioavailability of the drug.

The maximum concentration in blood plasma (Cmax) is achieved 3-4 hours after taking the tablet form of the drug. As the dose of the drug increases within the recommended limits, the concentration of candesartan increases linearly. The binding of candesartan to plasma proteins is more than 99%. The plasma volume of distribution (Vd) of candesartan is 0.1 l/kg.

The pharmacokinetic parameters of candesartan do not depend on the gender 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 may be reduced in patients with heart failure and severe edema.

Plasma protein binding is approximately 60%. Apparent Vd is approximately 0.8 l/kg.

Metabolism and excretion

Candesartan. Candesartan is mainly excreted unchanged from the body by the kidneys and through the intestines with bile and is only slightly metabolized in the liver.

The half-life (T1/2) of candesartan is approximately 9 hours. There is no accumulation of the drug in the body.

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

When radiolabeled candesartan is administered orally, approximately 26% of the administered amount is excreted in the urine as candesartan and 7% as an inactive metabolite, whereas 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. T1/2 is about 8 hours and does not change when used simultaneously 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 detected in comparison with monotherapy.

Pharmacokinetics in special clinical situations

Candesartan. In patients over 65 years of age, the Cmax and AUC of candesartan increase by 50% and 80%, respectively, compared with younger patients. However, the hypotensive effect and the incidence of side effects when using candesartan/hydrochlorothiazide do not depend on the age of the patients.

In patients with mild and moderate renal impairment, the Cmax and AUC of candesartan increased by 50% and 70%, respectively, while the T1/2 of the drug did not change compared to patients with normal renal function.

In patients with severe renal impairment and/or those on hemodialysis, the Cmax and AUC of candesartan increased by 50% and 110%, respectively, and the T1/2 of the drug increased by 2 times.

In patients with mild to moderate hepatic impairment, the AUC of candesartan increased by 23%.

Hydrochlorothiazide. T1/2 is longer in patients with renal failure.

Special instructions

Double blockade of the RAAS

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

If double blockade of the RAAS is considered absolutely necessary, then treatment should only occur under the supervision of a physician and should be accompanied by regular monitoring of renal function, electrolytes and blood pressure. The concomitant use of ACE inhibitors and ARB II in patients with diabetic nephropathy is contraindicated and is not recommended in other patients.

Kidney failure/kidney transplant

In patients with renal failure, the use of loop diuretics is preferable to thiazide diuretics. For patients with renal failure during therapy with Ordiss N®, it is recommended to regularly monitor potassium levels, creatinine and uric acid concentrations.

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

Renal artery stenosis

Drugs that affect the RAAS (eg, ACE inhibitors) may increase blood urea and serum creatinine concentrations in patients with bilateral renal artery stenosis or solitary renal artery stenosis. A similar effect should be expected from angiotensin II receptor antagonists.

Decrease in volume of bcc

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

Anesthesia and surgery

In patients receiving angiotensin II receptor antagonists, hypotension may develop during general anesthesia and during surgery as a result of blockade of the RAAS. Very rarely, cases of severe arterial hypotension may occur, requiring IV fluids and/or vasoconstrictors.

Liver dysfunction

Patients with impaired liver function or progressive liver disease should use thiazide diuretics with caution because minor fluctuations in fluid volume and fluid and electrolyte balance can cause hepatic coma.

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

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)

When prescribing Ordiss N® to patients with hypertrophic obstructive cardiomyopathy or hemodynamically significant stenosis of the aortic or mitral valve, caution should be exercised.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are usually resistant to therapy with antihypertensive drugs that affect the RAAS, therefore the use of Ordiss N® in such patients is not recommended.

Electrolyte imbalance

As in all cases of taking drugs that have a diuretic effect, the content of electrolytes in the blood plasma should be monitored.

Thiazide-based drugs that have a diuretic effect can reduce the excretion of calcium by the kidneys and can cause sudden changes and a slight increase in calcium levels in the blood plasma.

Thiazides, incl. and hydrochlorothiazide, can cause disturbances in water and electrolyte balance (hypercalcemia, hypokalemia, hyponatremia, hypomagnesemia and hypochloremic alkalosis).

Detected hypercalcemia may be a sign of latent hyperparathyroidism.

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

Hydrochlorothiazide increases potassium excretion in a dose-dependent manner, which may cause hypokalemia. This effect of hydrochlorothiazide is less pronounced if it is used simultaneously with candesartan. The risk of hypokalemia appears to be increased in patients with liver cirrhosis, increased diuresis, taking fluids with a reduced salt content, and undergoing concurrent treatment with corticosteroids or ACTH.

Based on experience with the use of drugs that affect the RAAS, the simultaneous use of Ordiss N® and diuretics that increase potassium excretion can be compensated by the use of nutritional supplements containing potassium or other drugs that can increase the content of potassium in the blood plasma.

The use of Ordiss N® may cause hypokalemia, especially in patients with heart or renal failure (such cases have not been documented).

Thiazide diuretics increase magnesium excretion, which can cause hypomagnesemia.

Metabolic and endocrine effects

The use of thiazide diuretics can change the concentration of glucose in the blood up to the manifestation of latent diabetes mellitus. Dosage adjustment of hypoglycemic agents, including insulin, may be required.

Increases in plasma cholesterol and triglyceride concentrations are associated with the use of thiazide diuretics. However, when using the drug Ordiss N®, a minimal amount or absence of such effects was observed.

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

Choroidal effusion, acute myopia and secondary angle-closure glaucoma

Sulfonamides or their derivatives (including hydrochlorothiazide) can cause an idiosyncratic reaction leading to choroidal effusion, the development of acute myopia and secondary angle-closure glaucoma. Symptoms include: sudden loss of vision or eye pain, usually occurring within hours to weeks of starting hydrochlorothiazide therapy. If left untreated, acute angle-closure glaucoma can lead to permanent vision loss. Treatment is to stop taking hydrochlorothiazide as soon as possible. If intraocular pressure remains uncontrolled, emergency medical treatment or surgery may be required. Risk factors for the development of acute angle-closure glaucoma are a history of an allergic reaction to sulfonamides or benzylpenicillins.

Non-melanoma skin cancer

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

Patients taking hydrochlorothiazide as monotherapy or in combination with other drugs should be aware of the risk of developing NMSC. In such patients, it is recommended that the skin be examined to identify any new suspicious lesions, as well as changes in existing skin lesions.

Any suspicious skin changes should be reported to your doctor immediately. Suspicious areas of skin should be examined by a specialist. To clarify the diagnosis, histological examination of skin biopsies may be required.

To minimize the risk of developing NMSC, patients should be advised to follow preventive measures, such as limiting exposure to sunlight and UV rays, and using appropriate protective equipment.

In patients with a history of non-melanoma skin cancer, it is recommended to reconsider the use of hydrochlorothiazide.

General

Patients whose vascular tone and renal function are predominantly dependent on the activity of the RAAS (for example, patients with severe chronic heart failure, kidney disease, including renal artery stenosis) are especially sensitive to drugs acting on the RAAS. The prescription of such drugs is accompanied in these patients by severe arterial hypotension, azotemia, oliguria and, less commonly, acute renal failure. The possibility of developing the listed effects cannot be excluded when using angiotensin II receptor antagonists. A sharp decrease in blood pressure in patients with ischemic cardiopathy, cerebrovascular diseases of ischemic origin when using any antihypertensive drugs can lead to the development of myocardial infarction or stroke.

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

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

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

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

Hydrochlorothiazide, which is part of the drug Ordiss N®, can give a positive result during doping control.

Use in pediatrics

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

Impact on the ability to drive vehicles and machinery

If undesirable effects from the central nervous system occur during therapy with Ordiss N®, caution should be exercised when performing actions that require increased concentration and speed of psychomotor reactions.

Active ingredient

Hydrochlorothiazide, Candesartan

Composition

1 tablet contains:
active ingredients: candesartan cilexetil 16.00 mg/32.00 mg; hydrochlorothiazide 12.50 mg/12.50 mg;
excipients: pregelatinized starch 15.00 mg/30.00 mg; povidone-K30 16.00 mg/32.00 mg; carmellose calcium 6.60 mg/13.20 mg; poloxamer 188 1.00 mg/2.00 mg; microcrystalline cellulose (type 102) 72.00 mg/148.00 mg; lactose monohydrate 177.60 mg/363.90 mg; red iron oxide dye (E172) 0.10 mg/-; magnesium stearate 3.20 mg/6.40 mg.

Pregnancy

The drug Ordiss N® is contraindicated for use during pregnancy and breastfeeding.
Patients taking the drug should be warned about this before planning pregnancy so that they can switch to alternative therapy with a proven safety profile for use during pregnancy. If pregnancy is diagnosed, drug therapy should be stopped immediately. Drugs that affect the RAAS can cause developmental disorders in the fetus and/or have a negative effect on the newborn, including death, if the drug is used during pregnancy. It is known that therapy with angiotensin II receptor antagonists can cause developmental disorders of the fetus (impaired renal function, oligohydramnios, delayed ossification of the skull bones) and the development of complications in the newborn (impaired renal function, arterial hypotension, hyperkalemia). Experience with the use of hydrochlorothiazide during pregnancy is limited. Hydrochlorothiazide crosses the placenta. Given the mechanism of action of hydrochlorothiazide, its use during pregnancy can cause disturbances in feto-placental circulation and undesirable effects in the fetus and newborn in the form of jaundice, water-electrolyte imbalance and thrombocytopenia. It is not known whether candesartan passes into breast milk. Candesartan is excreted into the milk of lactating rats. Hydrochlorothiazide passes into breast milk.

Contraindications

Hypersensitivity to candesartan, hydrochlorothiazide, other components of the drug and other sulfonamide derivatives; pregnancy; breastfeeding period; lactose intolerance; lactase deficiency; glucose-galactose malabsorption syndrome; primary hyperaldosteronism; gout; severe renal impairment (glomerular filtration rate (GFR) less than 30 ml/min/1.73 m2 body surface area); severe liver dysfunction; cholestasis; refractory hypokalemia, hypercalcemia; condition after kidney transplantation, children under 18 years of age; simultaneous use with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and/or moderate or severe renal impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 body surface area), simultaneous use with ACE inhibitors in patients with diabetic nephropathy.

With caution
Impaired renal function (creatinine clearance more than 30 ml/min), liver failure; severe chronic heart failure; bilateral renal artery stenosis; stenosis of the artery of a single kidney; hemodynamically significant stenosis of the aortic and/or mitral valve; coronary heart disease; hypertrophic obstructive cardiomyopathy; decrease in circulating blood volume (CBV); diabetes mellitus, cerebrovascular diseases; acute myopia; angle-closure glaucoma; systemic lupus erythematosus, history of non-melanoma skin cancer (see section “Special instructions”).

Side Effects

The incidence of side effects is classified according to the recommendations of the World Health Organization: very often – at least 10%; often – at least 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

Infections and infestations

Common: respiratory tract infection.

Blood and lymphatic system disorders

Very rare: leukopenia, neutropenia and agranulocytosis.

Metabolic and nutritional disorders

Very rare: hyperkalemia, hyponatremia.

Nervous system disorders

Common: dizziness/systemic dizziness, headache.

Respiratory, thoracic and mediastinal disorders

Very rare: cough.

Gastrointestinal disorders

Very rare: nausea.

Frequency unknown: diarrhea.

Disorders of the liver and biliary tract

Very rarely: increased activity of liver transaminases, impaired liver function or hepatitis.

Skin 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: impaired renal function, including renal failure in predisposed patients (see section “Special Instructions”).

Hydrochlorothiazide

The following adverse reactions have been reported with hydrochlorothiazide monotherapy, usually at doses of 25 mg or more:

Blood and lymphatic system disorders

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

Immune system disorders

Rarely: anaphylactic reactions.

Metabolic and nutritional disorders

Common: hyperglycemia, hyperuricemia, electrolyte disturbances (including hyponatremia and hypokalemia).

Mental disorders

Rarely: sleep disturbances, depression, anxiety.

Nervous system disorders

Common: lightheadedness, systemic dizziness.

Rarely: paresthesia.

Visual disorders

Rare: transient blurred vision, acute myopia, acute angle-closure glaucoma.

Frequency unknown: choroidal effusion.

Heart disorders

Rarely: arrhythmia.

Vascular disorders

Uncommon: postural hypotension.

Rarely: necrotizing angiitis (vasculitis, subcutaneous vasculitis).

Respiratory, thoracic and mediastinal disorders

Rare: breathing difficulties (including pneumonitis and pulmonary edema).

Gastrointestinal disorders

Uncommon: anorexia, loss of appetite, irritation of the gastric mucosa, diarrhea, constipation.

Rarely: pancreatitis.

Disorders of the liver and biliary tract

Rarely: jaundice (intrahepatic cholestatic jaundice).

Skin and subcutaneous tissue disorders

Uncommon: skin rash, urticaria, photosensitivity reaction.

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

Muscular, skeletal and connective tissue disorders

Rarely: muscle spasm.

Renal and urinary tract disorders

Common: glycosuria.

Rarely: renal dysfunction, interstitial nephritis.

General disorders and reactions at the injection site

Often: weakness.

Rarely: fever.

Laboratory and instrumental data

Often: increased concentrations of cholesterol and triglycerides in the blood plasma.

Rarely: increased concentrations of urea and creatinine in the blood plasma.

Interaction

In pharmacokinetic studies, the simultaneous use of candesartan/hydrochlorothiazide with hydrochlorothiazide, warfarin, digoxin, oral contraceptives (ethinyl estradiol/levonorgestrel), glibenclamide, nifedipine and enalapril was studied. No clinically significant drug interactions were identified.

Candesartan is metabolized in the liver to a small extent with the participation of the CYP2C9 isoenzyme. Interaction studies have not revealed any effect of the drug on the isoenzymes CYP2C9 and CYP3A4; the effect on other isoenzymes of the cytochrome P450 system has not been studied.

With simultaneous use of angiotensin II receptor antagonists and NSAIDs, including cyclooxygenase-2 inhibitors and non-selective NSAIDs, for example, acetylsalicylic acid more than 3 g per day, the hypotensive effect of candesartan may be reduced.

Concomitant use of candesartan/hydrochlorothiazide with other antihypertensive drugs enhances the hypotensive effect.

Dual blockade of the RAAS using angiotensin II receptor antagonists (ARA II), ACE inhibitors or aliskiren (renin inhibitor) may be accompanied by an increased risk of hypotension, syncope, hyperkalemia and renal dysfunction (including acute renal failure) compared with monotherapy. Regular monitoring of blood pressure, renal function and electrolyte levels in the blood is necessary in patients taking concomitantly candesartan/hydrochlorothiazide and other drugs that affect the RAAS.

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

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

With simultaneous use of ACE inhibitors and dipeptidyl peptidase type 4 inhibitors (for example, vildagliptin), the risk of developing angioedema may be increased.

The potassium-wasting effects of hydrochlorothiazide may be potentiated by other drugs that cause potassium wasting and hypokalemia (eg, diuretics, laxatives, amphotericin, carbenoxolone, sodium penicillin G, salicylic acid derivatives).

Experience with the use of other drugs acting on the RAAS shows that concomitant therapy with potassium-sparing diuretics, potassium preparations, salt substitutes containing potassium, and other drugs that increase potassium levels in the blood serum (for example, heparin) can lead to the development of hyperkalemia.

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

With the simultaneous use of lithium preparations with ACE inhibitors, a reversible increase in the concentration of lithium in the blood serum and the development of toxic reactions occur. Similar reactions can also occur when using angiotensin II receptor antagonists, and therefore it is recommended to monitor the lithium content in the blood serum.

The diuretic, natriuretic and hypotensive effects of hydrochlorothiazide are weakened by the simultaneous use of NSAIDs.

The absorption of hydrochlorothiazide is weakened by the use of colestipol and cholestyramine.

The effect of non-depolarizing muscle relaxants (for example, tubocurarine) can be enhanced by hydrochlorothiazide.

Thiazide diuretics may cause an increase in plasma calcium due to a decrease in its excretion. If it is necessary to use calcium-containing nutritional supplements or vitamin D, the calcium level in the blood plasma should be monitored and the dose adjusted if necessary.

Thiazide-like diuretics enhance the hyperglycemic effect of beta-blockers and diazoxide.

Anticholinergics (eg, atropine, biperiden) may increase the bioavailability of thiazide diuretics due to decreased gastrointestinal motility.

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

Thiazide-like diuretics can slow down the removal of cytotoxic drugs (such as cyclophosphamide, methotrexate) from the body and enhance their myelosuppressive effect.

The risk of hypokalemia may increase with concomitant use of glucocorticosteroids (GCS) or adrenocorticotropic hormone (ACTH).

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

When treated with thiazide diuretics, a decrease in glucose tolerance may occur, and therefore it may be necessary to adjust the dose of hypoglycemic drugs (including insulin).

Hydrochlorothiazide may reduce the effects of vasoconstrictor amines (eg, epinephrine).

Hydrochlorothiazide may increase the risk of acute renal failure, especially when taken with large doses of iodinated excipients.

No significant interaction of hydrochlorothiazide with food was found.

Overdose

Symptoms: analysis of the pharmacological properties of the drug suggests that the main manifestation of an overdose may be a clinically pronounced decrease in blood pressure and dizziness. Isolated cases of drug overdose (up to 672 mg of candesartan) have been described, resulting in the recovery of patients without serious consequences. The main manifestation of an overdose of hydrochlorothiazide is a decrease in blood volume and disturbance of water and electrolyte balance. Symptoms such as dizziness, marked decrease in blood pressure, dry oral mucosa, tachycardia, ventricular arrhythmia, loss of consciousness and muscle cramps were also observed.
Treatment: with the development of a clinically significant decrease in blood pressure, it is necessary to carry out symptomatic treatment and monitor the patient’s condition. Place the patient on his back and elevate his legs. If necessary, the blood volume should be increased, for example, by intravenous administration of a 0.9% sodium chloride solution. If necessary, sympathomimetic agents can be prescribed. Candesartan and hydrochlorothiazide are unlikely to be eliminated by hemodialysis.

Storage conditions

Store at a temperature not exceeding 25 °C. Keep out of the reach of children!

Shelf life

2 years

Manufacturer

Pliva Hrvatska d.o.o., Croatia