Hydrochlorothiazide, losartan

Pharmacological properties

Pharmacodynamics

Losartan / hydrochlorothiazide. It is known that the simultaneous use of losartan and hydrochlorothiazide leads to an additive effect with respect to lowering blood pressure, lowering it to a greater extent than each of the components separately. It is believed that this is due to the complementary effect of both components. In addition, as a result of the diuretic effect, hydrochlorothiazide increases plasma renin activity and aldosterone secretion, and also reduces potassium and increases angiotensin II levels in blood plasma. Losartan blocks all physiologically significant effects of angiotensin II and, through inhibition of aldosterone, reduces the loss of potassium ions caused by diuretics.

It is known that losartan exhibits a weak and transient uricosuric effect. Hydrochlorothiazide slightly increases the concentration of uric acid in the blood plasma; the combination of losartan and hydrochlorothiazide helps to reduce the hyperuricemia caused by diuretics.

The antihypertensive effect of losartan and hydrochlorothiazide lasts for 24 hours and persists with continuous treatment. Despite a significant decrease in blood pressure, the drug does not have a clinically significant effect on heart rate. It is known that after 12 weeks of using the combination of losartan 50 mg / hydrochlorothiazide 12.5 mg, a decrease in diastolic blood pressure in the sitting position was recorded by an average of 13.2 mm RT. Art.

The combination of losartan / hydrochlorothiazide equally effectively reduced blood pressure in men and women, in individuals of the black and other races, in patients young (65 years old) and elderly (≥65 years old); the drug is effective in patients with any severity of hypertension.

Losartan. It is a synthetic angiotensin II receptor antagonist (type AT₁), which is administered orally. Angiotensin II is a powerful vasoconstrictor, the main hormone of the renin-angiotensin system, and also a key link in the development of hypertension.

Angiotensin II binds to AT receptors₁that are found in many tissues (for example, in the smooth muscles of blood vessels, adrenal glands, kidneys and heart), and causes a number of important biological effects, including vasoconstriction and aldosterone release. Angiotensin II also stimulates the proliferation of smooth muscle cells.

Losartan selectively blocks AT₁receptors. In vitro and in vivo, losartan and its pharmacologically active carboxylic acid metabolite (E3174) blocks all physiologically significant effects of angiotensin II, regardless of the source or route of its synthesis.

Losartan does not have an agonistic effect, nor does it block receptors of other hormones or ion channels, which play an important role in the regulation of the cardiovascular system. In addition, losartan does not inhibit ACE (kinase II), an enzyme that breaks down bradykinin. Because of this, there is no increase in the severity of side effects associated with bradykinin.

When using losartan, inhibition of negative feedback on renin secretion is noted, which leads to an increase in renin activity in blood plasma.An increase in renin activity leads to an increase in the concentration of angiotensin II in blood plasma. Despite this, antihypertensive activity and a decrease in the concentration of aldosterone in blood plasma persist, which indicates an effective blockade of angiotensin II receptors. After cessation of treatment with losartan, renin plasma activity and angiotensin II concentration return to their initial values ​​within 3 days.

Both losartan and its main active metabolite have a significantly greater affinity for AT receptors.₁than to AT₂. In terms of mass, the active metabolite is 10–40 times more active than losartan.

It is known that the incidence of coughing in patients taking losartan or hydrochlorothiazide is significantly lower than with ACE inhibitors.

In patients with hypertension in combination with proteinuria without diabetes, the use of losartan potassium significantly reduced proteinuria, as well as fractional excretion of albumin and IgG. Losartan maintains glomerular filtration rate (GFR) and reduces the filtration fraction. In general, losartan causes a decrease in the concentration of uric acid in the blood plasma (usually 0.4 mg / dl), which persists during prolonged therapy.

Losartan does not affect autonomous reflexes and does not have a lasting effect on the level of norepinephrine in blood plasma.

In patients with left ventricular failure, doses of 25 and 50 mg of losartan caused positive hemodynamic and neurohormonal effects, characterized by an increase in the cardiac index and a decrease in pressure in the final pulmonary capillaries, a decrease in systemic vascular resistance, mean blood pressure, as well as heart rate and aldosterone and norepinephrine levels circulating in the blood. Manifestations of arterial hypotension in this group of patients with heart failure were dose-dependent.

Hydrochlorothiazide. This is a diuretic, a derivative of thiazides. The mechanism of the antihypertensive effect of hydrochlorothiazide is unknown. Thiazides act on the reabsorption of electrolytes and water in the distal tubules of the kidneys, approximately the same increase the release of sodium and chlorine ions. Hydrochlorothiazide reduces blood plasma volume, increases renin activity and enhances the release of aldosterone, increases the excretion of potassium and bicarbonate ions in the urine and reduces the concentration of potassium in the blood plasma. The relationship between renin and aldosterone is regulated by angiotensin II, so the simultaneous use of an angiotensin II receptor antagonist has the opposite effect on potassium excretion caused by thiazide diuretics. After administration, increased diuresis begins within 2 hours, reaches a peak after about 4 hours and lasts for 6-12 hours, the antihypertensive effect lasts for 24 hours.

Pharmacokinetics Suction

Losartan. After administration, losartan is well absorbed and undergoes primary metabolism in the liver, during which an active metabolite of carboxylic acid and other inactive metabolites are formed. The systemic bioavailability of losartan is about 33%. Medium C_max losartan and its active metabolite are achieved 1 and 3-4 hours after administration, respectively. Eating regular food does not significantly affect the plasma concentration profile of losartan.

Distribution

Losartan. Both losartan and its active metabolite bind to plasma proteins by more than 99%, mainly with albumin. The volume of distribution of losartan is 34 liters. It is known that losartan does not penetrate or slightly penetrates the BBB.

Hydrochlorothiazide. Hydrochlorothiazide crosses the placental barrier and into breast milk, but does not cross the BBB.

Biotransformation

Losartan. About 14% of an orally or iv dose of losartan is converted into an active metabolite. After administration or administration of losartan potassium labeled with radioactive carbon (¹⁴C), the radioactivity of the circulating blood plasma is mainly due to losartan and its active metabolite. Only about 1% of the examined losartan slightly turned into an active metabolite.

In addition to the active metabolite, inactive metabolites are also formed, including two major metabolites formed by hydroxylation of the butyl side chain and one secondary metabolite, N-2-tetrazole-glucuronide.

Breeding

Losartan. The clearance of losartan and its active metabolite is about 600 and 50 ml / min, respectively. The renal clearance of losartan and its active metabolite is about 74 and 26 ml / min, respectively. With oral administration of losartan, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in the urine as an active metabolite. Losartan and its active metabolite have a linear pharmacokinetics with oral administration of potassium losartan in a dose of up to 200 mg.

After oral administration, the concentrations of losartan and its active metabolite in blood plasma decrease exponentially with final T_½ about 2 and 6–9 hours, respectively. When taking the drug in a dose of 100 mg once a day, there is no significant cumulation in the blood plasma of either losartan or its active metabolite.

Excretion of losartan and its metabolites occurs with bile and urine. After taking losartan labeled with radioactive carbon ¹⁴C, about 35% of the radioactive label is detected in urine and 58% in feces.

Hydrochlorothiazide. Hydrochlorothiazide is not metabolized, but is rapidly excreted by the kidneys. When studying the level of hydrochlorothiazide in blood plasma for at least 24 hours it was found that T_½ is 5.6-14.8 hours. At least 61% of orally administered hydrochlorothiazide is excreted unchanged in the urine within 24 hours.

Features of use in special patient groups

Losartan / hydrochlorothiazide. Significant differences in the concentration of losartan and its active metabolite in blood plasma, as well as the absorption of hydrochlorothiazide in young and elderly patients with hypertension were not observed.

Losartan. After taking losartan by patients with cirrhosis of the liver of mild and moderate alcoholic genesis, the concentration of losartan in the blood plasma was 5 times higher, and the concentration of the active metabolite was 1.7 times higher compared with healthy volunteers.

Neither losartan nor its active metabolite can be excreted by hemodialysis.

Indications

Arg in patients in whom adequate hell control is not ensured with losartan alone or hydrochlorothiazide alone.

Application

The drug can be used in combination with other antihypertensive drugs. the drug should be taken with 1 glass of water, regardless of food intake.

AH. Losartan and hydrochlorothiazide are not intended for use at the initial stage of therapy, they are indicated for patients in whom blood pressure is not sufficiently controlled by taking only losartan or only hydrochlorothiazide.

It is recommended that the dose of the individual components (losartan and hydrochlorothiazide) be selected.

If there are indications in patients whose blood pressure is not sufficiently controlled, an initial transition from monotherapy to taking the combined drug in a fixed dose is possible.

The initial and maintenance dose of Co-Centor is 50 mg / 12.5 mg once a day.

For patients who do not adequately respond to therapy at a dose of 50 mg / 12.5 mg, the dose can be increased to 100 mg / 12.5 mg once a day or 100 mg / 25 mg once a day. The maximum dose is 1 tablet of Co-Centor 100 mg / 25 mg once a day. As a rule, the antihypertensive effect is achieved within 3-4 weeks after the start of therapy. The duration of treatment is determined by the doctor individually.

Use in patients with impaired renal function or on hemodialysis. For patients with moderate impaired renal function (creatinine clearance of 30-50 ml / min), initial dose adjustment is not required. It is not recommended to prescribe losartan and hydrochlorothiazide tablets to hemodialysis patients. The use of Co-Centor is contraindicated in patients with severe renal failure (creatinine clearance 30 ml / min) (see CONTRAINDICATIONS).

Use in patients with a decrease in intravascular volume. The volume and / or decrease in sodium content must be adjusted before using Co-Centor.

Use in patients with liver failure. Co-Centor is contraindicated in patients with severe hepatic impairment (see CONTRAINDICATIONS).

Use in elderly patients. Usually, dose adjustment for elderly patients is not required.

Contraindications

• Hypersensitivity to losartan, sulfonamide derivatives (including hydrochlorothiazide) or excipient; treatment-resistant hypokalemia or hypercalcemia; severe liver failure, cholestasis, and disorders accompanied by obstruction of the bile ducts; refractory hyponatremia; symptomatic hyperuricemia / gout; the period of pregnancy and lactation, as well as women planning a pregnancy (see use during pregnancy and lactation); severe renal failure (creatinine clearance 30 ml / min); anuria simultaneous use with aliskiren in patients with diabetes mellitus or impaired renal function (SCF 60 ml / min).

Side effects

There are no data on specific adverse reactions characteristic of the combined drug. these side effects have already been described with the use of losartan potassium and / or hydrochlorothiazide. adverse reactions during post-marketing use:

hepatobiliary disorders: hepatitis;

laboratory tests: hyperkalemia, increased levels of AlAT.

The following adverse reactions were noted with the use of active substances in monotherapy and can be detected when taking the drug losartan potassium / hydrochlorothiazide.

Losartan

On the part of the blood and lymphatic system: anemia, Shenlain-Purpura-Genoch, ecchymosis, hemolysis, thrombocytopenia.

From the side of the heart: arterial hypotension, orthostatic hypotension, sternalgia, angina pectoris, AV block II degree, cerebrovascular disorders, myocardial infarction, heart palpitations, arrhythmias (atrial fibrillation, sinus bradycardia, tachycardia, ventricular tachycardia).

From the side of the organ of hearing and balance: dizziness, ringing in the ears.

From the side of the organ of vision: blurred vision, burning in the eyes, conjunctivitis, decreased visual acuity, tingling sensation in the eyes.

From the digestive system: abdominal pain, nausea, diarrhea, dyspepsia, constipation, toothache, dry mouth, flatulence, gastritis, vomiting, severe constipation, pancreatitis.

Common disorders: asthenia, fatigue, chest pain, swelling of the face, swelling, fever, flu-like symptoms, malaise.

On the part of the liver and biliary tract: impaired liver function.

On the part of the immune system: hypersensitivity - anaphylactic reactions, angioedema, including swelling of the larynx and glottis, leading to impaired airway patency, and / or swelling of the face, lips, pharynx, and / or tongue; in some of these patients, angioedema has been reported in the past in connection with the use of other drugs, including ACE inhibitors.

From the side of metabolism: anorexia, gout.

From the side of musculoskeletal and connective tissue: muscle cramps, back pain, leg pain, myalgia, hand pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, coxalgia, fibromyalgia, muscle weakness, rhabdomyolysis.

From the nervous system: headache, dizziness, paresthesia, peripheral neuropathy, tremor, migraine, fainting.

Mental disorders: nervousness, insomnia, anxiety, anxiety neurosis, panic syndrome, confusion, depression, unusual dreams, sleep disorders, drowsiness, memory impairment.

On the part of the kidneys and urinary tract: impaired renal function, renal failure, nocturnal polyuria, frequent urination, urinary tract infection, nocturia.

From the reproductive system and mammary glands: decreased libido, erectile dysfunction / impotence.

From the respiratory system, chest and mediastinal organs: cough, upper respiratory tract infection, nasal congestion, sinusitis, dysfunction of the paranasal sinuses, oropharyngeal discomfort, pharyngitis, laryngitis, dyspnea, bronchitis, nosebleeds, rhinitis, congestive airways .

On the part of the skin and subcutaneous tissues: alopecia, dermatitis, dry skin, erythema, redness, photosensitivity, pruritus, rash, urticaria, increased sweating.

From the vessels: vasculitis.

Laboratory studies: hyperkalemia, a decrease in the level of hematocrit and hemoglobin, hypoglycemia, a slight increase in the level of urea and creatinine in blood plasma, an increase in the level of liver enzymes and bilirubin, hyponatremia.

Hydrochlorothiazide

From the hemopoietic system and the lymphatic system: agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, purpura, thrombocytopenia.

From the immune system: anaphylactic reactions.

From the side of metabolism: anorexia, hyperglycemia, hyperuricemia, hypokalemia, hyponatremia, hypercalcemia, hypomagnesemia.

Mental disorders: insomnia.

From the nervous system: headache.

From the side of the organ of vision: transient blurred vision, xanthopsia.

From the side of the vessels: necrotic angiitis (vasculitis, skin vasculitis).

From the respiratory system, chest and mediastinal organs: respiratory distress, including pneumonitis and pulmonary edema.

From the digestive system: sialadenitis, cramping, stomach irritation, nausea, vomiting, diarrhea, constipation.

From the liver and biliary tract: jaundice (intrahepatic cholestasis), pancreatitis.

From the skin and subcutaneous tissues: photosensitivity, urticaria, toxic epidermal necrolysis, systemic lupus erythematosus.

From the musculoskeletal and connective tissue: muscle cramps.

From the kidneys and urinary tract: glucosuria, interstitial nephritis, impaired renal function, renal failure.

Common disorders: fever, dizziness.

From the reproductive system: erectile dysfunction / impotence.

special instructions

Losartan

Angioneurotic edema. Patients with angioneurotic edema (swelling of the face, lips, throat, and / or tongue) should be closely monitored (see ADVERSE EFFECTS).

Arterial hypotension and decreased intravascular volume. In patients with a decrease in intravascular volume and / or hyponatremia caused by intensive use of diuretics, limiting salt intake, diarrhea or vomiting, symptomatic arterial hypotension may develop, especially after taking the first dose of the drug. These conditions should be adjusted before taking Co-Centor (see APPLICATION and CONTRAINDICATIONS).

Electrolyte imbalance. It should be borne in mind that electrolyte imbalance is often noted in patients with renal failure and associated diabetes or without it. Therefore, it is necessary to carefully monitor the plasma potassium content and creatinine clearance, especially in patients with heart failure and creatinine clearance in the range of 30-50 ml / min.

It is not recommended to take losartan / hydrochlorothiazide simultaneously with potassium-sparing diuretics, potassium-containing additives and salt substitutes (see INTERACTIONS).

Severe impairment of liver function. According to pharmacokinetic data in patients with cirrhosis of the liver, a significant increase in the concentration of losartan in the blood plasma was detected, in this regard, Co-Centor should be used with caution in patients with a mild to moderate history of liver dysfunction. There is no experience with losartan in patients with severely impaired liver function. Therefore, Co-Centor is contraindicated in patients with severe impaired liver function (see APPLICATION, CONTRAINDICATIONS, PHARMACOLOGICAL PROPERTIES).

Severe renal impairment. Inhibition of the renin-angiotensin-aldosterone system (RAAS) has impaired renal function, including renal failure (in particular, in patients whose renal function depends on RAAS activity, for example, in patients with severe heart failure or existing renal impairment). Such renal changes may be reversible after discontinuation of treatment.

As with other drugs that affect the renin-angiotensin system, when using losartan, an increase in blood urea and plasma creatinine was reported in patients with bilateral renal artery stenosis or stenosis of a single kidney artery. These changes are reversible after discontinuation of therapy. Caution must be exercised when administering losartan to patients with bilateral renal artery stenosis or a single kidney artery stenosis.

Kidney transplantation. There is no experience with the use of the drug in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism. Patients with primary hyperaldosteronism usually do not respond to therapy with antihypertensive drugs that act through inhibition of RAAS. Thus, the use of Co-Centor is not recommended.

IHD and cerebrovascular insufficiency. Like any antihypertensive drug, losartan can cause a significant decrease in blood pressure in patients with coronary artery disease and cerebrovascular insufficiency, which can lead to myocardial infarction or stroke.

Heart failure. In patients with heart failure (with or without concomitant renal failure), as with other drugs acting on the renin-angiotensin system, there is a risk of severe arterial hypotension and renal failure (often acute).

Stenosis of aortic and mitral valves, obstructive hypertrophic cardiomyopathy. As with other vasodilators, special care is needed when administering the drug to patients with aortic and mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Ethnic features. ACE inhibitors, losartan, and other angiotensin antagonists are known to be less effective in lowering blood pressure in members of the Negroid race than in other races.Perhaps this is due to the fact that among the representatives of the Negroid race with AH, persons with low renin activity predominate.

Period of pregnancy. Angiotensin II receptor antagonist therapy should not be started during pregnancy. In cases where the continuation of treatment with angiotensin II receptor antagonists is necessary, patients planning a pregnancy should be transferred to the reception of alternative antihypertensive drugs that have confirmed safety data when used during pregnancy. When pregnancy is confirmed, treatment with angiotensin II receptor antagonists should be stopped immediately and switch to alternative treatment (see CONTRAINDICATIONS and Use during pregnancy and lactation).

Hydrochlorothiazide

Arterial hypotension and disturbances in the water-electrolyte balance. As with other antihypertensive agents, some patients may experience symptomatic hypotension. Patients should be monitored to identify the clinical symptoms of water-electrolyte imbalance in a timely manner (e.g., dehydration, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia, which may develop with intercurrent diarrhea or vomiting). In such patients, regular monitoring of the electrolyte content in blood plasma is necessary. In hot weather, dilution hyponatremia may occur in patients with edema.

Metabolic and endocrine effects. Thiazide therapy may decrease glucose tolerance. In some cases, dose adjustment of antidiabetic agents, including insulin, may be required (see INTERACTIONS). Latent diabetes mellitus may occur during thiazide treatment.

Thiazides can reduce urinary calcium excretion and cause an occasional and slight increase in plasma calcium. Severe hypercalcemia may indicate the presence of latent hyperparathyroidism. The use of thiazides should be discontinued before examining the function of the parathyroid glands.

An increase in plasma cholesterol and triglycerides may also be associated with thiazide diuretic therapy.

In some patients, treatment with thiazides can lead to hyperuricemia and / or the development of gout. Since losartan reduces the concentration of uric acid, its combination with hydrochlorothiazide reduces the severity of hyperuricemia caused by diuretics.

Liver failure. Thiazides should be used with caution in patients with impaired liver function or progressive liver disease, since they can cause intrahepatic cholestasis, which, with minimal disturbance of the water-electrolyte balance, can pass into the hepatic coma.

Co-Centor is contraindicated in patients with severe hepatic impairment (see CONTRAINDICATIONS and PHARMACOLOGICAL PROPERTIES).

Other In patients taking thiazide diuretics, hypersensitivity reactions can occur even in the absence of a history of allergy or AD.There is evidence of an exacerbation or progression of systemic lupus erythematosus with thiazide.

Excipients. Patients with a rare inherited pathology of galactose intolerance, lactose intolerance or glucose-galactose malabsorption should not take this drug.

Co-Sentor, film-coated tablets, contains the sunset yellow colorant FCF (E110), which can cause allergic reactions.

Use during pregnancy and lactation. Co-Centor is contraindicated during pregnancy and lactation (see CONTRAINDICATIONS, SPECIAL INSTRUCTIONS). The drug should not be used by pregnant women or women planning a pregnancy. If pregnancy is confirmed during treatment with the drug, its administration should be stopped immediately and replaced with another drug approved for use during pregnancy.

Angiotensin II receptor antagonists. There is no convincing epidemiological evidence of teratogenic risk with the use of ACE inhibitors in the first trimester of pregnancy; however, a slight increase in this risk cannot be ruled out. Until data from controlled epidemiological studies regarding the risk of using angiotensin II receptor inhibitors are obtained, it should be assumed that similar risks may exist for this class of drugs. It is known that therapy with angiotensin II receptor antagonists in the II and III trimester of pregnancy has a toxic effect on the embryo (impaired renal function, oligohydramnios, slowing the formation of bone tissue of the skull) and on the body of a newborn baby (renal failure, hypotension, hyperkalemia).

If therapy with angiotensin II receptor antagonists was started from the second or third trimester of pregnancy, ultrasound of the kidney function and the structure of the skull of the newborn is recommended. Newborns whose mothers received angiotensin II receptor antagonists should be observed for the timely detection and correction of arterial hypotension.

In cases where continued treatment of hypertension is mandatory, patients planning a pregnancy should be transferred to alternative antihypertensive drugs that have confirmed safety data for use during pregnancy. When pregnancy is confirmed, treatment with angiotensin II receptor antagonists should be stopped immediately and switch to alternative antihypertensive therapy.

Hydrochlorothiazide. Given that the Co-Centor drug is combined, it is contraindicated during pregnancy (see CONTRAINDICATIONS).

The experience with hydrochlorothiazide during pregnancy (especially in the first trimester) is limited.

It is known that hydrochlorothiazide crosses the placental barrier. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use in the II and III trimester of pregnancy can have a negative effect on fetoplacental perfusion and can cause pathology such as jaundice, disturbed electrolyte balance and thrombocytopenia in the fetus and newborn.

Lactation. Co-Centor is contraindicated during lactation (see CONTRAINDICATIONS).

Angiotensin II receptor antagonists.During breastfeeding, alternative antihypertensive drugs with a better studied safety profile should be used.

Hydrochlorothiazide. Hydrochlorothiazide passes into breast milk in small amounts. Thiazides in high doses, causing intense diuresis, can inhibit lactation.

Children. There is no experience with the use of the drug in children. Co-Centor should not be used to treat children.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Studies of the impact on the ability to drive vehicles and work with mechanisms have not been conducted. Nevertheless, when driving a vehicle or mechanisms, it must be borne in mind that when taking antihypertensive drugs, dizziness or drowsiness, arterial hypotension, muscle cramps, blurred vision may occur, especially at the initial stage of administration or when the dose is increased.

Interactions

Losartan. there are reports that rifampicin and fluconazole reduce the level of active metabolite in the blood. the clinical significance of these interactions was not evaluated.

Like the use of other drugs - angiotensin II inhibitors, the simultaneous administration of losartan with potassium-sparing diuretics (e.g. spironolactone, triamteren, amiloride) and potassium preparations or salt substitutes containing potassium can lead to an increase in the level of potassium in the blood plasma. The combined use of losartan with these agents is not recommended.

Like other drugs that affect sodium excretion, losartan can inhibit the excretion of lithium from the body. Thus, with the simultaneous use of lithium salts and angiotensin II receptor antagonists, it is necessary to regularly and carefully monitor the level of lithium in blood plasma.

The simultaneous use of angiotensin II antagonists or diuretics and NSAIDs may increase the risk of developing renal dysfunction (including the risk of developing acute renal failure), as well as lead to an increase in plasma potassium, especially in patients with existing renal dysfunction. This combination of drugs should be prescribed with caution, especially for the elderly. Patients should drink plenty of fluids; in addition, after the start of combination therapy, it is necessary to monitor renal function and subsequently conduct it regularly.

In some patients with impaired renal function, taking NSAIDs, including selective COX-2 inhibitors, treatment with angiotensin II receptor antagonists can lead to further impairment of renal function. This effect is usually reversible.

Double blockade of the renin-angiotensin system (for example, by adding an ACE inhibitor or aliskiren to angiotensin II receptor antagonists) should be used only in individually defined cases with careful monitoring of renal function, blood pressure and electrolyte levels.In patients with revealed atherosclerosis, heart failure, or diabetes with target organ damage, the double blockade of the renin-angiotensin-aldosterone system is known to be associated with a higher incidence of arterial hypotension, fainting, hyperkalemia, and impaired renal function (including acute renal failure) blocker drug renin-angiotensin-aldosterone system. Aliskiren should not be used simultaneously with Co-Centor in patients with diabetes. Aliskiren should be avoided with Co-Centor in patients with renal failure (GFR 60 ml / min) (see CONTRAINDICATIONS).

Combined use with other drugs that cause hypotension, such as tricyclic antidepressants, antipsychotics, baclofen, amifostine, the main or side effect of which is a decrease in blood pressure, can increase the risk of developing hypotension.

Hydrochlorothiazide. The following drugs can interact with thiazide diuretics when used simultaneously:

alcohol (ethanol), barbiturates, drugs or antidepressants. May lead to increased orthostatic hypotension.

Antidiabetic drugs (oral antidiabetic