Kozaar - instructions for use, doses, side effects, contraindications

Composition:1 film coated tablet contains:
core tablet:
active substance: Losartan potassium 50.0 mg;
auxiliary substances: cellulose microcrystalline 52.5 mg, lactose monohydrate 25.5 mg, corn starch pregelatinized starch 20.95 mg, magnesium stearate 1.05 mg;
tablet shell:
giprolase (with 0.3% silicon dioxide) 1.80 mg, hypromellose 1.80 mg, titanium dioxide 0.90 mg, carnauba wax 0.05 mg.

Description:White film-coated tablets drop-shaped, on one side engraved 960, on the other - smooth.

Pharmacotherapeutic group:Angiotensin II receptor antagonist.

ATX: & nbsp

C.09.C.A.01 Losartan

C.09.C.A Angiotensin II antagonists

Pharmacodynamics:Mechanism of action
Angiotensin II is a potent vasoconstrictor, the main active hormone of the renin-angiotensin-aldosterone system (RAAS), and the decisive pathophysiological link in the development of hypertension (AH). Angiotensin II binds to AT₁receptors found in many tissues (in the smooth muscle tissues of the vessels, in the adrenal gland, kidneys and heart), and performs several important biological functions, including vasoconstriction and aldosterone release. In addition, angiotensin II stimulates the proliferation of smooth muscle cells. AT₁-receptors - the second type of receptors with which angiotensin II binds, but its role in regulating the function of the cardiovascular system is unknown.
Losartan is a selective antagonist of AT₁-receptor angiotensin II, highly effective when administered orally. Losartan and its pharmacologically active carboxylated metabolite (E-3174) both in vitro and in vivo block all the physiological effects of angiotensin II, regardless of its source or route of synthesis. Unlike some peptide angiotensin II antagonists losartan does not possess the properties of an agonist.
Losartan selectively binds to AT₁receptors and does not bind or block receptors of other hormones and ion channels, which play an important role in regulating the function of the cardiovascular system. Besides, losartan does not inhibit angiotensin-converting enzyme (ACE, kininase II), responsible for the destruction of bradykinin. Consequently, effects that are not directly related to AT blockade₁-receptors, such as increased bradykinin-mediated effects or development of edema (losartan 1.7%, placebo 1.9%), are not related to the action of losartan.
Pharmacodynamics
Losartan suppresses an increase in systolic and diastolic blood pressure (BP) during the infusion of angiotensin II. At the time of the maximum concentration of losartan in the blood plasma (C_max) after taking losartan in a dose of 100 mg, the above-mentioned effect of angiotensin II is inhibited by approximately 85%, and after 24 hours after a single and multiple doses - by 26-39%.
During the administration of losartan, the elimination of negative feedback, consisting in the suppression of renin secretion by angiotensin II, leads to an increase in plasma renin activity (ARP). Increased ARP leads to an increase in the concentration of angiotensin II in blood plasma.At long-term (6-week) treatment of patients with AH losartan at a dose of 100 mg / day there was a 2-3-fold increase in the concentration of angiotensin II in blood plasma at the moment of achieving C_max losartan. In some patients, an even greater increase in angiotensin II concentration was observed, especially with a short duration of treatment (2 weeks). Despite this, during the treatment, the antihypertensive effect and the decrease in the plasma aldosterone concentration were manifested after 2 and 6 weeks of therapy, which indicates an effective blockade of the angiotensin II receptors. After cancellation of losartan, ARP and angiotensin II concentration decreased for 3 days to the values observed before the start of losartan. Because the losartan is a specific AT antagonist₁receptors of angiotensin II, it does not inhibit ACE (kininase II), an enzyme that inactivates bradykinin. A study comparing the effects of losartan in doses of 20 mg and 100 mg with the effects of an ACE inhibitor on the effect on angiotensin I, angiotensin II, and bradykinin showed that losartan blocks the effects of angiotensin I and angiotensin II, without affecting the effects of bradykinin.This is due to the specific mechanism of action of losartan. The ACE inhibitor blocked the response to angiotensin I and increased the severity of the effects caused by the action of bradykinin, without affecting the severity of the response to angiotensin II, which demonstrates the pharmacodynamic difference between losartan and ACE inhibitors.
The concentration of losartan and its active metabolite in the blood plasma, as well as the antihypertensive effect of losartan increase with increasing dose of the drug. As losartan and its active metabolite are antagonists of angiotensin II receptors (ARA II), they both contribute to the antihypertensive effect.
In a study with a single dose of losartan in a dose of 100 mg, in which healthy volunteers (men) were included, taking the drug inward under high and low-fat diet conditions did not affect the glomerular filtration rate (GFR), the effective renal plasma flow and the filtration fraction. Losartan had a natriuretic effect that was more pronounced with a low-sal diet and, apparently, was not associated with the suppression of early sodium reabsorption in the proximal renal tubules. Losartan also caused a transient increase in the excretion of uric acid by the kidneys.
In patients with AH, proteinuria (not less than 2 g / 24 h), without diabetes mellitus and taking losartan for 8 weeks at a dose of 50 mg with a gradual increase to 100 mg, there was a significant decrease in proteinuria (by 42%), fractional excretion of albumin and immunoglobulins (IgG). In these patients losartan stabilized GFR and reduced the filtration fraction.
In postmenopausal women with AH, who took losartan in a dose of 50 mg for 4 weeks, there was no effect of therapy on the renal and systemic levels of prostaglandins.
Losartan does not affect vegetative reflexes and does not have a lasting effect on the concentration of noradrenaline in the blood plasma.
In patients with AH losartan in doses up to 150 mg / day did not cause clinically significant changes in the concentration of fasting triglycerides, total cholesterol and high-density lipoprotein cholesterol. In the same doses losartan did not affect the concentration of glucose in the blood on an empty stomach.
In a clinical study of HEAAL to assess the effect of high and low doses of ARA II (losartan) on the resultpatients with chronic heart failure (CHF) were included patients (n = 3834) with CHF (II-IV functional class according to the NYHA classification) and intolerance to ACE inhibitors. Patients were observed for more than 4 years (median follow-up was 4.7 years) to compare the effects of losartan 50 mg / day and 150 mg / day for a reduction in all-cause mortality or hospitalization for heart failure. This study showed that losartan at a dose of 150 mg / day significantly reduced the risk of death from all causes or hospitalization for heart failure compared with a dose of 50 mg / day (risk ratio [OR] 0.899, p = 0.027).
Generally losartan caused a decrease in the concentration of uric acid in the blood serum (usually less than 0.4 mg / dL), which persisted with long-term treatment. In controlled clinical trials involving patients with hypertension, there were no cases of drug withdrawal due to an increase in creatinine concentration or serum potassium levels.
In a 12-week parallel study, which included patients with left ventricular failure (NYHA class II-IV functional class),most of whom took diuretics and / or cardiac glycosides, compared the effects of losartan at doses of 2.5, 10, 25 and 50 mg / day with placebo. At doses of 25 and 50 mg / day, the drug exhibited positive hemodynamic and neurohormonal effects that persisted throughout the study. Hemodynamic effects included increased cardiac index and lowering wedge pressure in the pulmonary capillaries and decrease total peripheral vascular resistance, secondary systemic blood pressure and heart rate. The incidence of arterial hypotension in these patients depended on the dose of the drug. Neurohormonal effects included a decrease in the concentration of aldosterone and norepinephrine in the blood.

Pharmacokinetics:Suction
Ingestion losartan is well absorbed and metabolized by "primary passage" through the liver to form an active carboxylated metabolite and inactive metabolites. Systemic bioavailability of losartan in tablet form is approximately 33%. Average C_max losartan and its active metabolite are achieved after 1 h and 3-4 h respectively.When losartan was taken during the usual meal, there was no clinically significant effect on the profile of losartan concentration in the blood plasma.
Distribution
Lozartan and its active metabolite bind to plasma proteins (mainly albumin) by at least 99%. The volume of distribution of losartan is 34 liters. Studies in rats have shown that losartan practically does not penetrate the blood-brain barrier.
Metabolism
Approximately 14% of the dose of losartan for intravenous administration or ingestion is converted into its active metabolite. After ingestion or intravenous administration of radiolabeled radiolabel (¹⁴C losartan) the radioactivity of the circulating blood plasma is primarily due to the presence in it of losartan and its active metabolite. Low conversion efficiency of losartan in its active metabolite was observed in approximately 1% of the patients participating in the study. In addition to the active metabolite, biologically inactive metabolites are formed, including the two main metabolites formed as a result of hydroxylation of the butyl side chain, and one secondary N-2-tetrazole-glucuronide.
Excretion
The plasma clearance of losartan and its active metabolite is about 600 ml / min and 50 ml / min, respectively. The renal clearance of losartan and its active metabolite is approximately 74 ml / min and 26 ml / min, respectively. When taking losartan, about 4% of the dose is excreted by the kidneys unchanged and about 6% of the dose is excreted by the kidneys as an active metabolite. Losartan and its active metabolite have linear pharmacokinetics when administered to losartan in doses up to 200 mg.
After oral administration, the plasma concentrations of losartan and its active metabolite decrease polyexponentially with a finite half-life of about 2 and 6-9 hours, respectively. When the dosing regimen of the drug is 100 mg once a day, there is no significant accumulation in the blood plasma of either losartan or its active metabolite.
The excretion of losartan and its metabolites is carried out by the kidneys and through the intestine with bile. After oral administration ¹⁴C of losartan in men about 35% of radioactivity is found in urine and 58% in feces. After intravenous administration ¹⁴C of losartan in men approximately 43% of radioactivity is found in urine and 50% in feces.
Pharmacokinetics in specific patient groups
Elderly patients
The concentrations of losartan and its active metabolite in blood plasma in elderly male patients with AH do not significantly differ from these indices in young male patients with AH.
Floor
Values of losartan concentration in blood plasma in women with AH were 2 times higher than the corresponding values in men with AH. The concentrations of active metabolite in men and women did not differ. This apparent pharmacokinetic difference, however, has no clinical significance.
Patients with impaired hepatic function
When losartan was administered orally to patients with mild and moderate alcoholic cirrhosis, the concentrations of losartan and its active metabolite in blood plasma were respectively 5 and 1.7 times higher than in young healthy male volunteers.
Patients with impaired renal function
Concentrations of losartan in blood plasma in patients with creatinine clearance (CC) above 10 ml / min did not differ from those in patients with unchanged renal function. The area under the concentration-time curve (AUC) of losartan in patients on hemodialysis was approximately 2 times greater than in the AUC of losartan in patients with normal renal function.The concentrations of the active metabolite in the blood plasma did not change in patients with impaired renal function or patients on hemodialysis. Losartan and its active metabolite is not output by the hemodialysis procedure.

Indications:- Arterial hypertension.
- Reduced risk of associated cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy, manifested by a cumulative reduction in the incidence of cardiovascular mortality, stroke and myocardial infarction.
- Protection of the kidneys in patients with type 2 diabetes mellitus with proteinuria - slowing the progression of renal failure, manifested by a decrease in the frequency of hypercreatininemia, the frequency of development of the terminal stage
chronic renal failure requiring hemodialysis or kidney transplantation, mortality rates, and a decrease in proteinuria.
- Chronic heart failure with ineffective treatment with ACE inhibitors or intolerance to ACE inhibitors. It is not recommended to transfer patients with heart failure and stable parameters when taking ACE inhibitors for Kozaar therapy.

Contraindications:- Hypersensitivity to any of the components of this drug.
- Pregnancy and the period of breastfeeding.
- Age to 18 years (efficacy and safety of application not established).
- Simultaneous use with aliskiren or aliskirenoderzhaschimi drugs in patients with diabetes mellitus and / or renal dysfunction (GFR less than 60 ml / min / 1.73 m²) (see INTERACTION WITH OTHER DRUGS).
- Hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.
- Severe liver dysfunction (no experience of use).

Carefully:Bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney; hyperkalemia; condition after kidney transplantation (no experience of application); aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy: heart failure with concomitant severe impairment of kidney function; severe heart failure (IV functional class according to NYHA classification); heart failure with life-threatening arrhythmias; cardiac ischemia; cerebrovascular diseases; primary hyperaldosteronism; angioedema in history.
Patients with reduced circulating blood volume (eg, receiving treatment with large doses of diuretics) - symptomatic arterial hypotension may occur.

Pregnancy and lactation:Medicines that directly affect RAAS can cause serious damage and death of the developing fetus, so when diagnosing a pregnancy, the Cosaar drug should be immediately withdrawn and, if necessary, an alternative hypotensive therapy is prescribed.
Therapy with COSAAR should not be started during pregnancy. If patients planning a pregnancy continue losartan therapy is considered necessary, should be replaced losartan to alternative antihypertensive drugs that have an established safety profile when applied during pregnancy.
Although there is no experience with the use of Cosaar in pregnant women, preclinical studies in animals have shown that taking Cozaar leads to the development of serious embryonic and neonatal injuries and the death of the fetus or offspring. It is believed that the mechanism of these phenomena is due to the impact on the RAAS.
Renal perfusion in the fetus, depending on the development of RAAS, appears in the second trimester, so the risk to the fetus increases if the drug Cosaar is used in the second or third trimester of pregnancy.
The use of drugs that affect RAAS in the second and third trimester of pregnancy reduces the function of the kidneys of the fetus and increases the incidence and mortality of the fetus and newborns. The development of oligohydramnion can be associated with fetal lung hypoplasia and skeletal deformities. Possible adverse events in newborns include hypoplasia of the skull bones, anuria, arterial hypotension, renal failure and death.
The above undesirable outcomes are usually due to the use of drugs that affect RAAS in the second and third trimester of pregnancy. Most epidemiological studies on the development of fetal anomalies after the use of antihypertensive drugs in the first trimester of pregnancy have not revealed differences between drugs that affect RAAS and other antihypertensive drugs.When prescribing antihypertensive therapy for pregnant women, it is important to optimize the possible outcomes for the mother and fetus.
If it is not possible to select alternative therapy instead of therapy with drugs that affect RAAS, it is necessary to inform the patient about the possible risk of therapy for the fetus. It is necessary to conduct periodic ultrasound examinations to assess the intra-amniotic space. When identifying the oligohydramnion, it is necessary to stop taking the drug Cosaar, unless it is vital for the mother. Depending on the week of pregnancy, appropriate fetal tests are necessary. Patients and physicians should be aware that the oligohydramnios may not be detected until irreversible damage to the fetus occurs. It is necessary to closely monitor the newborns whose mothers took the drug Kozaar during pregnancy, in order to control arterial hypotension, oliguria and hyperkalemia.
It is not known whether losartan with breast milk. Since many drugs are excreted in breast milk and there is a risk of developing possible adverse effects in the child,breastfeeding should decide whether to stop breastfeeding or to cancel the drug, taking into account the need for its reception for the mother.

Dosing and Administration:The drug Cosaar is taken inside regardless of the meal.
The drug Cosaar can be taken in combination with other antihypertensive drugs.
Arterial hypertension
The standard initial and maintenance dose for the majority of patients is 50 mg of Kozaar preparation 1 time per day. The maximum antihypertensive effect is achieved in 3-6 weeks from the start of therapy. In some patients, to achieve a greater effect, the dose may be increased to a maximum daily dose of 100 mg of Cosaar preparation 1 time per day.
In patients with a reduced volume of circulating blood (for example, when taking large doses of diuretics) the initial dose of losartan should be reduced to 25 mg once a day (see SPECIAL INSTRUCTIONS).
There is no need to select an initial dose for elderly patients and patients with impaired renal function, including patients on dialysis.
Patients with a history of liver disease are recommended to prescribe lower doses of the drug Cosaar (see SPECIAL INSTRUCTIONS).
Reduced risk of associated cardiovascular morbidity and mortality in patients with hypertrophy and left ventricular hypertrophy
The standard initial dose of Kozaar is 50 mg once a day. It is recommended to add hydrochlorothiazide in low doses or increase
dose Kozaar to the maximum daily dose of 100 mg 1 time per day, taking into account the degree of decrease in blood pressure.
Kidney protection in patients with type 2 diabetes and proteinuria
The standard initial dose of Kozaar is 50 mg once a day. In the future, the dose of Kozaar can be increased to a maximum daily dose of 100 mg once a day, taking into account the degree of BP reduction. Cosaar may be administered in combination with other antihypertensive agents (eg, diuretics, slow calcium channel blockers, alpha and beta adrenoblockers, central antihypertensives), insulin and other hypoglycemic agents (eg, sulfonylurea, glitazone derivatives and inhibitors glucosidase).
Chronic heart failure
The initial dose of losartan for patients with CHF is 12.5 mg once a day (with the appointment of losartan in low dosages,that the drug Kozaar in a dosage of 12.5 mg is not available in the Russian market, use other drugs of losartan potassium available in the Russian market at a dosage of 12.5 mg). Typically, the dose is titrated at a weekly interval (ie, 12.5 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, up to a maximum (only for this indication) 150 mg once daily) depending on the individual portability.

Side effects:The frequency of adverse events (AEs) indicated below is given in accordance with the following classification: very frequent (≥ 10%); frequent (≥ 1% and <10%); infrequent (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%); the frequency is unknown: it is not possible to estimate the frequency based on the available data.
In general, the drug Cosaar is well tolerated by patients with AH. NEAs are light and transitory in nature and do not require withdrawal of the drug. The total frequency of AEs when taking Kozaar is comparable to this indicator when taking placebo. In controlled clinical trials, the frequency of cancellation due to clinically significant AE was 2.3% in the group of patients taking Cozaar and 3.7% in the placebo group.
The following AEs were observed in controlled clinical trials of the drug in patients with AH.
Disturbances from the nervous system
Frequent: dizziness.
Infrequent: drowsiness, headache, sleep disturbances.
Hearing disorders and labyrinthine disordersFrequent: systemic dizziness (vertigo).
Heart Disease
Infrequent: a feeling of heartbeat, angina.
Vascular disorders
Infrequent: (orthostatic) hypotension (including dose-mediated orthostatic effects) (especially in patients with reduced circulating blood volume (BCC), for example, in patients with severe heart failure or patients receiving treatment with high doses of diuretics).
Disorders from the gastrointestinal tract
Infrequent: pain in the abdomen, constipation.
Disturbances from the skin and subcutaneous tissues
Infrequent: skin rash.
General disorders
Infrequent: weakness, fatigue, swelling.
Laboratory and instrumental data
Frequent: hyperkalemia.
Rare: increased activity of alanine aminotransferase (ALT) (usually returned to normal after the abolition of therapy).
Controlled clinical studies have shown that the Cosaar preparation is generally well tolerated by patients with AH andhypertrophy of the left ventricle. The following AEs were observed in these studies.
Disturbances from the nervous system
Frequent: dizziness.
Hearing disorders and labyrinthine disordersFrequent: systemic dizziness (vertigo).
General disorders
Infrequent: weakness, increased fatigue.
In the LIFE study, in patients without diabetes mellitus, the incidence of new cases of diabetes mellitus was lower with Coxaar compared with atenolol (p <0.001). Since there was no placebo group in this study, it is not known whether this is a positive effect of Cozaar or an undesirable phenomenon of atenolol.
Controlled clinical studies have shown that the drug Cosaar is generally well tolerated by patients with type 2 diabetes and proteinuria. The following AEs were observed in these studies.
Disturbances from the nervous system
Frequent: dizziness.
Vascular disorders
Frequent: (orthostatic) hypotension (including dose-mediated orthostatic effects) (especially in patients with reduced circulating blood volume (BCC), for example, in patients with severe heart failure or patients,receiving treatment with high doses of diuretics).
General disorders
Infrequent: weakness, increased fatigue.
Laboratory and instrumental data
Frequent: hyperkalaemia (in a clinical study involving patients with type 2 diabetes mellitus and nephropathy, hyperkalemia (> 5.5 mmol / L) was observed in 9.9% of patients taking Cozaar and 3.4% of patients taking placebo) , hypoglycemia.
Controlled clinical studies have shown that the Cosaar preparation is generally well tolerated by patients with CHF. AEs observed in clinical trials were characteristic of this group of patients.
Violations of the blood and lymphatic system
Frequent: anemia.
Disturbances from the nervous system
Frequent: dizziness.
Infrequent: headache.
Rare: paresthesia.
Heart Disease
Rare: fainting, atrial fibrillation, impaired cerebral circulation.
Vascular disorders
Frequent: (orthostatic) hypotension (including dose-mediated orthostatic effects) (especially in patients with reduced circulating blood volume (BCC), for example, in patients with severe heart failure or patients receiving treatment with high doses of diuretics).
Disturbances from the respiratory system, chest and mediastinal organs
Infrequent: shortness of breath, cough.
Disorders from the gastrointestinal tract
Infrequent: diarrhea, nausea, vomiting.
Disturbances from the skin and subcutaneous tissues
Infrequent: urticaria, skin itch, skin rash.
Disorders from the kidneys and urinary tract
Frequent: renal dysfunction, kidney failure.
General disorders
Infrequent: weakness, increased fatigue.
Laboratory and instrumental data
Frequent: an increase in the concentration of creatinine, urea and potassium in the blood.
Infrequent: hyperkalemia (often in patients taking losartan in a dose of 150 mg per day than in patients taking losartan in a dose of 50 mg per day).
The following AEs were observed in clinical practice during the post-marketing period:
Violations of the blood and lymphatic system
The frequency is unknown: anemia, thrombocytopenia.
Immune system disorders
Rare: hypersensitivity reactions, anaphylactic reactions, angioedema (including angioedema of the larynx, pharynx, face, lips,pharynx and / or tongue (causing airway obstruction); some of these patients had a history of anginaevretric edema with other medications, including ACE inhibitors), vasculitis (including purple Shenlen-Genocha).
Disorders of the psyche
The frequency is unknown: depression.
Disturbances from the nervous system
The frequency is unknown: migraine, dysgeusia.
Hearing disorders and labyrinthine disordersThe frequency is unknown: tinnitus.
Disturbances from the respiratory system, chest and mediastinal organs
The frequency is unknown: cough.
Disorders from the digestive system
The frequency is unknown: diarrhea, pancreatitis.
Disturbances from the liver and bile ducts
Rare: hepatitis.
The frequency is unknown: hepatic dysfunction.
Disorders from the rut and subcutaneous tissues
The frequency is unknown: urticaria, skin itching, rash, photosensitivity.
Disturbances from musculoskeletal and connective tissue
The frequency is unknown: myalgia, arthralgia, rhabdomyolysis.
Violations of the genitals and mammary glandThe frequency is unknown: erectile dysfunction / impotence.
General disorders
Frequency unknown: general malaise.
Laboratory and instrumental data
Frequency unknown: hyponatremia.

Overdose:Information on overdose is limited. The most likely manifestation of an overdose is a marked decrease in blood pressure and tachycardia; Bradycardia can occur due to parasympathetic (vagal) stimulation. In the case of symptomatic arterial hypotension, maintenance therapy is indicated.
Treatment: symptomatic therapy.
Lozartan and its active metabolite are not excreted by hemodialysis.

Interaction:In clinical studies on pharmacokinetic interactions of drugs, clinically significant interactions of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine, and phenobarbital have not been identified. Rifampicin, being an inducer of the metabolism of drugs, reduces the concentration of the active metabolite of losartan in the blood. In clinical studies, the use of two inhibitors of the isoenzyme P450-O4: ketoconazole and erythromycin was studied. Ketoconazole did not affect the metabolism of losartan to the active metabolite after intravenous administration of losartan. Erythromycin did not have a clinically significant effect when taking losartan inside. Fluconazole, the inhibitor of the isoenzyme P450 2C9, decreases the concentration of the active metabolite of losartan, however the pharmacodynamic significance of simultaneous application of losartan and inhibitors of the isoenzyme P450 2C9 has not been studied. It was shown that in patients not metabolizing losartan in the active metabolite, there is a very rare and specific defect in the isoenzyme P450 2C9. These data suggest that the metabolism of losartan to the active metabolite is carried out by the P450 2C9 isoenzyme, rather than the P450 isoenzyme ZA4.
The simultaneous use of losartan, as well as other drugs blocking angiotensin II or its effects, with potassium-sparing diuretics (eg spironolactone, eplerenone, triamterene, amiloride), potassium supplements or potassium salts can lead to an increase in potassium in the serum.
As with the use of other drugs that affect the excretion of sodium, losartan can reduce the excretion of lithium, so when lithium and ARA II are used simultaneously, the concentration of lithium in serum should be monitored carefully.
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2), can reduce the effect of diuretics and other antihypertensive agents. As a result, the antihypertensive effect of APA II or ACE inhibitors may be weakened when used simultaneously with NSAIDs, including selective COX-2 inhibitors.
In some patients with impaired renal function (eg, in elderly patients or patients with dehydration, including those taking diuretics) receiving NSAID therapy, including selective COX-2 inhibitors, concomitant use of ARA II or ACE inhibitors may cause further impairment of function kidney, including the development of acute renal failure. These effects are usually reversible, so the simultaneous use of these medicines should be done with caution in patients with impaired renal function.
Double blockade of RAAS with application of ARA II,ACE inhibitors or aliskiren (renin inhibitor) is associated with an increased risk of developing arterial hypotension, syncope, hyperkalemia and renal dysfunction (including acute renal failure) compared with monotherapy. Regular monitoring of blood pressure, kidney function and electrolyte content in the blood should be performed in patients taking both COSAAR and other drugs that affect RAAS. Cosaar preparation should not be used concomitantly with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and / or renal dysfunction (GFR less than 60 ml / min / 1.73 m²).

Special instructions:Hypersensitivity reactions
Patients with an angioneurotic edema in the anamnesis (edema of the face, lips, pharynx / larynx and / or tongue) need control of the drug (see ADVERSE EFFECTS).
Embryotoxicity
The use of drugs that affect RAAS in the second and third trimester of pregnancy reduces the function of the kidneys of the fetus and increases the incidence and mortality of the fetus and newborns. The development of oligohydramnion can be associated with fetal lung hypoplasia and skeletal deformities.Possible adverse events in newborns include hypoplasia of the skull bones, anuria, arterial hypotension, renal failure and death. When diagnosing pregnancy, the Cosaar preparation should be immediately canceled (see PREGNANCY APPLICATION AND PERIOD OF BREASTFEEDING).
Arterial hypotension and disturbance of water-electrolyte balance or decrease in the volume of circulating blood
In patients with reduced BCC (eg, receiving treatment with large doses of diuretics) symptomatic arterial hypotension may occur. Correction of such conditions should be done prior to the appointment of Cosaar or to start treatment with a lower dose of Cosaar (see DOSAGE AND ADMINISTRATION). Violation of the water-electrolyte balance is characteristic of patients with impaired renal function with diabetes mellitus or without diabetes mellitus, therefore careful monitoring of these patients is necessary. In clinical trials involving patients with type 2 diabetes mellitus with proteinuria, the incidence of hyperkalemia was greater in the group taking the Cosaar drug than in the placebo group.Several patients discontinued therapy due to hyperkalemia (see SIDE EFFECTS, Laboratory indicators).
During treatment with the drug Kozaar, it is not recommended to take potassium-sparing diuretics, potassium preparations or potassium-containing substitutes for edible salt.
Aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy
Like all drugs that have a vasodilating effect, ARA II should be administered with caution to patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.
Ischemic heart disease and cerebrovascular disease
As with all drugs possessing vasodilating action, ARA II must be administered with caution to patients with coronary artery disease or cerebrovascular disease, because an excessive fall in blood pressure in this group of patients can lead to myocardial infarction or stroke.
Chronic heart failure
As with the use of other drugs that have an effect on RAAS, in patients with CHF and with or without renal dysfunction, there is a risk of developing severe arterial hypotension or acute renal dysfunction.
Since there is a lack of experience in using Kozaar in patients with heart failure and concomitant severe renal impairment, patients with severe heart failure (NYHA functional class IV), as well as patients with heart failure and symptomatic life-threatening arrhythmias, Cosaar should be administered with caution to patients in these groups.
Primary hyperaldosteronism
Since in patients with primary hyperaldosteronism, as a rule, there is no positive response to therapy with antihypertensive drugs that act by inhibiting RAAS, the use of Cozaar is not recommended in this group of patients.
Impaired liver function
The data of pharmacokinetic studies indicate that the concentration of losartan in the blood plasma in patients with cirrhosis of the liver is significantly increased, so patients with a history of liver dysfunction should be prescribed a drug Kozaar in a lower dose. There is no experience of using Kozaar in patients with severe impairment of liver function,therefore the drug should not be used in this group of patients (see PHARMACOLOGICAL PROPERTIES, Pharmacokinetics, CONTRAINDICATIONS, METHOD OF APPLICATION AND DOSES). Impaired renal function
Due to inhibition of RAAS in some predisposed patients, renal function changes, including renal failure, were observed. These changes in renal function may return to normal after discontinuation of treatment.
Some drugs that affect RAAS can increase the concentration of urea in the blood and serum creatinine in patients with bilateral stenosis of the renal arteries or stenosis of the renal artery of a single kidney. It was reported about the occurrence of similar effects with the drug Kozaar. Similar violations of kidney function can be reversible after the abolition of therapy. Losartan should be used with caution in patients with bilateral stenosis of the renal arteries or stenosis of the renal artery of a single kidney.
Special patient groups
Race
Analysis of the data of the entire population of patients included in the LIFE study on the effect of losartan on reducing the frequency of development of the main composite evaluation criterionstudies in patients with hypertrophy and left ventricular hypertrophy (n = 9193) showed that the ability of losartan compared to atenolol to reduce the risk of stroke and myocardial infarction, as well as to reduce the rate of cardiovascular mortality in patients with AH and left ventricular hypertrophy (at 13, 0%, p = 0.021) does not apply to patients of the Negroid race, although both regimens effectively reduced blood pressure in these patients. In this study, the Cosaar drug compared with atenolol reduced the incidence of cardiovascular morbidity and mortality in patients with AH and left ventricular hypertrophy of all races except Negroid (n = 8660, p = 0.003). However, in this study, patients of the Negroid race who received atenolol, had a lower risk of developing the main composite test evaluation criterion (ie, a lower combined rate of cardiovascular mortality, stroke, and myocardial infarction) compared to patients of the same race who took losartan (p = 0.03).
Children and teens
The effectiveness and safety of the use of the drug Kozaar in children and adolescents under 18 years of age have not been established.
If newborns, whose mothers took the drug Kozaar during pregnancy, develop oliguria or hypotension, it is necessary to carry out symptomatic therapy aimed at maintaining blood pressure and renal perfusion. You may need a blood transfusion or dialysis to prevent the development of arterial hypotension and / or maintain kidney function.
Elderly patients
Clinical studies have not revealed any specificities regarding the safety and effectiveness of losartan in elderly patients (over 65 years of age).

Effect on the ability to drive transp. cf. and fur:There have been no studies to assess the impact on ability to drive vehicles and work with mechanisms, but care must be taken when applying antihypertensive therapy and driving or working with mechanisms, since dizziness and drowsiness may develop especially at the beginning of therapy or with increasing doses.

Form release / dosage:Film-coated tablets 50 mg.

Packaging:For 14 tablets in PVC / Al blister.For 1 or 2 blisters are placed in a cardboard box together with instructions for use.

Storage conditions:In the dark place at a temperature of no higher than 25 ° C.
Keep out of the reach of children.

Shelf life:3 years.
Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N013242 / 01

Date of registration:24.12.2007 / 28.01.2015

Expiration Date:Unlimited

The owner of the registration certificate:Merck Sharp and Doum B.V.Merck Sharp and Doum B.V. Netherlands

Manufacturer: & nbsp

MERCK SHARP & DOHME, Ltd. United Kingdom

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp2016-11-02

Illustrated instructions

Instructions

Cosaar (Cozaar)