Lozartan N - instructions for use, doses, side effects, contraindications

Excipients: lactose monohydrate (sugar milk) - 64.25 mg, microcrystalline cellulose - 47.50 mg, sodium carboxymethyl starch - 9.50 mg, povidone-K25 - 3.80 mg, silicon dioxide colloid -0.95 mg, magnesium stearate-1 , 50 mg.

Shell composition: hypromellose - 2.90 mg, macrogol-4000 - 0.70 mg, titanium dioxide - 1.33 mg, iron-oxide oxide yellow - 0.07 mg.

Dosage 12.5 mg + 100 mg

Active substance: hydrochlorothiazide - 12.50 mg, potassium losartan - 100.00 mg.

Excipients: lactose monohydrate (milk sugar) 141.00 mg, microcrystalline cellulose 95.00 mg, sodium carboxymethyl starch 19.00 mg, povidone-K25 7.60 mg, silicon colloidal dioxide 1.90 mg, magnesium stearate 3 , 00 mg.

Shell composition: hypromellose - 5.80 mg, macrogol-4000 - 1.40 mg, titanium dioxide - 2.66 mg, ferric oxide yellow oxide - 0.14 mg.

Dosage of 25 mg + 100 mg

Active substance: hydrochlorothiazide -25,00 mg, potassium losartan - 100,00 mg.

Excipients: lactose monohydrate (sugar milk) - 128.50 mg, microcrystalline cellulose - 95.00 mg, sodium carboxymethyl starch - 19.00 mg, povidone-K25 - 7.60 mg, silicon dioxide colloid - 1.90 mg, magnesium stearate - 3 , 00 mg.

Shell composition: hypromellose - 5.80 mg, macrogol-4000 - 1.40 mg, titanium dioxide - 2.66 mg, ferric oxide yellow oxide - 0.14 mg.

Description:

Round biconvex tablets covered with a film coat of light yellow or light yellow with a beige shade of color. On the cross section of the tablet, two layers are visible: the nucleus is almost white and the film membrane.

Dosage of 25 mg + 100 mg with a risk on one side.

Pharmacotherapeutic group:A combined hypotensive drug (angiotensin II receptor antagonist + diuretic)

ATX: & nbsp

C.09.D.A.01 Losartan in combination with diuretics

Pharmacodynamics:

Mechanism of action

Combined antihypertensive drug with fixed doses of active components.

The active substances of the combination hydrochlorothiazide / losartan have an additive antihypertensive effect, reducing blood pressure (BP) more than each of the components individually. Due to the diuretic effect hydrochlorothiazide increases the activity of renin of blood plasma (ARP), stimulates the secretion of aldosterone, increases the concentration of angiotensin II and reduces the potassium content in the blood serum. The administration of losartan blocks all the physiological effects of angiotensin II and, as a result of suppression of aldosterone, contributes to a decrease in potassium loss caused by the intake of a diuretic.

Losartan has a moderate and transient uricosuric effect. Hydrochlorothiazide causes a slight increase in the level of uric acid in the blood; The combination of losartan and hydrochlorothiazide helps reduce the severity of hyperuricemia caused by a diuretic.

Losartan

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. Angiotensin II binds to AT₁receptors found in many tissues (for example, in 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 proliferation of smooth muscle cells. The role of the second type of angiotensin II receptor in the cardiovascular homeostasis of AT₂subtype is unknown.

Losartan is a selective antagonist of AT₁ - receptors of angiotensin II, is effective at ingestion. 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 the source or route of synthesis.Unlike some peptide angiotensin II antagonists, losartan does not have the effects of an agonist. Losartan selectively binds to AT₁-receptors do 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 the angiotensin-converting enzyme (ACE, kinase II), which contributes to the degradation of bradykinin. Consequently, effects that are not directly related to AT blockade₁- receptors, in particular, the enhancement of effects associated with exposure to bradykinin or the development of edema (losartan 1.7%, placebo 1.9%), are not related to the action of losartan.

Hydrochlorothiazide

The mechanism of antihypertensive action of thiazide diuretics is unknown. Thiazides have no effect on normal blood pressure. Hydrochlorothiazide is a diuretic and antihypertensive agent. It affects the reabsorption of electrolytes in the distal tubules of the kidneys. Hydrochlorothiazide approximately equally increases the excretion of sodium and chlorine. Sodium-sulfur may be accompanied by a small loss of potassium ions, bicarbonate.

When administered, the diuretic effect begins after 2 hours, reaches a maximum on average 4 hours and lasts from 6 to 12 hours.

Pharmacodynamics

Losartan H is a combination of losartan and hydrochlorothiazide. In patients with hypertension and left ventricular hypertrophy losartan, often in combination with hydrochlorothiazide, reduces the risk of cardiovascular morbidity and mortality, as evidenced by an estimate of the combined incidence of stroke and myocardial infarction in this group of patients, as well as the cardiovascular mortality.

Losartan

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). The growth of ARP is accompanied by an increase in the level of angiotensin II in blood plasma. With prolonged (6-week) treatment of patients with arterial hypertension losartan at a dose of 100 mg / day, at the time of reaching the maximum concentration in the blood plasma, there was a 2-3-fold increase in the level of angiotensin II in blood plasma. In some patients, there was an even greater increase, especially with a short duration of treatment (2 weeks).However, antihypertensive activity and a decrease in plasma aldosterone concentration were manifested at 2 and 6 weeks of therapy, which indicates an effective blockade of angiotensin II receptors. ARP and angiotensin II level were reduced to the initial values observed before the start of the drug, 3 days after the withdrawal of losartan. The effect of the drug on ARP and the level of angiotensin II was comparable to that with 50 mg 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 20 mg and 100 mg of losartan with the effects of an ACE inhibitor on the response to angiotensin I, angiotensin II, and bradykinin showed that losartan blocks the effects of angiotensin I and angiotensin II, without affecting the effects of bradykinin. These results correspond to data on the specificity of the mechanism of action of losartan. In contrast, the ACE inhibitor blocked the reaction to angiotensin I and increased the response to 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, both of which contribute to the antihypertensive effect. In a clinical study with a single dose of 100 mg of losartan potassium, which included healthy volunteers (men), the administration of the drug in high and low-fat diets did not affect the glomerular filtration rate (GFR), the effective renal plasma flow and the filtration fraction. Losartan has a natriuretic effect, which 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 arterial hypertension, proteinuria (> 2g / 24 hours), without diabetes mellitus and taking for 8 weeks losartan in 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 IgG also significantly decreased. In these patients losartan stabilized GFR and reduced the filtration fraction.

In postmenopausal women with hypertension, who took losartan in a dose of 50 mg / day 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 level of norepinephrine in the blood plasma. In patients with hypertension 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 (HDL). In the same doses losartan did not affect the concentration of glucose in the blood on an empty stomach.

Generally, losartan caused a decrease in serum uric acid concentration (usually less than 0.4 mg / dL), which persisted during prolonged therapy. In controlled clinical trials involving hypertensive patients, there were no reported cases of drug withdrawal due to an increase in serum creatinine or serum potassium.In a 12-week, parallel study in which patients with left ventricular insufficiency II-IV functional class according to NYHA classification were included and most of them received diuretics and / or cardiac glycosides, the effects of losartan at doses of 2.5, 10, 25 and 50 mg in day with placebo. At doses of 25 mg and 50 mg per day, the drug had positive hemodynamic and neurohormonal effects that were observed throughout the study. Hemodynamic effects included an increase in the cardiac index and a decrease in the wedge pressure in the pulmonary capillaries, as well as a decrease in systemic vascular resistance, mean systemic arterial pressure, and heart rate (HR). The incidence of arterial hypotension in these patients depended on the dose of the drug. Neurohormonal effects included a decrease in aldosterone and norepinephrine in the blood.

Pharmacokinetics:

Suction

Losartan

Ingestion losartan It is well absorbed and metabolized while "primary pass" through the liver, resulting in formation of the active carboxylated metabolite and inactive metabolites.Systemic bioavailability of losartan is approximately 33%. Mean maximum concentrations (C_m_Oh) of losartan and its active metabolite are reached after 1 hour and after 3-4 hours, respectively. When losartan was taken during a meal, there was no clinically significant effect on the concentration profile of losartan in the blood plasma; Hydrochlorothiazide

After oral intake of hydrochlorothiazide is 60-80%. FROM_m_Ohhydrochlorothiazide is achieved 1-5 hours after ingestion.

Distribution

Losartan

Lozartan and its active metabolite bind to plasma proteins (mainly albumin) by more than 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.

Hydrochlorothiazide

Communication with plasma proteins is 64%; penetrates through the placental (but not blood-brain barrier) and is excreted in breast milk.

Metabolism

Losartan

Approximately 14% of the dose of losartan administered intravenously orally is metabolized to form an active metabolite. After ingestion and / or intravenous administration of losartan, labeled ¹⁴C, the circulating radioactivity of blood plasma was mainly determined by losartan and its active metabolite. In addition to the active metabolite, inactive metabolites are formed, including the two main metabolites formed as a result of the hydroxylation of the butyl group of the chain, and one non-basic metabolite, N-2-tetrazole-glucuronide.

Taking the drug at the same time as eating does not have a clinically significant effect on its serum concentrations.

Hydrochlorothiazide not metabolized.

Excretion

Losartan

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. After oral administration, about 4% of the dose taken is excreted unchanged by the kidneys and about 6 % - in the form of an active metabolite. The pharmacokinetic parameters of losartan and its active metabolite when taken orally (in doses up to 200 mg) are linear. The half-life (T1 / 2) of losartan and the active metabolite in the terminal phase of losartan and the active metabolite is 2 hours and 6-9 hours, respectively.

Cumulation of losartan and its active metabolite when administered at a dose of 100 mg once a day is not. Excreted mainly through the intestines with bile - 58%, kidneys - 35%.

Hydrochlorothiazide

Hydrochlorothiazide is rapidly excreted through the kidneys. T1 / 2 is 5.6 - 14.8 hours. At least 61% of the ingested dose is excreted unchanged for 24 hours.

Pharmacokinetics in specific patient groups

Elderly patients

Losartan - hydrochlorothiazide

The concentration of losartan and its active metabolite in blood plasma and the rate absorption of hydrochlorothiazide in elderly patients with hypertension do not significantly differ from these indices in young patients with arterial hypertension.

Floor

Concentrations of losartan in blood plasma were 2 times higher in women with arterial hypertension compared with men with arterial hypertension. The concentrations of active metabolite in men and women did not differ. This is an explicit pharmacokinetic difference, has no clinical significance.

Dysfunction of the liver and kidneys

When administered to patients with mild and moderate alcoholic cirrhosis of the liver, concentrations of losartan and its active metabolite in the blood plasma were, accordingly, in 5 - 1,7 times more, than at young volunteers of a male.Concentrations of losartan in the blood plasma in patients with creatinine clearance (CC) above 10 ml / min. did not differ from those in patients with normal renal function. When comparing the area under the concentration curve (AUC) in patients with normal renal function, the corticosteroids of losartan in hemodialysis patients were approximately 2-fold greater. Plasma concentrations of the active metabolite do not change in patients with impaired renal function or patients on hemodialysis. Losartan and its active metabolite can not be removed by hemodialysis.

Indications:

- Treatment of hypertension in patients who are advisable the appointment of combination therapy.

- Reducing the 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.

Contraindications:

- Hypersensitivity to any of the components of the drug.

- Hypersensitivity to other drugs that are derivatives of sulfonylamides.

- Anuria.

- Severe renal dysfunction (CK ≤ 30 mL / min.).

- Severe violations of liver function, cholestasis and obstructive diseases of the biliary tract.

- Simultaneous use with aliskiren and preparations containing aliskiren, in patients with diabetes mellitus and / or moderate or severe renal dysfunction (glomerular filtration rate (GFR) less than 60 l / ml / min / 1.73 m² surface area of the body).

- Simultaneous use with angiotensin-converting enzyme inhibitors in patients with diabetic nephropathy.

- Women of reproductive age who plan pregnancy.

- Age to 18 years (efficiency and safety not established)

- Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome (lactose is included in the formulation).

Carefully:

Violations of the water-electrolyte balance of blood, for example, against diarrhea or vomiting (hyponatremia, hypochloraemic alkalosis, hypomagnesemia, hypokalemia); renal failure (CK 30-50 ml / min.); hepatic failure (less than 9 on the Child-Pugh scale); bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney; condition afterkidney transplantation (no experience of application); cardiac ischemia; heart failure with life-threatening arrhythmias; cerebrovascular diseases; aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy; primary hyperaldosteronism, diabetes mellitus, hypercalcemia; allergic anamnesis and bronchial asthma; systemic connective tissue diseases (including systemic lupus erythematosus); hypovolemia (including the use of high doses of diuretics); as well as, at the same time administration with non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 inhibitors (COX-2); acute attack of myopia and secondary closed angle glaucoma; angioedema in history; chronic heart failure IV functional class by classification NYHA; the use of Negroid race in patients; symptomatic hyperuricemia and gout.

Pregnancy and lactation:

Medicines that directly affect RAAS can cause serious damage and death of the developing fetus, so when diagnosing a pregnancy, Lozartan H should be immediately withdrawn.Despite the lack of data on the use of Lozartan H in pregnant women, animal studies have demonstrated that the use of losartan leads to the development of serious embryonic and neonatal lesions and fetal and progenital death. It is believed that the mechanism of these phenomena is due to the impact on the RAAS. In a human fetus, renal perfusion, which depends on the development of RAAS, begins in the second trimester; Thus, the risk of disrupting the development and death of the fetus increases with the use of the drug Losartan H during the second or third trimesters of pregnancy.

The use of drugs that have a direct effect on 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 deformity. Possible adverse events in newborns include hypoplasia of the skull bones, anuria, arterial hypotension, renal insufficiency and lethal outcome.

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. Periodic ultrasound study to assess intra-amniotic space. If oligohydramnion is detected, stop taking Lozartan N, unless it is vital to 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. Careful observation of newborns whose mothers took Lozartan H during pregnancy to control arterial hypotension, oliguria and hyperkalemia is necessary.

Thiazides penetrate the placental barrier and are detected in the blood of the umbilical cord. Routine use of diuretics in healthy pregnant women is not recommended, since it puts the mother and the fetus of unnecessary danger, namely the development of embryonic jaundice and jaundice of newborns, thrombocytopenia and other unwanted reactions that have been observed in adult patients. Diuretics do not prevent the development of toxicosis of pregnant women, and there is no reliable evidence that they are effective in treating toxicosis of pregnant women.

There is no evidence that losartan excreted in breast milk. It is known that thiazides are excreted in breast milk.

In connection with the risk of developing adverse events in infants, in all cases, a balanced decision should be made about taking the drug during the period of breastfeeding, taking into account the importance of therapy for the mother.

In the event that it is decided that you need to take the drug Lozartan H during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Losartan H can be taken irrespective of the time of food intake, washed down with enough water, once a day.

Losartan N may be administered in combination with other antihypertensive agents.

Arterial hypertension

The combination of hydrochlorothiazide / losartan is indicated in patients who do not have adequate blood pressure control when using hydrochlorothiazide or losartan in monotherapy. Usually the initial and maintenance doses of the drug are 1 Lozartan H tablet once a day. In patients without a proper therapeutic response to taking 1 tablet of Losartan H (50 mg of losartan / 12.5 mg of hydrochlorothiazide) for 2-4 weeks, the dose of the drug may be increased to 2 tablets Losartan H 50 / 12.5 mg 1 time per day. The maximum dose is 2 tablets Losartan H 50 / 12.5 mg once a day. Typically, the antihypertensive effect is achieved within 3 weeks after the initiation of therapy.

Reducing the 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

Typically, the initial dose of losartan is 50 mg once daily. Patients who fail to achieve target BP levels when taking losartan 50 mg / day,the choice of therapy is required by the combination of losartan with low doses of hydrochlorothiazide (12.5 mg) and, if necessary, it is necessary to increase the dose of losartan to 100 mg in combination with hydrochlorothiazide at a dose of 12.5 mg / day, then increase the dose to 2 tablets Losartan H 50 mg / 12.5 mg (total 100 mg of losartan and 25 mg of hydrochlorothiazide per day once).

Use in patients with impaired renal function or in patients on hemodialysis

It is not necessary to select an initial dose of the drug for patients with impaired renal function of moderate severity (KK 30-50 ml / min). The drug Losartan N is not recommended for patients on hemodialysis. Lozartan H should not be used in patients with severe renal dysfunction (CC less than 30 ml / min) (see "Contraindications").

Use in patients with reduced circulating blood volume (BCC)

Before starting therapy with Lozartan H, it is necessary to restore BCC and / or sodium content in the blood.

Use in patients with impaired hepatic function

The drug Losartan N is contraindicated in patients with severe impairment of liver function (see.section "Contraindications.")

Application in elderly patients

Selection of an initial dose of Lozartan H for elderly patients is not required.

Side effects:

The frequency of side effects is classified according to the recommendations of the World Health Organization: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1/10000, <1/1000), very rarely (<1/10000, including individual messages), the frequency is unknown (the incidence rate can not be estimated from the available data).

In clinical studies with losartan / hydrochlorothiazide, no adverse events specific to this combination drug have been observed. Undesirable effects were limited to those reported earlier when using losartan and hydrochlorothiazide in monotherapy.

In the post-marketing application of losartan / hydrochlorothiazide, the following adverse events were observed:

From the digestive system: rarely - hepatitis.

Laboratory indicators: rarely - hyperkalemia, increased activity of "liver" transaminases.

The following adverse events were observed with the use of losartan and hydrochlorothiazide in monotherapy.

Losartan

From the side of the blood and lymphatic system: infrequently - anemia, purpura Shenlaine-Henoch, ecchymosis, hemolytic anemia; frequency unknown - thrombocytopenia. Allergic reactions: rarely anaphylactic reactions, angioedema, including laryngeal and pharyngeal edema, causing airway obstruction, and / or edema of the face, lips, pharynx and / or tongue; in some patients angioedema has also been noted in the history of treatment with other drugs, including ACE inhibitors; hives.

From the central nervous system: often - headache, dizziness, insomnia; infrequent anxiety, paresthesia, peripheral neuropathy, tremor, migraine, fainting, anxiety, anxiety disorder (excessive, uncontrollable and often irrational anxiety about everyday events), panic disorder, confusion, depression, drowsiness, sleep disorders, memory impairment.

From the side of the organ of vision: infrequent - a breach of vision, a feeling of dryness and burning / feeling tingling in the eyes, conjunctivitis, reduced visual acuity.

From the side of the hearing organ and labyrinthine disorders: infrequently - vertigo, noise in the ears.

From the respiratory system: often - nasal congestion, cough, upper respiratory tract infections (fever, sore throat, sinusopathy, sinusitis, pharyngitis); infrequently - pharyngitis, laryngitis, dyspnoea, bronchitis, rhinitis, epistaxis, discomfort in the pharyngeal region, congestion in the respiratory tract.

From the digestive system: often - nausea, diarrhea, dyspeptic phenomena, abdominal pain; infrequent - dryness of the oral mucosa, toothache, vomiting, flatulence, gastritis, constipation, intestinal obstruction; frequency unknown - pancreatitis, impaired liver function.

From the side of the musculoskeletal system: often - muscle cramps, myalgia, back pain, in the legs; infrequently - arthralgia, pain in the hands, in the shoulder, knee, arthritis, fibromyalgia, stiffness, muscle weakness, swelling of the joints, musculoskeletal pain; frequency is unknown - rhabdomyolysis.

From the side of the cardiovascular system: infrequent - marked decrease in blood pressure, orthostatic hypotension (dose-dependent), palpitation, arrhythmia (atrial fibrillation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation), angina pectoris,pain in the chest, cerebral circulation, atrioventricular blockade of degree II, cerebrovascular events, myocardial infarction (with excessive lowering of blood pressure), vasculitis.

From the genitourinary system: often - renal dysfunction, kidney failure; infrequently, nocturia. frequent urination, urinary tract infections, weakening of libido, impotence.

From the skin: infrequent - dry skin, erythema, "tides" of blood to the skin of the face, photosensitivity, itching, rash, increased sweating, alopecia, dermatitis.

Other: often - asthenia, fatigue, anorexia; infrequently - swelling of the face, swelling, fever; frequency is unknown - flu-like symptoms, malaise.

Laboratory indicators: often - hyperkalemia, decreased hematocrit and hemoglobin, hypoglycemia; infrequently - increased concentrations of urea and creatinine; very rarely - increased activity of "liver" transaminases.

Hydrochlorothiazide

From the side of the blood and lymphatic system: infrequently - agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, purpura, thrombocytopenia.

Allergic reactions: rarely anaphylactic reactions; very rarely - urticaria, Stevens-Johnson syndrome, erythema multiforme, erythema, reversible pemphigoid reactions, exfoliative dermatitis, allergic alveolitis, eosinophilic pneumonia, angioedema, larynx, pharynx, tongue, face, lips, mucous membranes (including fatal) .

Disorders from the metabolism and nutrition: infrequently, loss of appetite, hyperglycemia, hyperuricemia, water-electrolyte balance disorders (in particular hypokalemia and hyponatremia, hypomagnesemia and hypochloraemia, and hypercalcemia). Treatment with thiazides can reduce glucose tolerance, and latent diabetes mellitus can manifest; very rarely - metabolic alkalosis.

From the nervous system: often - headache; infrequently - insomnia, dizziness.

From the side of the organ of vision: rarely - reduced tear fluid production, impaired vision; very rarely - conjunctivitis; frequency unknown - acute myopia, acute angle-closure glaucoma.

From the cardiovascular system: infrequently - necrotizing angiitis (vasculitis, cutaneous vasculitis).

On the part of the respiratory system: infrequently - respiratory distress syndrome, including pneumonitis and non-cardiogenic pulmonary edema.

From the digestive system: infrequently - sialodenitis, irritation of the mucous membrane of the gastrointestinal tract, nausea, vomiting, diarrhea, constipation, jaundice (intrahepatic cholestasis), pancreatitis.

From the skin and subcutaneous tissue: infrequently - photosensitization, urticaria, toxic epidermal necrolysis, lupus-like syndrome.

From the musculoskeletal system: infrequently - muscle cramps.

From the urinary system: infrequently - glucosuria, interstitial nephritis, impaired renal function, renal failure.

Common violations: infrequent - an increase in body temperature.

Overdose:

Symptoms: losartan - marked decrease in blood pressure, tachycardia, bradycardia (as a result of vagal stimulation).

Hydrochlorothiazide - loss of electrolytes (hypokalemia, hypochloraemia, hyponatremia); dehydration (excess diuresis).

Treatment: symptomatic and supportive therapy. If the drug is taken recently, the stomach should be washed; if necessary, correct the water-electrolyte disturbances. Losartan and its active metabolite are not removed by hemodialysis. It is not established to what extent hydrochlorothiazide can be removed from the body by hemodialysis.

Interaction:

Losartan

In clinical studies of pharmacokinetics, there were no clinically significant interactions with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin. Rifampicin reduces the concentration of the active metabolite. The clinical significance of this interaction is not established.

Simultaneous application with aliskiren and preparations containing aliskiren, in patients with diabetes mellitus and / or moderate or severe renal dysfunction (GFR less than 60 mL / min / 1.73 m² surface area of the body) is contraindicated.

Fluconazole and rifampicin decreased plasma concentrations of the active metabolite of losartan. The clinical significance of this interaction has not been studied.

The simultaneous use of losartan, as well as other agents that affect RAAS, with potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), Potassium-containing additives or potassium salts can lead to an increase in the potassium content in the blood serum. Simultaneous use is not recommended.

As with the use of other agents that affect the excretion of lithium, treatment with losartan may be accompanied by a decrease in excretion and an increase in serum lithium concentration, so when treating with lithium preparations simultaneously, its serum concentration should be monitored.

With simultaneous use of the angiotensin II receptor antagonists (ARA II) with NSAIDs, including selective inhibitors of COX-2 and acetylsalicylic acid at doses greater than 3 grams per day can reduce the effect of antihypertensive agents. Therefore, the antihypertensive effect of ARA II may be attenuated NSAIDs, including COX-2 inhibitors, and aspirin in a dose of 3 g per day.

In some patients with impaired renal function receiving NSAID therapy, including COX-2 inhibitors, treatment ARA II can cause a further deterioration of renal function, including the development of acute renal failure, and an increase in the potassium content (especially in patients with existing renal dysfunction history ). At the same time, it should be used with NSAIDs with caution, especially in elderly patients. At the same time, it is necessary to adequately fill the BCC and periodically monitor the kidney function from the start of therapy and in the future.In some patients with impaired renal function using NSAIDs, including selective COX-2 inhibitors, the simultaneous use of APA II can cause further impairment of renal function.

Double blockade of RAAS: a double blockade of the RAAS; the addition of an ACE inhibitor to ARAP therapy is only possible in selected cases under close monitoring of renal function. In patients with atherosclerosis, heart failure or diabetes mellitus with target organ damage, the double blockade of RAAS (with simultaneous application of ARA II, ACE inhibitors or aliskiren) is accompanied by an increased incidence of arterial hypotension, fainting, hyperkalemia and renal dysfunction (including acute renal failure) compared with the use of a drug in one of the groups listed.

The simultaneous use of losartan with ACE inhibitors in patients with diabetic nephropathy is contraindicated.

Other drugs that cause arterial hypotension, including tricyclic antidepressants, antipsychotics, baclofen, amifostine: simultaneous use of drugs that reduce blood pressure (the main or side effect) may increase the risk of developing arterial hypotension.

Hydrochlorothiazide

With thiazide diuretics, such medicines as ethanol, barbiturates and narcotics, can potentiate the risk of developing orthostatic hypotension.

Hypoglycemic agents (for oral administration and insulin) - dosage correction of hypoglycemic agents may be required, hydrochlorothiazide affects glucose tolerance.

Metformin should be used with caution in connection with the risk of developing lactic acidosis against a background of kidney damage caused by hydrochlorothiazide.

Other antihypertensives additive effect.

Kolestyramine and colestipol - in the presence of anion-exchange resins, hydrochlorothiazide absorption is impaired. Kolestyramine and colestipol in a single dose bind hydrochlorothiazide and reduce its absorption in the gastrointestinal tract by 85% and 43%, respectively.

Corticosteroids, ACTH (adrenocorticotropic hormone) or glycyrrhizic acid (found in licorice root) - a marked decrease in the electrolyte content, in particular, the risk of hypokalemia.

Pressor amines (e.g., epinephrine, norepinephrine) - decrease in the severity of response to the reception of pressor amines.

Muscle relaxants of nondepolarizing action type (eg, tubocurarine) - strengthening the effect of muscle relaxants.

Lithium - diuretics reduce renal clearance of lithium and increase the risk of developing toxic effects of lithium; simultaneous use is not recommended.

NSAIDs (including COX-2 inhibitors) - can reduce the diuretic, natriuretic and antihypertensive effect of diuretics.

Drugs used for treated gout (probenecid, sulfinpyrazone and allopurinol): it may be necessary to adjust the dose of uricosuric drugs, since hydrochlorothiazide can cause an increase in the concentration of uric acid in the serum. Thiazide diuretics can increase the incidence of hypersensitivity reactions by allopurinol.

Anticholinergic drugs (eg, atropine, biperidene): increase the bioavailability of thiazide diuretics due to decreased gastrointestinal motility and gastric emptying rate.

Cytostatic drugs, for example, cyclophosphamide, methotrexate: increases mielopodavlivayuschee action due to the slowing of excretion from the body. Salicylates - when taking high doses of salicylates hydrochlorothiazide can enhance their toxic effect on the central nervous system.

Methyldopa: described individual cases of hemolytic anemia with the simultaneous use of hydrochlorothiazide and methyldopa.

Simultaneous application cyclosporine increases the risk of hyperuricemia and exacerbation of gout.

Cardiac glycosides: Hypokalemia and hypomagnesemia caused by the use of thiazide diuretics, increases the risk of arrhythmias in the treatment of cardiac glycosides.

Salts of calcium - Thiazide diuretics can increase the calcium content in the serum due to a decrease in its excretion. If it is necessary to use calcium preparations, the dose is selected under the control of the calcium content in the blood serum.

Vitamin D - increases the risk of hypercalcemia.

Impact on laboratory results - due to the effect on calcium excretion, thiazides can distort the results of studies of the function of parathyroid glands.

Carbamazepine - increases the risk of symptomatic hyponatremia. It is necessary to control the sodium content in the blood serum.

Iodine-containing contrast agents - with dehydration caused by taking diuretics, the risk of acute renal failure increases, especially when high doses of iodine-containing drugs are administered. Before the introduction of such funds, the patient should be rehydrated.

Amphoteric B (for intravenous administration), laxative stimulant or ammonium glycyrrhizinate (contained in liquorice) - hydrochlorothiazide can enhance violations of water-electrolyte balance, especially hypokalemia.

Medicines that intensely bind to proteins, enhance the diuretic effect. It may be necessary to adjust the dose of anticoagulants for oral administration, probenecid and sulfinpyrazone, since hydrochlorothiazide can suppress their action.

The simultaneous use of thiazide diuretics with antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amiodarone, sotalol, dofetilide, ibutilide), some antipsychotic drugs (neuroleptics) (thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol) and other drugs (bepridil, cisapride, difemanyl, erythromycin, halofantrine, misolastine, pentamidine, terfenadine, wincamine, pentamidine) may be accompanied by the development of hypokalemia, which in turn can lead to the development of piruet-type arrhythmias.

Special instructions:

Losartan

Perhaps the manifestation of such a symptom of hypersensitivity as angioedema, so patients with an angioedema in the anamnesis (swelling of the face, lips, pharynx / larynx and / or tongue) require careful monitoring of the drug.

Losartan H, like some drugs that affect RAAS, can increase the concentration of blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney. Losartan should be used with caution in patients with bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney.

Pharmacokinetic data 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 disease should use the drug in a lower dose.

In patients with hypovolemia and / or a decrease in sodium in the blood plasma, against the background of diuretic therapy, restriction of consumption of table salt, diarrhea or vomiting, it is possible to develop symptomatic arterial hypotension, especially after taking the first dose of the drug Lozartan N. Before using the drug should be restored BCC and / or the content of sodium in the blood plasma.

During treatment with Lozartan H, as with any antihypertensive therapy, there may be a marked decrease in blood pressure. Patients should be examined for the purpose of revealing clinical signs of a decrease in BCC and violations of water-electrolyte balance, including hyponatremia, hypochloraemic alkalosis, hypomagnesemia, or hypokalemia, which can occur due to episodes of diarrhea or vomiting, as a result of diuretic therapy, while limiting intake of table salt. Such patients need control of the content of plasma electrolytes.

Simultaneous use with potassium preparations, potassium-sparing diuretics is not recommended (see the section "Interaction with other medicinal products").

The experience of using the drug Lozartan H in patients who underwent kidney transplantation is absent.

In patients with primary hyperaldosteronism, the use of antihypertensive drugs that affect RAAS, including Lozartan N, is ineffective. A sharp decrease in blood pressure during therapy with Lozartan H, as well as other antihypertensive drugs, in patients with ischemic cardiovascular and cerebrovascular diseases can lead to the development of acute myocardial infarction or stroke.

In patients whose renal function depends on the state of RAAS (eg, in chronic heart failure III-IV functional class by classification NYHA, accompanied by impaired renal function), therapy with drugs that affect RAAS, may be accompanied by rare arterial hypotension, oliguria and / or progressive azotemia, in rare cases - acute renal failure. It is impossible to exclude the development of these disorders due to the suppression of RAAS activity against the background of taking ARA II.

Caution should be exercised when using Lozartan H in patients with aortic stenosis, mitral stenosis and hypertrophic obstructive cardiomyopathy.

It should be borne in mind that the ARA II, including losartan, are less effective for the treatment of hypertension when used in patients of the Negroid race than in other patients.

Hydrochlorothiazide

As in the case of taking any antihypertensive drugs, some patients may experience symptomatic hypertension. In some patients hydrochlorothiazide can increase water-electrolyte imbalance (decrease in BCC, hyponatremia, hypochloraemic alkalosis, hypomagnesemia, hypokalemia), impair glucose tolerance, reduce calcium excretion by the kidneys, cause a slight slight increase in calcium in the blood plasma, increase the concentration of cholesterol and triglycerides, provoke the onset hyperuricemia and / or gout (since losartan reduces the concentration of uric acid, the severity of hyperuricemia caused by a diuretic is reduced).

Can give positive results in the conduct of doping control. Hydrochlorothiazide in connection with the impact on calcium metabolism, can distort the results of parathyroid function analysis.

In patients taking thiazide diuretics, hypersensitivity reactions can occur if there is no history of allergic reactions or bronchial asthma.There are reports of the development of exacerbation or progression of systemic lupus erythematosus on the background of thiazide diuretics.

Thiazide diuretics should be used with caution in patients with impaired liver function or progressive liver disease, this can lead to the development of intrahepatic cholestasis, which, in combination with a disturbance of the water electrolyte balance, can lead to the development of a "hepatic" coma.

Thiazide therapy may impair glucose tolerance, in some cases, a dose adjustment of hypoglycemic agents, including insulin, may be required. Expressed hypercalcemia may indicate latent hyperparathyroidism. In connection with the effect of thiazides on calcium metabolism, their administration can distort the results of the investigation of parathyroid gland function, before the study of parathyroid gland function, the thiazide diuretic should be canceled.

Acute myopic attack and angle-closure glaucoma

Against the background of the use of hydrochlorothiazide there have been cases of transient myopia and acute development of closed-angle glaucoma. Risk factors for the acute development of an angle-closure glaucoma may be anamnestic data on allergic reactions to sulfonamide derivatives and penicillin.Symptoms: sudden onset, sudden drop in vision or pain in the eye, usually occurring between a few hours and a week after the start of therapy. An untreated attack of angle-closure glaucoma can lead to persistent loss of vision. The first step is to stop taking hydrochlorothiazide. If intraocular pressure does not decrease after hydrochlorothiazide cancellation, medical or surgical treatment may be required.

Ischemic heart disease (IHD) and cerebrovascular disease.

As with the treatment of any hypotensive drugs, an excessive reduction in blood pressure in patients with IHD or cerebrovascular disease can lead to the development of myocardial infarction or stroke.

Interaction with drugs that affect RAAS.

Double blockade of RAAS ARA II ACE inhibitors or preparations containing aliskiren is associated with an increased risk of developing arterial hypotension, syncope, hyperkalemia and changes in kidney function (including acute renal failure) compared with monotherapy. It is necessary to monitor blood pressure, kidney function and electrolyte content in patients who simultaneously use several drugs that affect RAAS.The combined use of aliskiren with preparations containing hydrochlorothiazide + losartan in patients with diabetes mellitus and in patients with renal insufficiency (CK ≤ 60 mL / min).

Effect on the ability to drive transp. cf. and fur:

When using the drug, caution should be exercised when managing transport and working with machinery, requiring increased attention and speed of psychomotor reactions, due to the possible development of unwanted side effects from the nervous system (dizziness, drowsiness).

Form release / dosage:

Tablets, film-coated 12.5 mg + 50 mg; 12.5 mg + 100 mg and 25 mg + 100 mg.

Packaging:

By 7, 10, 14, 25, 30 tablets into the contour cell package from the film polyvinylchloride and aluminum foil printed lacquered.

10, 14, 20, 28, 30, 40, 50, 56, 60, 90 or 100 tablets into cans of polyethylene terephthalate for medicinal products sealed with screw caps with a first opening control or a "push-turn" system of polypropylene or polyethylene or cans of polypropylene for drugs, sealed with lids pulled with the control of the first opening of polyethylene,or polypropylene cans for medicinal products sealed with caps tightened with the control of the first opening of high pressure polyethylene.

One jar or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 contour mesh packages together with the instruction for use are placed in a cardboard package.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004142

Date of registration:13.02.2017

Expiration Date:13.02.2022

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Information update date: & nbsp24.03.2017

Illustrated instructions

Instructions

Losartan H (Losartan-H)