Lozarel Plus - instructions for use, dose, side effects, contraindications

core tablet: active components: hydrochlorothiazide 12.5 mg and potassium losartan * 50 mg; auxiliary components: lactose monohydrate 26.9 mg, microcrystalline cellulose 60 mg, pregelatinized starch 23.6 mg, magnesium, stearate 1.5 mg, silicon dioxide colloid 0.5 mg;

tablet shell: hypromellose 1.925 mg, giprolose 1.925 mg, iron dye oxide yellow 0.02 mg, titanium dioxide 1.13 mg.

For a dosage of 25 mg + 100 mg

1 tablet contains:

core tablet: active components: hydrochlorothiazide 25 mg and potassium losartan * 100 mg; auxiliary components: lactose monohydrate 53.8 mg, microcrystalline cellulose 120 mg, pregelatinized starch 47.2 mg, magnesium stearate 3 mg, silicon dioxide colloid 1 mg;

tablet shell: hypromellose 3.85 mg, giprolose 3.85 mg, iron dye oxide yellow 0.04 mg, titanium dioxide 2.26 mg.

* Each film-coated tablet, with a dosage of 12.5 mg + 50 mg, contains 45.8 mg of losartan in the form of 50 mg of potassium losartan and 4.24 mg of potassium.

Each film-coated tablet, with a dosage of 25 mg + 100 mg, contains 91.6 mg of losartan in the form of 100 mg of potassium losartan and 8.48 mg of potassium.

Description:

Light yellow, round, biconvex tablets, covered with a film membrane.

On a cross-section: tablets of white to white with a yellowish shade of color.

Pharmacotherapeutic group:hypotensive combined agent (angiotensin II receptor blocker + diuretic)

ATX: & nbsp

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

Pharmacodynamics:

Lozarel® Plus is a combination of an angiotensin receptor antagonist II (losartan) and a thiazide diuretic (hydrochlorothiazide). The combination of these components has an additive antihypertensive effect and lowers blood pressure (BP) more than each of the components separately.

Losartan is a specific antagonist of angiotensin II receptors (type ATI). Angiotensin II selectively binds to AT₁receptors located in many tissues (vascular smooth muscle, adrenal gland, kidneys and the heart) and performs several important biological functions, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates proliferation of smooth muscle cells.

Research in vitro and in vivo proved that losartan and its pharmacologically active metabolite (E-3174) block all the physiological effects of angiotensin II, regardless of the source or route of its synthesis. Losartan does not inhibit angiotensin-converting enzyme (ACE) - kininase II and, accordingly, does not interfere with the destruction of bradykinin, therefore side effects mediated by bradykinin (eg, angioedema) are rare. Losartan and its active metabolite have a greater affinity for angiotensin I receptors than for angiotensin receptors II. The active metabolite is 10-40 times more active than losartan. 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.

Reduces the overall peripheral vascular resistance (OPSS), concentration in the blood of aldosterone, blood pressure in the "small" circle of blood circulation, reduces afterload, has a diuretic effect. It prevents the development of myocardial hypertrophy, increases exercise tolerance in patients with chronic heart failure (CHF) Stabilizes the concentration of urea in the blood plasma.Does not affect vegetative reflexes and does not have a long-term effect on the concentration of norepinephrine in blood plasma.

After a single oral intake, the hypotensive effect (systolic and diastolic blood pressure decreases) reaches a maximum after 6 hours, then gradually decreases within 24 hours. The maximum hypotensive effect develops 3-6 weeks after the start of the drug.

In controlled clinical trials involving patients with primary mild and moderate arterial hypertension, a statistically significant decrease in systolic and diastolic blood pressure occurred once a day with losartan.

Comparison of blood pressure, measured after 5-6 hours and 24 hours after ingestion of the dose, showed that the blood pressure remains lowered for 24 hours while maintaining a natural daytime rhythm. Decrease in blood pressure at the end of the dosing period was approximately 70-80% of the effect observed after 5-6 hours after ingestion.

Discontinuation of losartan by patients with hypertension does not lead to a sharp increase in blood pressure (withdrawal syndrome).Despite the pronounced decrease in blood pressure losartan does not have a clinically significant effect on the heart rate.

Losartan is equally effective both in the treatment of men and women, young patients, and elderly patients with hypertension.

Hydrochlorothiazide is a thiazide diuretic, it disrupts the reabsorption of sodium, chlorine, potassium, magnesium ions in the distal nephron, delays the excretion of calcium, uric acid. The increase in renal excretion of these ions is accompanied by an increase in the amount of urine (due to the osmotic binding of water). Hydrochlorothiazide reduces the volume of blood plasma, increases the activity of renin in the blood plasma and the secretion of aldosterone. When taken in high doses hydrochlorothiazide increases excretion bicarbonates, with prolonged intake reduces calcium excretion. Antihypertensive effect develops due to a decrease in the volume of circulating blood (BCC), changes in the reactivity of the vascular wall, decrease of the pressor influence of vasoconstrictive amines (epinephrine, noradrenaline) and intensification of the depressor effect on the ganglion. Does not affect normal blood pressure.Diuretic effect occurs after 1-2 hours, reaches a maximum after 4 hours and lasts 6-12 hours.

Antihypertensive effect occurs in 3-4 days, but to achieve the optimal therapeutic effect, 3-4 weeks is necessary.

Pharmacokinetics:

Losartan

Ingestion losartan is well absorbed from the gastrointestinal tract, metabolized by "primary passage" through the liver by carboxylation with the participation of the cytochrome isoenzyme CYP2C9 with the formation of an active metabolite. Systemic bioavailability of losartan is about 33%. Eating does not affect the bioavailability of losartan. The maximum concentration (C_max) of losartan and its active metabolite in the blood serum is achieved after 1 hour and 3-4 hours after ingestion, respectively. More than 99% losartan and its active metabolite binds to blood plasma proteins, mainly with albumins. The volume of distribution is 34 liters. Losartan practically does not penetrate the blood-brain barrier. About 14% of the dose of losartan after ingestion is converted into its active metabolite. After ingestion of losartan, labeled ¹⁴C, the radioactivity of the circulating blood plasma is primarily associated with the presence in it of losartan and its active metabolite. Approximately 1% of patients had a low level of losartan metabolism.

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 in the form of an active metabolite.

After oral administration, the plasma concentrations of losartan and its active metabolite decrease polyexponentially with a finite half-life (T_1/2) approximately 2 hours and 6-9 hours respectively. With a single dose of the drug inside at a dose of 100 mg / day nor losartan, nor its active metabolite significantly accumulate in the blood plasma.

The excretion of losartan and its metabolites occurs with bile and kidneys. After ingestion of losartan, labeled ¹⁴C, about 35% of radioactivity is found in urine and 58% in feces. After iv introduction of losartan, labeled ¹⁴C, approximately 43% of radioactivity is detected in urine and 50% in feces.

Linearity

When administered doses of the drug to 200 mg, the pharmacokinetics of losartan and its active metabolite is linear.

When taking the drug inside once a day, there is no significant cumulation in the plasma of either losartan or its active metabolite.

In patients with alcoholic liver cirrhosis of mild and moderate severity, the concentration of losartan was 5 times, and the active metabolite was 1.7 times higher than in healthy male volunteers. When the creatinine clearance (CK) is above 10 ml / min, the concentration of losartan in the blood plasma does not differ from that with normal kidney function. In patients on hemodialysis, the area under the concentration-time curve (AUC) is approximately 2 times higher than in patients with normal renal function. Neither losartan, nor its active metabolite is removed from the body by hemodialysis. The concentrations of losartan and its active metabolite in blood plasma in elderly patients with arterial hypertension do not differ significantly from the values of these parameters in young patients of men with arterial hypertension.Values of plasma concentrations of losartan in women with arterial hypertension are 2 times higher than the corresponding values in men with arterial hypertension. The concentrations of the active metabolite in men and women do not differ. This pharmacokinetic difference is not clinically relevant.

Hydrochlorothiazide

Ingestion hydrochlorothiazide quickly absorbed from the gastrointestinal tract (about 80%). It is not metabolized in the liver. Systemic bioavailability is about 70%. The maximum concentration in the blood plasma is reached after 2-5 hours after ingestion. Relationship with blood plasma proteins - 64%; volume distribution of 0.5-1.1 l / kg. It is excreted by the kidneys, mostly in unchanged form (more than 95%). The half-life is about 6-8 hours with normal kidney function. With violations of kidney function, the half-life period increases and in the case of severe renal failure (CC less than 30 ml / min) reaches 20 hours.

Antihypertensive action combination drug remains for 24 hours, the maximum therapeutic effect is achieved 4 weeks after the start of treatment.

Indications:Arterial hypertension (in patients who are shown combined therapy).

Contraindications:

- Hypersensitivity to the components of the drug;

- hypersensitivity to drugs that are derivatives of sulfonamides;

- severe hepatic insufficiency (more than 9 on the Child-Pugh scale);

- severe renal failure (creatinine clearance (CK) less than 30 ml / min);

- anuria;

- deficiency of lactase, lactose intolerance and malabsorption syndrome;

- pregnancy, lactation;

- age under 18 years (effectiveness and safety not established);

- refractory hypokalemia and hyperkalemia, hypercalcemia, refractory hyponatremia;

- symptomatic hyperuricemia and / or gout;

- dehydration, including on the background of taking high doses of diuretics;

- severe arterial hypotension;

- difficultly controlled diabetes mellitus;

- Addison's disease;

- simultaneous use with aliskiren and aliskirenoderzhaschimi drugs in patients with diabetes mellitus and / or impaired function of the night (glomerular filtration rate less than 60 ml / min / 1.73 m²).

Carefully:

Violations of the water-electrolyte balance of blood, for example,on the background of diarrhea or vomiting (hyponatremia, hypochloraemic alkalosis, hypomagnesemia), patients with renal insufficiency (CK 30-50 ml / min), bilateral stenosis of the renal arteries or stenosis of the single kidney artery, diabetes mellitus, progressive liver disease and liver dysfunction (less 9 points on the Child-Pugh scale), weighed allergic anamnesis and bronchial asthma, systemic connective tissue diseases (including lupus erythematosus), heart failure with life-threatening arrhythmias, ischemic disease erdtsa, stenosis of aortic or mitral valve, obstructive hypertrophic cardiomyopathy, cerebrovascular insufficiency, primary aldosteronism, acute myopia and secondary angle-closure glaucoma (preparation comprises hydrochlorothiazide), with concomitant administration with non-steroidal anti-inflammatory drugs (NSAIDs) (including inhibitors and cyclooxygenase COX-2), condition after kidney transplantation (no experience), in patients of the Negroid race (see section "Special instructions") .

Pregnancy and lactation:

The use of Lozarel® Plus during pregnancy and during breastfeeding is contraindicated.

The use of drugs that directly affect the renin-angiotensin-aldosterone system in the second and third trimesters of pregnancy can cause harm to the developing fetus and even cause its death. Immediately after the pregnancy is established, the drug Lozarel® Plus should be discontinued.

Controlled epidemiological studies on the risk of angiotensin II receptor antagonists have not been carried out, and similar risks may exist for this class of drugs. Unless continued therapy with angiotensin receptor antagonists is considered vital, patients planning to become pregnant should switch to alternative antihypertensive drugs with established safety characteristics that allow them to be used during pregnancy.

Thiazides penetrate the placental barrier and are detected in the blood of the umbilical cord. The use of diuretics in pregnant women is not recommended. this increases the risk of developing fetal adverse events such as embryonic jaundice and jaundice of newborns, and the mother - thrombocytopenia.

There is no evidence that losartan excreted in breast milk. However, 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 taking Lozarel® Plus is necessary, breastfeeding should be discontinued.

Dosing and Administration:

Inside, 1 time per day, regardless of food intake.

With arterial hypertension usual initial and maintenance doses of the drug - 1 tablet Lozarel® Plus 12.5 mg + 50 mg / day.

If there is no adequate therapeutic effect, for 3-4 weeks the dose of the drug should be increased to 2 tablets Lozarel® Plus 12.5 mg + 50 mg or 1 tablet Lozarel® Plus 25 mg + 100 mg (maximum daily dose).

In patients with a reduced volume of circulating blood (for example, when taking large doses of diuretics), the recommended initial dose of losartan is 25 mg once a day. In this regard, therapy with the drug Lozarel® Plus should be started after the abolition of diuretics and correction of hypovolemia.

In elderly patients and patients with moderate renal failure, including those on dialysis, no correction of the initial dose is required.

Side effects:

According to the World Health Organization (WHO), adverse reactions are classified according to their developmental frequency as follows: very often (≥1/10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, < 1/100), rarely (≥1 / 10000, <1/1000) and very rarely (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence. In clinical studies with losartan-hydrochlorothiazide there were no undesirable reactions specific for this combination drug.

Unwanted reactions were limited to those already reported with losartan and / or hydrochlorothiazide alone. The total incidence of adverse reactions reported with this combination was comparable to that of placebo. The frequency of discontinuation of therapy was also comparable to that of patients taking placebo. In general, treatment with losartan hydrochlorothiazide was well tolerated. In most cases, adverse reactions were mild, transient, and did not require drug withdrawal.

In controlled clinical trials in the treatment of essential hypertension, dizziness was the only drug-related adverse reaction whose frequency exceeded that of placebo for more than one percent or more. As shown in controlled clinical trials, in patients with hypertension and left ventricular hypertrophy, the most frequent adverse reactions were systemic and non-systemic dizziness, weakness / fatigue.

In the course of post-marketing use of the drug, clinical studies and / or post-marketing use of individual active components of the drug, the following adverse reactions were reported:

Disturbances from the nervous system

often: dizziness.

Disturbances from the liver and bile ducts

rarely: hepatitis.

Laboratory and instrumental data

rarely: hyperkalemia, increased activity of "liver" transaminases.

Losartan

Common violations

often: asthenia, increased fatigue, pain in the chest, peripheral edema;

infrequently: swelling of the face, fever;

frequency is unknown: malaise, flu-like symptoms.

Disorders from the cardiovascular system

often: palpitation, tachycardia;

infrequently: pronounced BP reduction, orthostatic hypotension (dose-dependent), epistaxis, arrhythmias (atrial and ventricular fibrillation, ventricular tachycardia, sinus bradycardia, tachycardia), angina pectoris, vasculitis, myocardial infarction, retrosternal pain, atrioventricular (AV) blockade of degree II, cerebrovascular disorders.

Violations with hand digestive system

often: abdominal pain, diarrhea, dyspepsia, nausea;

infrequently: anorexia, dryness mucous membrane of the oral cavity, toothache, vomiting, flatulence, gastritis, constipation, hepatitis, a violation of liver function;

frequency is unknown: pancreatitis.

Disturbances from musculoskeletal and connective tissue

often: pain in the back, legs, spasms of the calf muscles, myalgia, muscle pains;

infrequently: arthralgia, arthritis, pain in the hands, shoulder, knee, hip joint, fibromyalgia, muscle weakness;

frequency is unknown: rhabdomyolysis.

Disturbances from the nervous system

often: dizziness, headache, insomnia;

infrequently: anxiety, sleep disorders, drowsiness, memory impairment, peripheral neuropathy, paresthesia, hyposthenia, tremor, ataxia, depression, anxiety, panic conditions, confusion, vertigo, fainting, ringing in the ears, taste disorder, blurred vision, visual impairment, conjunctivitis, migraine.

Disturbances from the respiratory system

often: cough, congestion of the nose, sinusitis, infections of the upper respiratory tract;

infrequently: laryngitis, dyspnoea, rhinitis, pharyngitis, bronchitis.

Disturbances from the skin and subcutaneous tissues

infrequently: dry skin, erythema, ecchymosis, photosensitivity, increased sweating, alopecia, dermatitis.

Immune system disorders

infrequently: exacerbation of gout, urticaria, skin rash, itching, hypersensitivity reactions (anaphylactic reactions, angioedema, swelling of the larynx and tongue causing airway obstruction and / or swelling of the face, lips, pharynx). In some of these patients, angioedema developed earlier with the use of other drugs, including ACE inhibitors.

Violations of the blood and lymphatic system

infrequently: anemia (a slight decrease in hemoglobin and hematocrit, an average of 0.11 g% and 0.09% v / v, respectively, rarely having clinical significance), thrombocytopenia, eosinophilia, purpura Shenlen-Henoch, hemolysis.

Disorders from the genitourinary and reproductive system

infrequently: imperative urges for urination, nocturia, urinary tract infections, renal dysfunction, renal failure, decreased libido, impotence.

Laboratory and instrumental data

often: hyperkalemia (the content of potassium in the blood plasma is more than 5.5 mmol / l), hypoglycemia;

infrequently: increasing the concentration of urea and residual nitrogen and creatinine in the blood serum;

rarely: a moderate increase in the activity of "hepatic" transaminases (aspartate aminotransferase (ACT) and alanine aminotransferase (ALT)), hyperbilirubinemia;

frequency unknown: hyponatremia.

Hydrochlorothiazide

Disorders from the metabolism and nutrition

infrequently: hyperglycemia, glucosuria, hypokalemia, hyponatremia, hyperuricemia with the development of an attack of gout, hypomagnesemia,hypercalcemia and hypochloraemic alkalosis: dryness of the oral mucosa, thirst, irregular heart rhythm, changes in mood or psyche, convulsions and muscle pain, nausea, vomiting, unusual fatigue or weakness.

Hypochloremic alkalosis can cause hepatic encephalopathy or hepatic coma.

Hyponatremia: confusion, convulsions, lethargy, slowing down the process of thinking, increased fatigue, excitability, muscle cramps. Treatment with thiazides may interfere with glucose tolerance, latent diabetes mellitus may manifest. When using high doses, lipid concentrations in the serum can increase.

Violations with hand digestive system

infrequently: intrahepatic cholestasis, cholecystitis or pancreatitis, cholestatic jaundice, diarrhea, nausea, vomiting, spasms, sialadenitis, constipation, anorexia, irritation of the gastric mucosa.

Disorders from the cardiovascular system

infrequently: arrhythmias, orthostatic hypotension, vasculitis.

Disturbances from the nervous system

often: headache;

infrequently: paresthesia, dizziness, insomnia.

Disturbances on the part of the organ of sight

infrequently: temporarily blurred vision, xanthopsia;

frequency is unknown: acute closed angle glaucoma.

Violations of the blood and lymphatic system

infrequently: leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia.

Immune system disorders

infrequently: urticaria, purpura, necrotizing vasculitis, Stevens-Johnson syndrome, respiratory distress syndrome (including pneumonitis and noncardiogenic pulmonary edema);

rarely: anaphylactic reactions up to shock.

Disturbances from the skin and subcutaneous tissue

infrequently: photosensitivity, toxic epidermal necrolysis;

frequency is unknown: lupus erythematosus.

Disorders from the kidneys and urinary tract

infrequently: renal impairment function, renal failure, interstitial nephritis.

Other

infrequently: decreased potency, muscle twitching.

Overdose: Symptoms: losartan - marked decrease in blood pressure, tachycardia, bradycardia (as a result of vagal stimulation). Hydrochlorothiazide - loss of electrolytes (hypokalemia, hyperchloremia, hyponatremia),as well as dehydration resulting from excessive diuresis, with the simultaneous administration of cardiac glycosides, hypokalemia can aggravate the course of arrhythmias.

Treatment: symptomatic and supportive therapy. If the drug is taken recently, the stomach should be washed; if necessary, correct the water-electrolyte disturbances.

Lozartan and its active metabolites are not removed by hemodialysis.

Interaction:

Losartan

There were no pharmacokinetic interactions of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin. Reportedly rifampicin and fluconazole reduce the concentration of the active metabolite in the blood plasma. The clinical significance of these interactions is still unknown. 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.

The combination of losartan, as well as other agents that are angiotensin II receptor antagonists (ARA II) or its effects, with potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride and eplerenone (a derivative of spironolactone)), potassium-containing additives or potassium salts can lead to an increase in the potassium content in the blood serum.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective and incyclooxygenase-2 (COX-2), acetylsalicylic acid at a dose above 3 g per day, can reduce the effectiveness of ARA II (their diuretic, natriuretic and antihypertensive action) and ACE inhibitors.

The combined use of ARA II with NSAID preparations, including selective COX-2 inhibitors, especially if there is a reduced renal function, can lead to impaired renal function, including acute renal failure and an increase in potassium levels in the blood plasma. This effect is usually reversible. Simultaneous reception of these medicines should be carried out with caution in patients with impaired renal function.

With the joint application of ARA II and lithium it is possible to increase the concentration of lithium in blood plasma. Considering this, it is necessary to weigh the benefits and risks of joint use of losartan with lithium salts. In case it is necessary to apply the drugs together, it is necessary to regularly monitor the concentration of lithium in the blood plasma.

The combined use of losartan with diuretics has an additive effect.

Strengthens (mutually) the effect other antihypertensive drugs (diuretics, beta-blockers, sympatholytics).

In the literature there are reports that double blockade of the renin-angiotensin aldosterone system (RAAS) in patients with established diagnosis atherosclerosis, heart failure or diabetes with target organ damage is associated with a higher incidence of arterial hypotension, fainting, hyperkalemia, and impaired renal function (including the development of acute renal failure) compared with the use of a single-component blockade of the RAAS. The question of double blockade of RAAS (for example, by combining the ACE inhibitor with APA II) should be addressed in each case individually and with regular monitoring of kidney function.

When used simultaneously with drugs, causing a decrease in blood pressure (tricyclic antidepressants, antipsychotics, baclofen, amifostine), there is a risk of developing arterial hypotension.

Hydrochlorothiazide

With the simultaneous use of thiazide diuretics with barbiturates, narcotic analgesics, ethanol may increase the risk of development orthostatic hypotension.

Diuretics reduce renal clearance of lithium and increase the risk of its toxic effects; combined use of diuretics and lithium preparations Not recommended. Before prescribing lithium preparations, refer to the instructions for their use.

When used simultaneously with pressor amines (norepinephrine, epinephrine), an insignificant decrease in the effect of pressor amines, which does not prevent their use, with nondepolarizing muscle relaxants (gubokurarinom) - strengthening their action.

When applying glucocorticosteroids, adrenocorticotropic hormone (ACTH) possibly increased loss of electrolytes, aggravation of hypokalemia.

Thiazides may reduce renal excretion cytotoxic drugs and enhance their myelosuppressive effect.

Hypoglycemic agents (for oral administration and insulin) - dosage correction of hypoglycemic agents may be required.

Metformin should be used with caution because of the risk of lactic acidosis caused by a possible renal failure associated with hydrochlorothiazide.

Other antihypertensives - additive effect; colestramine and colestipol - in the presence of anion-exchange resins, hydrochlorothiazide absorption is impaired, colestramine and colestipol in a single dose bind hydrochlorothiazide and reduce its absorption in the gastrointestinal tract (GIT) by 85% and 43%, respectively.

When used simultaneously with glycyrrhizic acid (found in the root of licorice), amphotericin B intravenously (IV), laxatives there is a risk of hypokalemia.

When used simultaneously with drugs, designed to treat gout (probenecid, sulfinpyrazone, allopurinol), it may be necessary to adjust the dose of the latter, since Hydrochlorothiazide is able to increase the concentration of uric acid in the blood serum. Simultaneous reception of thiazide diuretics can increase the frequency of development of hypersensitivity reactions to allopurinol. Hyperuricemia and / or gout are a contraindication to the use of drugs containing hydrochlorothiazide.

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

Thiazide diuretics can reduce renal excretion cytotoxic agents (cyclophosphamide, methotrexate).

When taking high doses salicylates hydrochlorothiazide can increase their toxic effect on the central nervous system (CNS).

Hemolytic anemia has been reported with concomitant use with methyldopa.

Simultaneous application with cyclosporin may increase the risk of hyperuricemia and exacerbation of gout.

Hypokalemia or hypomagnesemia caused by thiazide diuretics may contribute to the development of cardiac rhythm disorders in patients receiving cardiac glycosides.

When used simultaneously with drugs, (cardiac glycosides, antiarrhythmics), as well as with drugs that can cause the development of ventricular pirouette tachycardia (including some antiarrhythmic drugs), it is recommended to monitor the potassium content in the blood serum and the ECG.Because of the risk of hypokalemia, caution should be exercised when used with the following medicines:

- antiarrhythmic drugs class IA (eg, quinidine, hydroquinidine, disopyramide);

- antiarrhythmic drugs of class III (for example, amiodarone, sotalol, dofetilide, ibutilide);

- some antipsychotics (for example, thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride amisulpride, tiapride, pimozide, haloperidol, droperidol);

- other medications (eg, bepridil, cisapride, difemanyl, erythromycin intravenous, halofantrine, misolastine, pentamidine, terfenadine, vancomycin intravenously).

Thiazide diuretics can increase the calcium content in the blood serum due to the decrease in its excretion in the night.

If it is necessary to use preparations of calcium it is recommended that the calcium content in the blood serum be monitored regularly and that the dosage of calcium preparations is corrected.

When used simultaneously with carbamazepine possibly the development of symptomatic hyponatremia. It is recommended to control the sodium content in the blood serum.

With dehydration caused by the use of thiazide diuretics, the risk of developing acute liver failure increases, especially when high doses are used iodine containing preparations. Before the introduction of iodine preparations, dehydration should be carried out.

The results of laboratory research: due to the effect on calcium excretion, thiazides can affect the results of parathyroid function analysis.

Special instructions:

Safety and effectiveness of the drug in children are not established.

Losartan

Drugs that affect RAAS can increase the concentration of urea in the blood and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney. Similar effects were observed with losartan; these changes in renal function were reversible and disappeared after therapy was discontinued. There are reports that a number of patients taking the drug experienced changes in kidney function due to the suppression of the function of RAAS, including kidney failure; these changes were reversible and disappeared after the abolition of therapy.

As with the use of other antihypertensive drugs, excessive reduction in blood pressure in patients with ischemic vascular and cerebrovascular diseases can lead to the development of myocardial infarction and stroke.

In patients with heart failure with insufficient kidney function or without it, there is a risk of developing a reduction in blood pressure and acute renal failure.

Losartan, like other antagonists of angiotensin II receptors, is less effective in patients of the Negroid race due to the prevalence of patients with hypertension with low renin activity.

There is no experience of using the drug in patients after kidney transplantation.

Hydrochlorothiazide

As in the case of taking any antihypertensive drugs, some patients may have symptomatic arterial hypotension. Patients need to be monitored for the timely detection of clinical signs of water-electrolyte balance disorders, for example, dehydration, hyponatremia, hypochloraemic alkalosis, hypomagnesemia or hypokalemia that can develop against intercurrent diarrhea or vomiting.Such patients need control of the content of electrolytes in the blood serum.

Thiazide therapy can lead to impaired glucose tolerance. In some cases, it may be necessary to correct the dose of hypoglycemic agents (including insulin).

Thiazides can reduce the excretion of calcium by the kidneys and cause an occasional and insignificant increase in the serum calcium level. Expressed hypercalcemia may indicate latent hyperparathyroidism.

Due to the influence of thiazides on calcium metabolism, their administration can distort the results of the investigation of parathyroid gland function, therefore, before the investigation of parathyroid gland functions, the thiazide diuretic should be discarded.

Increasing the concentration of cholesterol and triglycerides of blood can also be associated with therapy with thiazide diuretics.

In some patients, the use of thiazide diuretics can lead to hyperuricemia and / or exacerbation of gout. These conditions are a contraindication to the use of drugs containing hydrochlorothiazide (see section "Contraindications"). But since losartan reduces the concentration of uric acid, its combination with hydrochlorothiazide reduces the severity of hyperuricemia caused by a diuretic.

In patients receiving thiazides, hypersensitivity reactions can occur even if there is no indication of a history of allergy or bronchial asthma. There are reports of the development of exacerbation or progression of systemic lupus erythematosus on the background of thiazide diuretics.

In patients with impaired hepatic function or with progressive liver diseases, intrahepatic cholestasis may occur, minor changes in the water-electrolyte balance may cause hepatic coma. In such patients, the drug should be used with caution.

Hydrochlorothiazide can cause an idiosyncratic reaction leading to the development of acute transient myopia and acute closed-angle glaucoma. Symptoms include a sudden decrease in visual acuity or pain in the eyes and occur within a few hours to a week from the start of therapy. The lack of treatment for acute closed-angle glaucoma can lead to complete loss of vision. It is necessary to stop taking the drug as soon as possible.If intraocular pressure remains uncontrolled, immediate medical treatment or surgery may be required.

Risk factors for the development of acute angle-closure glaucoma include allergic reactions to sulfanilamides or penicillin in the anamnesis.

Patients with primary hyperaldosteronism usually do not respond to antihypertensive agents acting through inhibition of RAAS. Therefore, it is not recommended to use the drug Lozarel® Plus for the treatment of such patients.

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

During the treatment with Lozarel® Plus (especially at the beginning of the course of therapy and with increasing doses), care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions, due to the risk of drowsiness and dizziness .

Form release / dosage:

Film-coated tablets are 12.5 mg + 50 mg and 25 mg +100 mg.

Packaging:

For 7 or 10 tablets in a double aluminum foil blister.

For 3.4, 5, 6, 8, 10 or 14 blisters together with instructions for use are placed in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001502

Date of registration:13.02.2012 / 10.12.2013

Expiration Date:13.02.2017

The owner of the registration certificate:Sandoz d.Sandoz d. Slovenia

Manufacturer: & nbsp

LEK d.d. Slovenia

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp26.11.2016

Illustrated instructions

Instructions

Lozarel® Plus (Losarel® Plus)