Bloctran GT, 12.5mg+50 mg 30 pcs

Pharmacotherapeutic group:hypotensive combination drug

(angiotensin P receptor antagonist + diuretic).

ATX code: CO9AO1

Pharmacological properties

Mechanism of action

The components of Bloktran GT have an additive antihypertensive effect, lowering blood pressure (BP) to a greater extent than each of the components alone. It is believed that this effect is due to the complementary action of both components. Due to its diuretic effect, hydrochlorothiazide increases plasma renin activity (PRA), stimulates aldosterone secretion, increases angiotensin II concentration and decreases serum potassium. Administration of losartan blocks all physiologic effects of angiotensin II and, due to the suppression of aldosterone effects, may help to reduce potassium loss associated with diuretic administration.

Losartan has moderate and transient uricosuric effects.

Hydrochlorothiazide causes a slight increase in plasma uric acid concentration. The combination of losartan and hydrochlorothiazide reduces the severity of diuretic-induced hyperuricemia.

Lozartan

Angiotensin II is a potent vasoconstrictor, the main active hormone of the renin-angiotensin-aldosterone system (RAAS), and a crucial pathophysiological link in the development of arterial hypertension (AH). Angiotensin II selectively binds to AT₁ receptors located in many tissues (vascular smooth muscle tissues, adrenal, kidney, and heart) and performs several important biological functions, including vasoconstriction and aldosterone release. Angiotensin II also stimulates smooth muscle cell overgrowth. AT₂ receptors are the second type of receptors that angiotensin II binds to, but its role in the regulation of cardiovascular function is unknown.

Lozartan is a selective angiotensin II receptor antagonist (type AT₁) that is highly effective when taken orally. Losartan and its pharmacologically active carboxylated metabolite (E-3174) both in vitro and in vivo block all physiological effects of angiotensin II, regardless of its source or synthesis pathway. Unlike some peptide angiotensin II antagonists, losartan does not have agonist properties.

Losartan selectively binds to AT₁ receptors and does not bind to or block receptors for other hormones and ion channels that play an important role in the regulation of cardiovascular function. In addition, losartan does not inhibit angiotensin-converting enzyme (ACE), which is responsible for bradykinin degradation. Therefore, side effects not directly related to AT₁ receptor blockade, such as increased bradykinin-mediated effects or development of edema (losartan 1.7%, placebo 1.9%), are not relevant to the action of losartan.

Hydrochlorothiazide

The mechanism of antihypertensive action of thiazide diuretics is unknown. Thiazide diuretics usually have no effect on normal BP.

Hydrochlorothiazide is a diuretic and a hypotensive agent. It affects reabsorption of electrolytes in the distal tubules of the kidneys. Hydrochlorothiazide increases excretion of sodium and chlorine ions approximately to the same extent.

Natriuresis may be accompanied by a small loss of potassium and bicarbonate ions.

When taken orally, the diuretic effect develops within 2 hours, reaches a maximum on average after 4 hours and lasts from 6 to 12 hours.

Pharmacodynamics

Blocktaran GT is a combination of losartan and hydrochlorothiazide. In patients with arterial hypertension and left ventricular hypertrophy, losartan, including in combination with hydrochlorothiazide, reduces the risk of cardiovascular morbidity and mortality, which has been proven by evaluating the combined incidence of stroke and myocardial infarction as well as the cardiovascular mortality rate in this patient population.

Lozartan

Lozartan suppresses the increase in systolic and diastolic blood pressure (BP) with angiotensin II infusion. At the time of reaching the maximum plasma concentration (Cmax) of losartan after a 100-mg dose of losartan, the above effect of angiotensin II is suppressed by approximately 85% and 26-39% after 24 hours of single and multiple administrations.

Losartan use eliminates the negative feedback of suppressing angiotensin II secretion of renin, resulting in increased ARP. Increased ARP leads to increased plasma angiotensin II concentrations. During long-term (6-week) treatment of patients with AH with losartan at a dose of 100 mg/day, a 2-3-fold increase in plasma angiotensin II concentrations was observed when the Cmax of losartan was reached. In some patients, even greater increases in angiotensin II concentrations were observed, especially with a short duration of treatment (2 weeks). Despite this, during treatment, the antihypertensive effect and decrease in plasma aldosterone concentration were evident after 2 and 6 weeks of therapy, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan, ARP and angiotensin II concentrations decreased within 3 days to values observed before the start of losartan. The effects of the combination of losartan (50 mg) and hydrochlorothiazide (12.5 mg) on ARP and angiotensin II concentrations were similar to those observed with the 50-mg dose of losartan.

Since losartan is a specific AT₁ angiotensin II receptor antagonist, it does not inhibit ACE (kinase P), an enzyme that inactivates bradykinin.

A study comparing the effects of losartan at doses of 20 mg and 100 mg with those of an ACE inhibitor for effects 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 angiotensin I response and increased the bradykinin-dependent effects without affecting the angiotensin II response, demonstrating the pharmacodynamic difference between losartan and ACE inhibitors.

The plasma concentrations of losartan and its active metabolite and the antihypertensive effect of losartan increase with increasing drug dose. Because losartan and its active metabolite are angiotensin II receptor antagonists (ARA II), they both contribute to the antihypertensive effect.

In a study with a single dose of 100 mg of losartan that included healthy volunteers (men), oral administration of the drug on a high-salt and low-salt diet had no effect on glomerular filtration rate (GFR), effective renal plasma flow, or filtration function. Losartan had a natriuretic effect that was more pronounced on the low-salt diet and did not appear to be associated with suppression of early sodium reabsorption in the proximal renal tubules. Lozartan also caused a transient increase in renal uric acid excretion. In patients with AH, proteinuria (at least 2 g/24 h), without diabetes mellitus, taking losartan for 8 weeks at a dose of 50 mg with a gradual increase to 100 mg, there was a significant reduction in proteinuria (by 42%), fractional albumin and immunoglobulin (IgG) excretion. In these patients, losartan stabilized GFR and decreased filtration fraction.

In postmenopausal women with AH taking losartan in a dose of 50 mg for 4 weeks, no effect of therapy on renal and systemic prostaglandin levels was found.

Lozartan has no effect on autonomic reflexes and no lasting effect on plasma noradrenaline concentration.

In AH patients taking losartan in doses of 150 mg/day, it did not cause clinically significant changes in fasting triglycerides, total and high density lipoprotein cholesterol. At the same doses, losartan had no effect on fasting blood glucose concentration.

In general, losartan caused a decrease in serum uric acid concentration

(generally less than 0.4 mg/dL) that persisted with long-term treatment. In controlled clinical trials with AH patients no cases of drug withdrawal due to an increase in serum creatinine concentration or serum potassium have been reported.

In a 12-week parallel study that included patients with left ventricular failure (NYHA functional class II-IV), most of whom were taking diuretics and/or cardiac glycosides, the effects of losartan at doses of 2.5, 10, 25 and 50 mg/day were compared 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 an increase in cardiac index and a decrease in pulmonary capillary congestion pressure, as well as a decrease in total peripheral vascular resistance, mean systemic BP, and heart rate. The incidence of arterial hypotension in these patients depended on the drug dose. Neurohormonal effects included decreases in aldosterone and norepinephrine blood concentrations.

Pharmacokinetics

.Absorption

Lozartan

.When ingested, losartan is well absorbed from the gastrointestinal tract and undergoes metabolism by “primary passage” through the liver, producing an active carboxylated metabolite and inactive metabolites. The systemic bioavailability of losartan is approximately 33%. Maximum concentration (Cmax) of losartan and its active metabolite is reached in 1 h and 3-4 h, respectively. No clinically significant effect on the plasma concentration profile of losartan has been identified when losartan is taken with a normal meal.

Distribution

Lozartan

Losartan 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 has almost no penetration through the blood-brain barrier.

Hydrochlorothiazide

Hydrochlorothiazide penetrates the placental barrier, does not penetrate the blood-brain barrier and is excreted with breast milk.

Metabolism

Lozartan

.Approximately 14% of the dose of losartan administered intravenously or orally is converted to its active metabolite. After ingestion or intravenous administration of losartan, the radioactive carbon-labeled losartan (¹⁴C) radioactivity of circulating blood plasma is primarily related to the presence of losartan and its active metabolite. Low conversion efficiency of losartan to its active metabolite was observed in about 1% of patients in the study.

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

Elimation

Lozartan

Plasma clearance of losartan and its active metabolite is approximately 600 mL/min and 50 mL/min, respectively. Renal clearance of losartan and its active metabolite is approximately 74 mL/min and 26 mL/min, respectively. When losartan is taken orally, approximately 4% of the dose is excreted unchanged by the kidneys and approximately 6% of the dose is excreted as an active metabolite. Pharmacokinetics of losartan and its active metabolite are linear with oral administration of losartan up to 200 mg.

After oral administration, plasma concentrations of losartan and its active metabolite decrease polyexponentially with a final half-life (T 1/2) of approximately 2 and 6-9 hours, respectively. Neither losartan nor its active metabolite significantly accumulate in plasma when administered as a single dose of 100 mg. Excretion of losartan and its metabolites is through the intestine with the bile and kidneys. After oral administration of ¹⁴C-labeled losartan in men, approximately 35% of the radioactive label is detected in urine and 58% in feces. After intravenous administration of ¹⁴C-labeled losartan, approximately 43% of the radioactive label is detected in the urine and 50% in the feces.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys. When plasma levels of the drug were monitored for at least 24 hours, the elimination half-life ranged from 5.6 to 14.8 hours. At least 61% of the oral dose is excreted unchanged within 24 hours.

Pharmacokinetics in special patient groups

Lozartan-hydrochlorothiazide

Elderly patients

The plasma concentrations of losartan and its active metabolite in elderly patients with AH are not significantly different from those in younger patients with AH.

Losartan

Gender

The plasma concentrations of losartan in women with AH were twice as high as in men with AH. Concentrations of the active metabolite did not differ between men and women. This pharmacokinetic difference is not clinically significant.

Patients with impaired liver function

.Patients with mild to moderate alcoholic liver cirrhosis had 5-fold higher concentrations of losartan and 1.7-fold higher concentrations of the active metabolite than young healthy male volunteers.

Patients with impaired renal function

Patients with a creatinine clearance (CK) above 10 mL/min have plasma concentrations of losartan no different from those in patients with unchanged renal function. In patients on hemodialysis, the area under the concentration-time curve (AUC) was approximately 2 times higher than in patients with normal renal function. Plasma concentrations of the active metabolite were not altered in patients with impaired renal function or patients on hemodialysis. Neither losartan nor its active metabolite is excreted by hemodialysis.

Indications

– Arterial hypertension (patients who are indicated for combination therapy);

Left ventricular hypertension and hypertrophy decrease the risk of associated cardiovascular morbidity and mortality, as manifested by a combined reduction in cardiovascular mortality, stroke and heart attack rates.

Active ingredient

Composition

Active substances: potassium losartan – 50 mg, hydrochlorothiazide – 12.5 mg;

Ancillary substances: microcrystalline cellulose – 40.1 mg, potato starch – 23.4 mg, sodium carboxymethyl starch (sodium starch glycolate) – 7.0 mg, lactose monohydrate – 3,5 mg, povidone (polyvinylpyrrolidone low molecular weight medical, povidone K 17) – 1.4 mg, colloidal silica (aerosil) – 1.4 mg, magnesium stearate – 0.7 mg; sheath: Opadray II Pink 57U36011 [hypromellose (HPMC 2910) – 2.0150 mg, polydextrose – 1.6900 mg, titanium dioxide (E 171) – 1.6887 mg, talc – 0.4550 mg, maltodextrin or dextrin – 0.3250 mg, medium-chain triglycerides – 0.2600 mg, carmine red dye (carmine E 120) – 0.0663 mg] – 6.5 mg.

How to take, the dosage

Blocktran® GT is taken orally, regardless of meals.

Blocktran® GT may be taken in combination with other hypotensive agents.

Arterial hypertension

The initial and maintenance dose is usually 1 tablet once daily. In patients without adequate therapeutic response to 1 tablet of Bloctran® HT (containing 50 mg losartan + 12.5 mg hydrochlorothiazide) once daily for 2-4 weeks, the drug dose may be increased to 2 tablets once daily. The maximum daily dose is 2 tablets of Bloctran® GT (50 mg + 12.5 mg). As a rule, the antihypertensive effect is achieved within 3 weeks after the beginning of therapy.

Risk reduction for cardiovascular events and mortality in patients with arterial hypertension and left ventricular hypertrophy.

The initial dose of losartan is usually 50 mg once daily. Patients who have failed to achieve target BP on losartan 50 mg/day require selection of therapy by combining losartan with low-dose hydrochlorothiazide (12.5 mg). If necessary, the dose of losartan should be increased to 100 mg in combination with 12.5 mg hydrochlorothiazide per day, subsequently increasing to 2 tablets of Bloktran® GT (total 100 mg losartan and 25 mg hydrochlorothiazide) once daily.

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

There is no need to adjust the initial dose of Bloktran® GT for patients with moderate renal dysfunction (CKR 30-50 mg/min). Bloketran® GT is not recommended for patients on hemodialysis. Bloctran® GT should not be used in patients with severe renal dysfunction (CK values less than 30 ml/min) (see section “Contraindications”).

Application in patients with decreased circulating blood volume

Before starting therapy with Bloctran® GT, circulating blood volume and/or blood sodium content should be restored.

Application in patients with hepatic impairment

Blocktran® GT is contraindicated in patients with severe hepatic impairment (see “Contraindications” section).

Application in older patients

There is no need to adjust the starting dose of Bloctran® GT for older patients.

Interaction

Lozartan

No clinically significant pharmacokinetic interaction of the drug with such drugs as hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital has been observed. Rifampicin, as an inducer of drug metabolism, reduces the blood concentration of the active metabolite losartan. Two inhibitors of P450 CA4 isoenzyme have been studied in clinical trials: ketoconazole and erythromycin. Ketoconazole had no effect on the metabolism of losartan to the active metabolite after intravenous administration of losartan. Erythromycin had no clinically significant effect with oral administration of losartan. Fluconazole, a P450 2C9 isoenzyme inhibitor, reduces the concentration of the active metabolite of losartan, but the pharmacodynamic significance of concomitant use of losartan and P450 2C9 isoenzyme inhibitors has not been studied. Patients who do not metabolize losartan to an active metabolite have been shown to have a very rare and specific defect in the P45O 2C9 isoenzyme. These data suggest that the metabolism of losartan to the active metabolite is by the P450 2C9 isoenzyme rather than by the P450ZA4 isoenzyme.

Simultaneous use of losartan, as well as other drugs that block angiotensin II or its effects, with potassium-saving diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or potassium salts may result in increased serum potassium levels.

As with other drugs that affect sodium excretion, treatment with losartan may be accompanied by decreased excretion and increased serum concentrations of lithium, so serum concentrations should be monitored when concomitantly treated with lithium preparations.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 (COX-2) inhibitors, can decrease the effect of diuretics and other hypotensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists (ARA II) may be impaired with concomitant use of NSAIDs, including selective COX-2 inhibitors.

In some patients with impaired renal function (e.g., elderly patients or patients with dehydration, including those taking diuretics) who are treated with NSAIDs, including selective COX-2 inhibitors, concomitant administration of ARA II or ACE inhibitors may cause further impairment of renal function, including acute renal failure. Usually this effect is reversible, therefore, concomitant use of these drugs should be conducted with caution in patients with impaired renal function.

Double RAAS blockade with APA II, ACE inhibitors or aliskiren (renin inhibitor) is associated with an increased risk of arterial hypotension, syncope, hyperkalemia and impaired renal function (including acute renal failure) compared to monotherapy. Regular monitoring of BP, renal function and blood electrolytes in patients taking Bloktrane® GT and other drugs that affect the RAAS at the same time is necessary. Blocktragar® GT should not be used concomitantly with aliskiren in patients with diabetes mellitus. Concomitant use of Blocktragar® GT and aliskiren should be avoided in patients with renal insufficiency (FFR less than 60 ml/min).

Hydrochlorothiazide

The following effects have been described with the following drugs concomitantly used with hydrochlorothiazide.

Ethanol, barbiturates, and narcotic analgesics-may potentiate the risk of orthostatic hypotension.

Hypoglycemic agents (oral and insulin) – Dose adjustment of hypoglycemic agents may be required.

Other hypotensive agents – additive effect.

Colestyramine and colestipol- in the presence of anion exchange resins, absorption of hydrochlorothiazide is impaired. Colestiramine or colestipol in a single dose binds hydrochlorothiazide and reduces its absorption in the gastrointestinal tract by 85% and 43%, respectively.

Corticosteroids, corticotropin, glycyrrhizic acid (contained in licorice root)-expressed decrease in electrolytes, especially potassium (risk of hypokalemia).

Pressor amines (e.g., epinephrine) – possible reduced response to the administration of pressor amines, but does not preclude their simultaneous use.

Myorelaxants of the non-depolarizing type of action (e.g., tubocurarine) – possible enhancement of the effects of myorelaxants.

Lithium – Diuretics decrease renal clearance of lithium and increase the risk of lithium toxicity. Their simultaneous use is not recommended. Before prescribing lithium preparations, refer to the instructions for their use.

NSAIDs (including COX-2 inhibitors)- In some patients, NSAIDs, including selective COX-2 inhibitors, may decrease the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide.

In some patients with impaired renal function (e.g., elderly patients or patients with dehydration, including those taking diuretics) who have received NSAID therapy, including COX-2 inhibitors, treatment with ARA II or ACE inhibitors may cause further impairment of renal function, including development of acute renal failure. These effects are usually reversible. Therefore, concomitant use of these drugs should be conducted with caution in patients with impaired renal function.

Influence of the drug on the results of laboratory tests

In connection with the effect of thiazide diuretics on calcium metabolism, their administration may distort the results of parathyroid gland function tests (see section “Special Precautions”).

Special Instructions

Lozartan-hydrochlorothiazide

Hypersensitivity reactions

.In patients with a history of angioedema (swelling of the face, lips, pharynx/larynx and/or tongue) the use of the drug should be monitored (see section “Adverse effects”). See section “Side effects”).

Renal dysfunction

Blocktran® GT is contraindicated in patients with severe hepatic dysfunction and severe renal dysfunction (CKG of 30 ml/min or less) (see “Contraindications. See section “Contraindications”).

Embryotoxicity

The use of drugs affecting the RAAS in the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and mortality. The development of oligohydramnios may be associated with fetal lung hypoplasia and skeletal deformities. Possible adverse events in neonates include skull bone hypoplasia, anuria, arterial hypotension, renal failure, and death. If pregnancy is diagnosed, Bloctran® GT should be withdrawn immediately (see section “Use in pregnancy and during breastfeeding”).

Lozartan

.Arterial hypotension and decreased circulating blood volume (CBC)

.Asymptomatic arterial hypotension may occur in patients with decreased RBC or blood sodium content due to intensive therapy with diuretics, dietary restriction of table salt, diarrhea or vomiting, especially after the first dose of Bloctran® GT. Correction of such conditions should be performed before prescribing Bloktran® GT.

Water-electrolyte imbalance

Water-electrolyte imbalance is common in patients with renal insufficiency with or without diabetes, therefore these patients should be closely monitored. Blood potassium or IQ should be monitored closely, especially in patients with heart failure and IQ of 30-50 ml/min.

When treated with Bloctran® GT, potassium-saving diuretics, potassium supplements or potassium containing salt substitutes are not recommended.

Aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy

.As with all drugs with vasodilatory effects, APA II should be prescribed with caution in patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Ischemic heart disease and cerebrovascular disease

.As with all drugs with vasodilator effects, ARA II should be prescribed with caution in patients with ischemic heart disease or cerebrovascular disease, as excessive BP reduction in this group of patients may lead to myocardial infarction or stroke.

Chronic Heart Failure

As with other drugs acting on the RAAS, patients with CHF and with or without impaired renal function are at risk of developing severe arterial hypotension or acute renal failure.

Primary hyperaldosteronism

.Because patients with primary hyperaldosteronism generally do not respond positively to therapy with hypotensive agents that act by inhibiting the RAAS, the use of Bloctran® GT is not recommended in this patient population.

Hepatic dysfunction

According to pharmacokinetic studies, plasma concentrations of losartan are significantly increased in cirrhotic patients, therefore patients with a history of mild to moderate hepatic impairment should use Blocktaran® GT with caution. There is no experience of using losartan in patients with severe hepatic impairment (more than 9 points on the Child-Pugh score), so Bloketran® GT should not be used in this group of patients (see sect.

Kidney function impairment

In some predisposed patients, changes in renal function, including renal failure, have been observed as a result of RAAS inhibition. These changes have been reversible and disappeared after discontinuation of therapy.

Some drugs affecting the RAAS can increase blood urea and serum creatinine concentrations in patients with bilateral renal artery stenosis or renal artery stenosis of the single kidney. Similar effects have been reported with losartan. Such renal dysfunction may be reversible after discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or renal artery stenosis of the single kidney.

Hydrochlorothiazide

Arterial hypotension and water-electrolyte imbalance

Some patients may develop symptomatic arterial hypotension when using hypotensive agents. Patients should be watched for timely detection of clinical signs of water-electrolyte balance disorders, such as dehydration, hyponatremia, hypochloremic alkalosis, hypomagnesemia or hypokalemia, which may develop with concomitant diarrhea or vomiting. Regular monitoring of serum electrolytes in such patients is necessary. In patients with edemas, dilutional hyponatremia may be observed in hot weather.

Metabolic and endocrine effects

The thiazide therapy may impair glucose tolerance. In some cases it may be necessary to adjust the dose of hypoglycemic agents, including insulin (see section “Interaction with other medicinal products”).

The thiazides may decrease renal calcium excretion and cause a transient and slight increase in serum calcium. Severe hypercalcemia may indicate occult hyperparathyroidism. Due to the effect of thiazides on calcium metabolism, their administration may distort the results of parathyroid function study, so the thiazide diuretic should be discontinued before parathyroid function study.

Elevated blood cholesterol and triglyceride concentrations may also be associated with thiazide diuretic therapy.

In some patients, thiazide diuretics may lead to hyperuricemia and/or gout. Because losartan reduces uric acid concentrations, its concomitant use with hydrochlorothiazide reduces the severity of diuretic-induced hyperuricemia.

Hepatic dysfunction

Tiazides should be used with caution in patients with impaired liver function or advanced liver disease, as this may lead to intrahepatic cholestasis, and minor changes in water-electrolyte balance may provoke the development of hepatic coma.

The drug Blocktaran® GT is contraindicated in patients with severe hepatic impairment.

Acute myopia and secondary closed-angle glaucoma

Hydrochlorothiazide is a sulfonamide that can cause idiosyncratic reactions in the form of acute transient myopia and acute closed-angle glaucoma. Symptoms include a sudden decrease in visual acuity or eye pain, which usually appears within hours or weeks of starting therapy with hydrochlorothiazide. Untreated, an acute attack of closed angle glaucoma may lead to permanent loss of vision. Treatment: Hydrochlorothiazide should be stopped as soon as possible. If intraocular pressure remains uncontrolled, emergency medication or surgery may be necessary. Risk factors for acute angle-closure glaucoma include a history of allergic reaction to sulfonamides or penicillin.

Other effects

In patients taking thiazide diuretics, hypersensitivity reactions may occur even in the absence of a history of allergic reactions or bronchial asthma. Relapses or worsening of the severity of systemic lupus erythematosus have been reported in patients taking thiazide diuretics.

Special patient groups

Race

.An analysis of data from the entire population of patients enrolled in the LIFE study of the effect of losartan on reducing the incidence of the primary composite measure of the study in patients with AH and left ventricular hypertrophy (n=9193) showed that the ability of losartan compared with atenolol to reduce the risk of stroke and myocardial infarction and reduce cardiovascular mortality in patients with AH and left ventricular hypertrophy (by 13.0%, p=0.021) did not extend to non-Hispanic patients, although both therapies effectively reduced BP levels in these patients. In this study, losartan compared with atenolol reduced cardiovascular morbidity and mortality in patients with AH and left ventricular hypertrophy of all races except non-Hispanic (n=8660, p=0.003). However, in this study, patients of non-HG races receiving atenolol had a lower risk of developing the main composite criterion of the study evaluation (that is, a lower combined incidence of cardiovascular mortality, stroke, and myocardial infarction) compared with patients of the same race taking losartan (p=0.03).

Children and adolescents

The efficacy and safety of Bloctran® GT in children and adolescents under 18 years of age has not been established.

If neonates whose mothers have taken a combination of losartan and hydrochlorothiazide during pregnancy develop oliguria or arterial hypotension, symptomatic therapy to maintain BP and renal perfusion is necessary. Blood transfusion or dialysis may be required to prevent the development of arterial hypotension and/or to maintain renal function.

Patients in the elderly

Clinical studies have not demonstrated any differences in the safety and effectiveness of the combination of losartan and hydrochlorothiazide in elderly patients (over 65 years).

Nemelanoma skin cancer

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

Patients taking hydrochlorothiazide as monotherapy or in combination with other medications should be aware of the risk of NSCLC. These patients are advised to have regular skin examinations to look for any new suspicious lesions as well as changes to existing skin lesions.

All suspicious skin changes should be immediately reported to the physician. Suspicious skin areas should be examined by a specialist. Histological examination of skin biopsy specimens may be necessary to confirm the diagnosis.

Patients should be advised to use preventive measures such as limiting exposure to sunlight and UV radiation and appropriate protective equipment to minimize the risk of developing SLE.

In patients with a history of nonmelanoma skin cancer, it is recommended that hydrochlorothiazide be reconsidered.

Influence on the ability to drive and operate vehicles

No studies have been conducted to evaluate the effect on the ability to drive and operate machinery. Some side effects of the drug, such as dizziness, weakness, drowsiness and visual disturbances may adversely affect the ability to drive vehicles and perform potentially dangerous activities requiring increased concentration and rapid psychomotor reactions (see section “Side effects”). Caution should be exercised while driving vehicles or operating mechanisms.

Synopsis

Circular, biconvex film-coated tablets from light pink to dark pink or dark pink with violet tint. On cross section the core is white or almost white.

Blocktran® GT is a hypotensive agent and is a combined product of losartan and hydrochlorothiazide. The components of Blocktaran GT have an additive antihypertensive effect, lowering blood pressure (BP) to a greater extent than each of the components separately. Lozartan has a moderate and transient uricosuric effect. In combination with hydrochlorothiazide, losartan reduces the risk of cardiovascular morbidity and mortality.

The drug is available in tablet form (12.5 mg + 50 mg). It is indicated for arterial hypertension to decrease risk of associated cardiovascular morbidity and mortality in patients with arterial hypertension and left ventricular hypertrophy, manifested by cumulative decrease in cardiovascular mortality, stroke and heart attack frequency.

It has contraindications. Prescription is available.

Prescription.

Contraindications

– anuria;
– concomitant use with aliskiren in patients with diabetes mellitus (see.
– severe renal function disorders (creatinine clearance less than 30 ml/min);
– severe liver function disorders (more than 9 points on the Child-Pugh scale);
– pregnancy and breast-feeding;
– age less than 8 years (the effectiveness and safety of use have not been established.- age less than 8 years old (efficacy and safety of use have not been established);
– hypersensitivity to any drug component;
– hypersensitivity to other sulfonamide derivatives;
– lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

With caution

Bilateral renal artery stenosis or artery stenosis of the single kidney; hyperkalemia; conditions after renal transplantation (no experience of use); aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy; heart failure with concomitant severe renal failure; heart failure with life-threatening arrhythmias; ischemic heart disease; cerebrovascular disease; primary hyperaldosteronism; history of angioedema; acute onset myopia and closed-angle glaucoma (on hydrochlorothiazide).
Symptomatic arterial hypotension may occur in patients with decreased circulating blood volume (e.g., those treated with high doses of diuretics).
Nemelanoma skin cancer in anamnesis (see section “Special Precautions”).

Side effects

In clinical trials with losartan-hydrochlorothiazide, no adverse events specific to this combination drug were observed.

The adverse events were limited to those previously reported with losartan and/or hydrochlorothiazide alone. The cumulative incidence of adverse events reported with this combination was comparable to that with placebo. The rate of therapy withdrawal was also comparable to that of patients taking placebo.

In general, treatment with losartan-hydrochlorothiazide was well tolerated. In most cases, the adverse reactions were mild and transient and did not require discontinuation of therapy.

In controlled clinical studies of AH treatment, dizziness was the only adverse reaction associated with the drug and had a greater than 1% frequency of adverse reactions compared to placebo.

Losartan in combination with hydrochlorothiazide has been shown to be generally well tolerated in patients with AH and left ventricular hypertrophy in controlled clinical trials. The most common adverse events were systemic and non-systemic dizziness, weakness/increased fatigue.

The following additional adverse reactions have been reported during post-registration use of the drug, clinical studies conducted and/or post-registration use of individual active ingredients of the drug.

Blood and lymphatic system:thrombocytopenia, anemia, aplastic anemia, leukopenia, agranulocytosis, hemolytic anemia.

From the immune system: Anaphylactic reactions, angioedema, including laryngeal and vocal fold edema with development of airway obstruction and/or edema of the face, lips, pharynx and/or tongue in patients taking losartan were rarely observed (> 0.01% and 0.1% cases); some of these patients had a history of developing angioedema when using other medications, including ACE inhibitors.

Metabolism and nutrition: anorexia, hyperglycemia, hyperuricemia, blood electrolyte imbalances, including hyponatremia and hypokalemia.

Mental disorders: insomnia, anxiety.

Nervous system disorders:dysgeusia, headache, migraine, paresthesia.

Visual disorders: xanthopsia, transient visual focusing disorder.

Cardiac side: palpitations, tachycardia.

Vascular side: dose-dependent orthostatic effects, necrotizing angiitis (vasculitis), cutaneous vasculitis.

Injuries to the respiratory system, thoracic and mediastinal organs: nasal congestion, cough, pharyngitis, sinus disorders (sinusitis), upper respiratory tract infections, adult respiratory distress syndrome (including pneumonitis and pulmonary edema).

Gastrointestinal tract disorders: dyspepsia, abdominal pain, esophageal reflux, gastrointestinal colic, diarrhea, constipation, nausea, vomiting, pancreatitis, sialadenitis.

Hepatic and biliary tract disorders:hepatitis, jaundice (intrahepatic cholestatic jaundice).

Skin and subcutaneous tissue: photosensitization, skin itching, skin rash, purpura (including Schönlein-Henoch purpura), toxic epidermal necrolysis, urticaria, erythroderma, lupus-like syndrome.

Muscular and connective tissue: muscle cramps, myalgia, back pain, arthralgia, muscle spasms.

Kidney and urinary tract disorders: glucosuria, impaired renal function, interstitial nephritis, renal failure.

Gender and mammary gland disorders: erectile dysfunction/impotence. General disorders and disorders at the site of administration: chest pain, edema, malaise, weakness, fever.

Laboratory and instrumental data: liver function disorders (rarely increased alanine aminotransferase activity).

Laboratory findings

In controlled clinical studies, clinically significant changes in standard laboratory parameters were rarely observed with the combination of losartan and hydrochlorothiazide. Hyperkalemia (serum potassium > 5.5 mEq/L) was observed in 0.7% of patients, but in these studies there was no need to cancel the drug due to hyperkalemia. Elevation of alanine aminotransferase activity was rarely observed; it usually returned to normal after discontinuation of therapy.

Overdose

There are no data on the specific treatment of overdose with Bloketran® GT. In case of overdose the drug Bloktran® GT should be discontinued, the patient should be carefully monitored for vital organ function parameters, symptomatic therapy – induction of vomiting if the drug was taken recently, as well as treatment of dehydration, water-electrolyte disturbances, hepatic coma and BP reduction using standard methods.

Lozartan

There is limited evidence of overdose. The most likely manifestation of overdose:

Magnified BP decrease, tachycardia; bradycardia due to parasympathetic (vagus) stimulation may occur.

Treatment: symptomatic therapy.

Lozartan and its active metabolite are not excreted by hemodialysis.

Hydrochlorothiazide

The most common symptoms of overdose are due to electrolyte deficiency (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. When concomitant administration of cardiac glycosides, hypokalemia may aggravate the course of arrhythmias.

It is not known to what extent hydrochlorothiazide can be removed from the body by hemodialysis.

Pregnancy use

Drugs acting directly on the RAAS can cause serious damage and death to the developing fetus, so Bloctran® GT should be stopped immediately if pregnancy is diagnosed.

While there is no experience with Bloctran® GT in pregnant women, preclinical animal studies have shown that administration of losartan causes serious fetal and neonatal damage and death to the fetus or offspring.

The mechanism of these events is thought to be due to effects on the RAAS.

Fetal renal perfusion dependent on the development of RAAS appears in the second trimester, so the risk to the fetus is increased if Bloctran® GT is used in the second or third trimester of pregnancy.

The use of drugs affecting the RAAS during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and mortality. The development of oligohydramnios may be associated with fetal lung hypoplasia and skeletal deformities. Possible adverse events in newborns include skull bone hypoplasia, anuria, arterial hypotension, renal failure, and death.

The above mentioned adverse outcomes are usually caused by the use of drugs affecting the RAAS in the second and third trimesters of pregnancy. Most epidemiologic studies of fetal abnormalities after the use of hypotensive drugs in the first trimester of pregnancy have found no differences between RAAS-acting drugs and other hypotensive agents. When prescribing hypotensive therapy in pregnant women it is important to optimize possible outcomes for the mother and fetus.

If an alternative therapy cannot be selected to replace therapy with drugs acting on the RAAS, the patient should be informed about the possible risks of therapy for the fetus. Periodic ultrasound examinations should be performed to assess the intra-amniotic space. If oligohydramnion is detected, Bloctran ® GT should be discontinued unless it is vital for the mother. Depending on the week of pregnancy, appropriate fetal tests should be performed. Patients and physicians should be aware that oligohydramnios may not be detected until irreversible fetal damage has occurred. Careful monitoring of newborns whose mothers have taken Bloctran® GT during pregnancy is necessary to control arterial hypotension, oliguria and hyperkalemia.

Thiazides penetrate the placental barrier and are found in umbilical cord blood. Diuretics use in healthy pregnant women is not recommended because it increases the risk of fetal adverse events such as development of fetal and neonatal jaundice, thrombocytopenia and other possible adverse reactions that have been observed in adult patients. Diuretics do not prevent the development of maternal toxemia, and there is no reliable evidence that they are effective in treating maternal toxemia.

It is not known whether losartan is excreted with breast milk. Thiazides are excreted with breast milk. Because many drugs are excreted with breast milk and there is a risk of possible adverse reactions in the breastfed infant, a decision should be made whether to stop breastfeeding or to discontinue the drug in light of the need for the mother.

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