Bloktran GT tablets coated with film 12.5 mg+50 mg, 20 pcs.

Pharmacotherapeutic group: Hypotensive combination therapy (angiotensin II receptor antagonist [ARA II] + diuretic)

ATC code: C09DA01

Pharmacodynamics:

The components of the drug Bloktran® GT have an additive antihypertensive effect reducing blood pressure (BP) to a greater extent than each of the components separately. Due to the 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 reduce potassium loss associated with diuretic intake.

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

Losartan

Angiotensin II is a powerful vasoconstrictor the main active hormone of the renin-angiotensin-aldosterone system and a crucial pathophysiological link in the development of arterial hypertension. Losartan is an angiotensin II receptor antagonist (type AT|). Angiotensin II binds selectively to AT1 receptors located in many tissues (vascular smooth muscle tissues in adrenal glands, kidneys and heart) and has several important biological functions including vasoconstriction and aldosterone release. Angiotensin II also stimulates smooth muscle cell outgrowth. Losartan and its pharmacologically active metabolite (E 3174) both in vitro and in vivo block all physiological effects of angiotensin II regardless of the source or synthesis pathway.

Losartan does not bind to or block other hormone receptors and ion channels that play an important role in regulating cardiovascular function. In addition, losartan does not inhibit angiotensin-converting enzyme (ACE) responsible for bradykinin degradation. Therefore, bradykinin-mediated side effects (e.g., angioedema) are rare. With losartan, the lack of negative feedback on renin secretion results in an increase in ARP. Increased ARP leads to an increase in plasma angiotensin II. However, antihypertensive activity and decreased plasma aldosterone concentration persist, indicating effective angiotensin II receptor blockade. Losartan and its active metabolite have greater affinity for angiotensin I receptors than for angiotensin II receptors. The active metabolite is 10-40 times more active than losartan. After a single oral administration, the antihypertensive effect reaches a maximum after 6 hours and then gradually decreases within 24 hours. The maximum antihypertensive effect develops 3-6 weeks after starting to take the drug. The antihypertensive effect increases with increasing dose of losartan.

Losartan does not affect vegetative reflexes and has no lasting effect on plasma norepinephrine concentration.

In patients with arterial hypertension and left ventricular hypertrophy, losartan including and in combination with hydrochlorothiazide reduces the risk of cardiovascular morbidity and mortality.

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 electrolyte reabsorption in the distal tubules of the kidneys. Hydrochlorothiazide increases excretion of sodium and chlorine ions about equally. Sodium diuresis may be accompanied by a slight loss of bicarbonate potassium ions and retention of calcium ions in the body. When administered orally, the diuretic effect begins after 2 hours, reaches a maximum on average after 4 hours and lasts 6 to 12 hours.
Pharmacokinetics:

The pharmacokinetics of losartan and hydrochlorothiazide when taken simultaneously are not different from those when they are used separately.

Absorption

Lozartan

. When administered orally, losartan is well absorbed from the gastrointestinal tract and undergoes metabolism by “primary passage” through the liver, resulting in the formation of an active carboxylated metabolite and inactive metabolites involving the CYP2C9 isoenzyme. The systemic bioavailability of losartan is approximately 33%. Maximum concentration (Cmax) of losartan and its active metabolite is reached after 1 h and 3-4 h, respectively. No clinically significant effect on the plasma concentration profile of losartan has been observed when losartan is taken with a normal meal.

Hydrochlorothiazide

Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract when ingested. The time to reach maximum concentration is 15-3 hours.

Distribution

Lozartan

Lozartan and its active metabolite bind to plasma proteins (mainly to 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 binds to plasma proteins by 40-60% penetrates the placental barrier does not penetrate the blood-brain barrier is secreted with breast milk.

Metabolism

Lozartan

About 14% of the dose of losartan administered intravenously or orally is converted to its active metabolite. After oral or intravenous administration of 14C-labeled losartan, the radioactivity of circulating blood plasma is primarily related to the presence of losartan and its active metabolite. In addition to the active metabolite, biologically inactive metabolites are also formed, including two metabolites formed by hydroxylation of the butyl side chain and one minor metabolite, N-2-tetrazol-glucuronide.

Elevation

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 ingested, approximately 4% of the dose is excreted unchanged by the kidneys and approximately 6% of the dose is excreted as an active metabolite. Losartan and its active metabolite have linear pharmacokinetics with oral administration of potassium losartan at doses up to 200 mg. After oral administration, plasma concentrations of losartan and its active metabolite decrease polyexponentially with a terminal elimination half-life (T 1/2) of approximately 2 and 6-9 hours, respectively. Neither losartan nor its active metabolite significantly accumulates in plasma when administered as a single dose of 100 mg. Excretion of losartan and its metabolites is through the intestine and the kidneys. After oral administration of 14C-labeled losartan, approximately 35% of the radioactive label is detected in the urine and 58% in the feces. After intravenous administration of 14C-labeled losartan, approximately 43% of the radioactive label is detectable in urine and 50% in feces.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys. The elimination half-life varies from 56 to 148 hours. At least 61% of the oral dose is excreted unchanged within 24 hours.

Pharmacokinetics in special groups of patients.

In patients with mild to moderate alcoholic cirrhosis, the concentration of losartan was 5 times and the active metabolite 17 times higher than in healthy male volunteers.

In creatinine clearance (CK) above 10 mL/min, plasma concentrations of losartan are not different from those in normal renal 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 eliminated from the body by hemodialysis.

Plasma concentrations of losartan and its active metabolite in elderly patients with arterial hypertension are not significantly different from those in younger male patients with arterial hypertension.

The values of plasma concentrations of losartan in women with arterial hypertension are twice as high as in men with arterial hypertension. Concentrations of the active metabolite do not differ in men and women. This pharmacokinetic difference is not clinically significant.

Indications

Active ingredient

Composition

Core:

The active ingredients:

Potassium losartan – 50 mg, hydrochlorothiazide – 12.5 mg

Excipients: Microcrystalline cellulose – 40.1 mg, potato starch – 23.4 mg, sodium carboxymethyl starch (sodium starch glycolate) – 7.0 mg, lactose monohydrate (milk sugar) – 3,

Povidone (polyvinylpyrrolidone low molecular weight medical, povidone K 17) – 1.4 mg, colloidal silica (aerosil) – 1.4 mg, magnesium stearate – 0.7 mg.

Shell:

. Opadray II Pink 57U36011 [hypromellose (HPMC 2910) – 2.0150 mg, polydextrose – 1.6900 mg, titanium dioxide (E171) – 1.6887 mg, talc – 0.4550 mg, maltodextrin or dextrin – 0.3250 mg, medium-chain triglycerides 0.2600 mg, carmine red dye (Carmine E120) – 0.0663 mg] – 6.5 mg.

How to take, the dosage

Bloctran® GT is taken orally, regardless of meals, and the number of times per day.

Hypertension

The initial and maintenance dose is 1 tablet once daily. In individual cases, to achieve a greater effect, the dose is increased to 2 tablets once a day. The maximum daily dose is 2 tablets of Bloktran® GT. It is not required to adjust the dose in elderly patients and patients with moderate renal insufficiency (CKD 30-50 ml/min).

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

The standard starting dose of losartan is 50 mg once daily. Patients who have failed to achieve target BP on losartan 50 mg/day should be treated by combining losartan with low-dose hydrochlorothiazide (125 mg) and, if necessary, the dose of losartan should be increased to 100 mg combined with hydrochlorothiazide 125 mg/day and further increased to 2 tablets of Bloktran® GT (100 mg losartan and 25 mg hydrochlorothiazide once daily).

Interaction

May be administered with other hypotensive agents.

Lozartan

There have been no clinically significant pharmacokinetic interactions of the drug with such drugs as hydrochlorothiazide digoxin warfarin cimetidine phenobarbital ketoconazole and erythromycin. Rifampicin decreases the concentration of the active metabolite. The clinical significance of this interaction has not been established. As with other drugs that block angiotensin II formation and its effects, concomitant administration of potassium-saving diuretics (spironolactone triamterene amiloride eplerenone) potassium-containing supplements and salts containing potassium may lead to an increase in serum potassium. As with other agents affecting sodium excretion, treatment with losartan may be accompanied by decreased excretion and increased serum concentrations of lithium, therefore serum concentrations should be monitored when concomitant treatment with lithium preparations.

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

In some patients with impaired renal function who have been treated with NSAIDs including COX-2 selective inhibitors, concomitant administration of angiotensin II receptor antagonists may cause further impairment of renal function including acute renal failure. This effect is usually reversible. Dual RAAS blockade – combined use of angiotensin II receptor blocker and ACE inhibitor – leads to a significant increase in the frequency of adverse events such as arterial hypotension fainting hyperkalemia impaired renal function acute renal failure. The highest risk is in patients diagnosed with atherosclerosis heart failure diabetes mellitus (with any complication). Double RAAS blockade (for example, by simultaneous prescription of ACE inhibitor and angiotensin II receptor antagonist) should be solved individually in each case with careful monitoring of renal function.

The CYP2C9 isoenzyme inhibitor fluconazole decreases plasma concentrations of the active metabolite and increases losartan concentrations, but the pharmacodynamic significance of this phenomenon has not been established. Individuals who do not metabolize losartan to the active metabolite have been shown to have a very rare and specific defect in the CYP2C9 isoenzyme.

Hydrochlorothiazide

Concomitant use with barbiturates narcotic analgesics and ethanol may result in orthostatic hypotension. In concomitant use with hypoglycemic agents (for oral administration and insulin) the dose of hypoglycemic agents may need to be adjusted. Because of the risk of lactoacidosis due to possible renal dysfunction, metformin should be used with caution when using hydrochlorothiazide.

In concomitant use with other hypotensive agents, an additive effect is observed.

Concomitant use with lithium salts should be avoided (renal clearance of lithium decreases and its toxicity increases).

Concomitant use with corticosteroids adrenocorticotropic hormone glycyrrhizic acid (contained in licorice root) amphotericin B results in a marked decrease in electrolytes especially potassium.

Concomitant use with nondepolarizing myorelaxants (tubocurarine) may increase their effect.

NSAIDs including selective COX-2 inhibitors may decrease the diuretic natriuretic and antihypertensive effects of hydrochlorothiazide. A single administration of colestiramine or colestipol may reduce absorption of hydrochlorothiazide in the gastrointestinal tract by 85 and 43%, respectively. Simultaneous use of the drug with pressor amines (norepinephrine epinephrine) may slightly reduce the effect of pressor amines. Medicines used for the treatment of gout (probenecid sulfinpyrazone and allopurinol) – dose adjustment may be required (increasing the dose of probenecid and sulfinpyrazone) because hydrochlorothiazide may increase the concentration of uric acid in the blood serum. Concomitant use of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol. Anticholinergic agents (e.g., atropine biperidene) – increase bioavailability of thiazide diuretics by reducing gastrointestinal motility and gastric emptying rate.

Thiazide diuretics may decrease renal excretion of cytotoxic drugs (e.g., cyclophosphamide methotrexate) and enhance their myelosuppressive effect.

Thiazide diuretics may increase the toxic effects of salicylates on the central nervous system when used in high doses.

Individual cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.

The concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout.

Hypokalemia or hypomagnesemia caused by thiazide diuretics may contribute to arrhythmias when used concomitantly with cardiac glycosides.

. Concomitant use of thiazide diuretics with antiarrhythmic drugs (quinidine hydroquinidine disopyramide amiodarone sotalol dofetilide ibutilide) some antipsychotic drugs (neuroleptics) (thioridazine chlorpromazine levomepromazine trifluoperazine ciamemazine sulpiride sultopride amisulpride thiapride pimozide haloperidol droperidol) and other drugs (bepridil cisapride difemanyl erythromycin halofantrine misolastine pentamidine terfenadine vincamine) may be accompanied by the development of hypokalemia which in turn may cause “pirouette” type arrhythmia.

Thiazide diuretics can lead to hypercalcemia as a result of decrease of its excretion; therefore it is necessary to control serum calcium levels. Because of the effect of thiazide diuretics on calcium metabolism, their administration may distort the results of parathyroid gland function tests.

In concomitant use with carbomazepine there is a risk of symptomatic hyponatremia.

In case of dehydration with diuretics there is a possibility of acute renal failure especially with concomitant use of iodine preparations.

Special Instructions

Contraindications

Side effects

The incidence of adverse effects is classified according to the World Health Organization guidelines: very common, at least 10%; common, at least 1% but less than 10%; infrequent, at least 01% but less than 1%; rare, at least 001% but less than 01%; very rare, 001% including isolated reports.

In clinical trials with losartan/hydrochlorothiazide, no adverse events specific to this combination drug were observed. Adverse events were limited to those previously reported with losartan and hydrochlorothiazide alone.

The following adverse events were observed when using losartan and hydrochlorothiazide in monotherapy.

Lozartan

Blood and lymphatic system disorders: infrequent anemia Schoenlein-Genoch purpura ecchymosis hemolytic anemia.

Allergic reactions: rare – anaphylactic reactions angioedema urticaria.

Metabolism and nutrition: infrequent – anorexia exacerbation of gout. Central nervous system: common – headache dizziness insomnia; infrequent – anxiety paresthesia peripheral neuropathy tremor migraine fainting anxiety anxiety panic disorder confusion depression sleepiness sleep disorders memory impairment.

A visual organ disorders: infrequent – visual disturbances with dryness and burning sensation in the eyes conjunctivitis decreased visual acuity.

Hearing organ: infrequent – vertigo tinnitus.

The respiratory system frequently – nasal congestion cough upper respiratory tract infections (fever in the throat sinusopathy sinusitis pharyngitis); infrequent – pharyngitis laryngitis dyspnea bronchitis rhinitis nasal bleeding discomfort in the throat area.

Gastro-intestinal tract: frequently – nausea diarrhea dyspeptic phenomena abdominal pain; infrequently – dry mucous membrane of the mouth toothache vomiting flatulence gastritis constipation.

Musculoskeletal system: often – cramps myalgia back pain in legs; infrequent – arthralgia pain in hands in shoulder knee arthritis fibromyalgia muscle weakness swollen joints musculoskeletal pain.

Cardiovascular system disorders: infrequent – arterial hypotension orthostatic hypotension (dose-dependent) palpitations tachy or bradycardia arrhythmia angina pectoris chest pain Grade II AV blockade cerebrovascular events myocardial infarction vasculitis.

Urogenital system disorders: infrequent nycturia, frequent urination urinary tract infections, impaired libido, impotence.

Skin disorders: infrequent dry skin erythema “rush” of blood to the skin photosensitization itching skin rash increased sweating alopecia dermatitis.

Others: frequent – asthenia increased fatigue; infrequent – facial edema fever. Laboratory indices: frequently – hyperkalemia, decrease of hematocrit and hemoglobin; infrequent – increase of concentration of urea and creatinine; very rarely – increase of liver transaminases activity.

Hydrochlorothiazide

Blood and lymphatic system disorders: infrequent – agranulocytosis aplastic anemia hemolytic anemia leukopenia purpura thrombocytopenia.

Allergic reactions: rare – anaphylactic reactions.

Metabolism and nutrition: infrequent – anorexia hyperglycemia hyperuricemia hypokalemia hyponatremia.

Nervous system disorders: frequent – headache infrequent – dizziness insomnia.

An organ of vision: infrequent – transient visual impairment xanthopsia.

Cardiovascular system: infrequent – necrotizing vasculitis.

Respiratory system disorders: infrequent respiratory distress syndrome, pneumonitis and pulmonary edema.

Gastrointestinal system: infrequent – sialodenitis irritation of the mucous membrane of the gastrointestinal tract nausea vomiting diarrhea constipation jaundice (intra-hepatic cholestasis) pancreatitis.

Skin and subcutaneous tissue disorders: infrequent photosensitization urticaria toxic epidermal necrolysis.

Motor system disorders: infrequent – muscle cramps.

Urinary system disorders: infrequent glucosuria interstitial nephritis renal failure.

General disorders: infrequent – fever.

The following adverse events have been observed during postmarketing use of losartan/hydrochlorothiazide:

Digestive system: rarely – hepatitis.

Laboratory parameters: rare – hyperkalemia increased activity of “hepatic” transaminases.

Overdose

There are limited data on the specific treatment of overdose of losartan/hydrochlorothiazide combination. In case of overdose the drug Bloktaran® GT should be discontinued patient should be provided with close monitoring of the parameters of vital organs functions carrying out symptomatic therapy – induction of vomiting if the drug is taken recently as well as elimination of dehydration electrolyte disturbances hepatic coma and BP reduction using standard methods.

Lozartan

Symptoms: marked decrease in BP tachycardia may appear bradycardia due to parasympathetic (vagus) stimulation.

Treatment: maintenance therapy is indicated in case of marked BP decrease. Losartan and its active metabolite are not excreted by hemodialysis.

Hydrochlorothiazide

Symptoms: electrolyte deficiency (hypokalemia hypochloremia hyponatremia); dehydration (due to excessive diuresis). When concomitant administration of cardiac glycosides, hypokalemia may aggravate the course of arrhythmias.

Treatment: if the drug was taken recently – gastric lavage administration of activated charcoal; if necessary, correction of water-electrolyte disturbances is carried out. It has not been established to what extent hydrochlorothiazide can be removed from the body with hemodialysis.

Pregnancy use

Similarities