GIZAAR

Active material: Gidroxlorotiazid, Lozartan
When ATH: C09DA01
CCF: Antihypertensive drugs
ICD-10 codes (testimony): I10
When CSF: 01.09.16.05
Manufacturer: MERCK SHARP & DOHME B.V.. (Netherlands)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills, coated yellow color, Oval, labeled “717” on one side and Valium – another.

Excipients: microcrystalline cellulose, lactose, water, pre-gelatinized starch, magnesium stearate.

The composition of the shell: hydroxypropyl, hydroksypropyltsellyuloza, Titanium dioxide, quinoline yellow aluminum lake, carnauba wax.

7 PC. – blisters (1) – cardboard boxes.
7 PC. – blisters (2) – cardboard boxes.
14 PC. – blisters (1) – cardboard boxes.
14 PC. – blisters (2) – cardboard boxes.

Gizaar^® forte

Pills, Film-coated white, Oval, Engraved “745” on one side.

Excipients: microcrystalline cellulose (Avicel PH102), lactose monohydrate, pregelatinized corn starch 1500, magnesium stearate.

The composition of the coating film: giproloza, gipromelloza, Titanium dioxide (E171), carnauba wax.

10 PC. – blisters (5) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.

Pharmacological action

Antihypertensive drugs of the combined structure.

Active substance formulation Gizaar® exert an additive antihypertensive effect, reducing blood pressure to a greater degree, than either component separately. Due hydrochlorothiazide diuretic effect increases plasma renin activity (ARP), It stimulates the secretion of aldosterone, Angiotensin II increases the level and lowers the level of potassium in blood serum. Losartan blocks all physiological effects of angiotensin II and aldosterone effects due to the suppression helps to reduce loss of potassium, called diuretics.

Losartan has a mild and transient effect urikozuricheskim. Hydrochlorothiazide causes a slight increase in the level of uric acid in the blood; the combination of losartan and hydrochlorothiazide reduces the severity of hyperuricemia, caused by the diuretic.

Lozartan

Lozartan – antagonist retseptorov angiotensin II.

Angiotensin II is a potent vasoconstrictor, mainly active hormone of the renin-angiotensin system, as well as the decisive pathophysiological link arterial hypertension. Angiotensin II binds to the AT1 receptor subtype, found in many tissues (eg, in vascular smooth muscle, adrenal glands, kidney and heart) and it raises a number of important biological effects, incl. vasoconstriction and aldosterone release. Angiotensin II also stimulates smooth muscle cell proliferation. The role of the second type angiotensin II receptor – subtype AT2 – in cardiovascular homeostasis unknown.

Angiotensin II binds selectively to the AT1-receptor. Losartan and its pharmacologically active metabolite (E-3174) how in vitro, in vivo and block all physiological effects of angiotensin II, regardless of the source or synthetic route. Unlike some peptidic angiotensin II antagonists, Losartan does not have an agonist effect.

Losartan binds selectively to the AT1-receptor and does not bind to or block other hormone receptors and ion channels, play an important role in the regulation of cardiovascular function. Besides, losartan does not inhibit ACE, which promotes the degradation of bradykinin. Hence, effects, not directly related to the blockade of AT1-receptor, in particular, strengthening effect, associated with exposure to bradykinin or the development of edema (lozartan 1.7%, placebo 1.9%), They have nothing to do with the action of losartan.

Losartan eliminates the negative feedback, which consists in suppressing the secretion of renin angiotensin II, which leads to increased blood ATM. Increasing the BDA accompanied by increased angiotensin II levels in plasma. Prolonged (6-weekly) treatment of patients with hypertension losartan 100 mg /, at the time of reaching the maximum blood plasma concentration of the drug, observed a 2-3 fold increase in the level of angiotensin II. In some patients, there was an even greater increase, especially in short duration of treatment (2 of the week). Antihypertensive activity and reduced concentration of plasma aldosterone manifested through 2-6 weeks of therapy, indicating that effective blockade of angiotensin II receptors. ATM and reduced levels of angiotensin II to the initial values ​​via 3 days after discontinuation of losartan. Gizaara impact on the ATM and angiotensin II level was comparable to that at the reception 50 mg losartan.

Since losartan is a specific antagonist of the angiotensin II AT1-receptor, it does not inhibit ACE (kininazu II) – enzyme, which inactivates bradykinin. results of the study, wherein compared action 20 mg 100 mg losartan, and ingibitora AFP of angiotensin I, angiotensin II and bradykinin, shown, losartan that blocks the effects of angiotensin I and angiotensin II, without affecting the effects of bradykinin. These data support a specific mechanism of action of losartan. In turn, ACE inhibitor, blocked the response to angiotensin I and increased severity of the response to Bradykinin, without affecting the intensity of the response to angiotensin II, demonstrating pharmacodynamic difference between losartan and ACE inhibitors.

Concentrations of losartan and its active metabolite in the blood plasma, and the antihypertensive effect of losartan increase with increasing dose. Since losartan and its active metabolite are antagonists of angiotensin II receptors, they both contribute to the antihypertensive effect.

In a clinical study with a single dose of 100 mg losartan, in which included healthy male volunteers, the drug in a highly- and malosolevoy diet had no effect on glomerular filtration rate (SKF), effective renal plasma flow and renal filtration fraction. Losartan showed natriuretic effect, which was more pronounced in the diet and malosolevoy, apparently, It was not associated with suppression of early sodium reabsorption in the proximal renal tubules. Losartan also induced a transient increase in the excretion of uric acid kidney.

In patients with hypertension, proteinuria (> 2 g /), non-diabetic and host for 8 weeks of losartan 50 mg, with a gradual increase to 100 mg, there was a significant decrease in proteinuria 42%. Fractional excretion of albumin also decreased significantly. These patients stabilized losartan reduced GFR and filtration fraction.

In post-menopausal women with hypertension, taking losartan 50 mg / within 4 weeks, It showed no treatment effect on renal and systemic levels of prostaglandins.

Losartan has no effect on autonomic reflexes and has a lasting effect against norepinephrine levels in the blood plasma. In patients with hypertension losartan doses up to 150 mg / not cause clinically significant changes in fasting triglyceride level, total cholesterol and HDL-cholesterol. At the same doses of losartan had no effect on the blood glucose level on an empty stomach.

Generally, losartan caused a decrease in serum levels of uric acid (usually, less 0.4 mg / dL), retains during long-term therapy. In controlled clinical trials, in which included patients with hypertension, Discontinuations due to increased creatinine or potassium levels of the blood serum registered.

In a 12-week, parallel, placebo-controlled study in patients with left ventricular failure (II-IV functional class NYHA classification), most of whom are receiving diuretics and / or digitalis, compared the effects of losartan potassium in doses 2.5, 10, 25 and 50 mg / dose 25 mg 50 mg / drug provided positive Hemodynamic and neurohormonal effects, which were observed throughout the study. Hemodynamic effects included an increase in cardiac index and a decrease in wedge pressure in the pulmonary capillaries, as well as a decrease in systemic vascular resistance, average systemic blood pressure and heart rate. Neurohormonal effects are manifested in the form of lower levels of aldosterone and norepinephrine in the blood.

In patients with hypertension and left ventricular hypertrophy, losartan, often in combination with hydrochlorothiazide, It reduces the risk of cardiovascular morbidity and mortality, that has been proven by evaluating the combined frequencies of stroke and myocardial infarction, as well as the rate of cardiovascular mortality in these patients.

Gidroxlorotiazid

The mechanism of antihypertensive action thiazides unknown. Thiazides do not usually affect the normal levels of blood pressure.

Hydrochlorothiazide is a diuretic and antihypertensive agent. It affects the reabsorption of electrolytes in distal tubules of the kidneys. Hydrochlorothiazide approximately equally increases the excretion of sodium and chloride. Natriuresis is accompanied by a slight loss of potassium ions and bicarbonate.

If ingestion diuretic effect begins 2 no, It reaches a maximum at a mean 4 hours and lasts from 6 to 12 no.

Pharmacokinetics

Absorption

Lozartan

When ingestion of losartan is well absorbed from the gastrointestinal tract, It is metabolized at “first pass” through the liver, resulting form the active carboxylated metabolite and inactive metabolites. Systemic bioavailability of losartan in tablet form is about 33%. Cmax losartan and its active metabolite are achieved through the 1 h and 3-4 h, respectively. When losartan mealtime clinically significant impact on the profile of the plasma concentration of losartan was not detected.

Losartan and its active metabolite are linear pharmacokinetics when losartan inwardly at doses up to 200 mg.

Distribution

Lozartan

Losartan and its active metabolite is bound to plasma proteins (mostly to albumin) more than 99%. Vd is losartan 34 l. Studies in rats have shown, losartan practically does not penetrate the blood-brain barrier.

Gidroxlorotiazid

Hydrochlorothiazide crosses the placental barrier, excreted in breast milk. Do not cross the BBB.

Metabolism

Lozartan

About 14% doses of losartan, entered in / in or into, It is converted into its active metabolite. Following oral administration, and on / in the losartan, 14C-labeled, circulating plasma radioactivity was primarily due to the presence therein of losartan and its active metabolite.

In addition to the active metabolite resulting from hydroxylation of the butyl side chain formed of biologically inactive metabolites, incl. Two main metabolites and one secondary – N-2-tetrazol-glucuronide.

Deduction

Lozartan

Plasma clearance of losartan and its active metabolite is about 600 ml / min 50 ml / min, respectively. Renal clearance of losartan and its active metabolite is about 74 ml / min 26 ml / min, respectively. When losartan in about 4% the dose is excreted in the urine as unchanged, and about 6% dose – in the form of active metabolite.

After oral administration, plasma concentrations of losartan and its active metabolite are reduced with a final polieksponentsialno T1 / 2 of about 2 and h 6-9 h, respectively. In single dose of the drug at a dose of 100 mg / audio losartan, or its active metabolite were not significantly accumulate in the blood plasma.

Excretion losartan and its metabolites occurs in the bile and urine. After oral losartan, 14C-labeled, about 35% radioactivity found in urine and 58% – Calais. After the on / in the losartan, 14C-labeled, about 43% radioactivity detected in urine and 50% – Calais.

Gidroxlorotiazid

Hydrochlorothiazide is not metabolized and is rapidly eliminated by the kidneys. T1 / 2 ranges from 5.6 to 14.8 no. No less 61% of an oral dose is excreted unchanged during 24 no.

Pharmacokinetics in special clinical situations

Lozartan – gidroxlorotiazid

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

Lozartan

Concentrations of losartan in plasma were 2 times higher in hypertensive women than men, suffering from hypertension. This apparent pharmacokinetic difference has no clinical significance. The concentrations of the active metabolite in both men and women did not differ.

In patients with mild to moderate alcoholic cirrhosis of the liver when taken orally concentrations of losartan and its active metabolite in plasma were respectively 5-1.7 times higher, than in young male volunteers.

Concentrations of losartan in the blood plasma of patients with CC more 10 ml / min did not differ from those in patients with intact renal function. AUC lozaratana patients, hemodialysis, was about 2 times, than in patients with normal renal function. Concentrations of the active metabolite in the blood plasma are not changed in patients with impaired renal function or patients, hemodialysis. Losartan and its active metabolite could not be removed by dialysis.

Indications

- Arterial hypertension (patients, which shows the combination therapy);

- Reducing the risk of cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy.

Dosage regimen

Gizaar® can be taken regardless of the meal.

When hypertension is prescribed 1 tablets 1 time /

Gizaar® forte administered to patients without adequate therapeutic response to receiving 1 Gizaar® drug pills 50/12.5 mg for 2-4 weeks. Usually, antihypertensive effect is achieved within 3 weeks after start of therapy. In the absence of the therapeutic effect of the drug dose Gizaar® 50/12.5 mg can be increased to 2 tablets 1 time / maximum dose – 2 Gizaar® drug pills 50/12.5 mg 1 time / or 1 drug tablets Gizaar® forte (100/12.5 mg).

Selection of the initial dose Gizaara for elderly patients is not required.

To reduce the risk of cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy drug administered in a standard initial dose of losartan, component 50 mg 1 time / Patients, who did not manage to achieve the target values ​​of blood pressure in patients receiving losartan 50 mg /, It requires the selection of treatment by a combination of losartan with a low dose of hydrochlorothiazide (12.5 mg), and, in case of need, should increase the dose of losartan to 100 mg in combination with hydrochlorothiazide in a dose of 12.5 mg /, further – increase the dose to 2 tablets Gizaara 50 mg / 12.5 mg (Total 100 mg and losartan 25 mg of hydrochlorothiazide per day once).

Gizaar® fort on 1 tablets 1 time / prescribed to patients, who did not manage to achieve the target values ​​of blood pressure in patients receiving 1 Gizaar® drug pills (50/12.5 mg).

Side effect

In clinical trials with losartan / hydrochlorothiazide adverse events were observed, specific for a given combined formulation.

Adverse reactions were limited to those, which has been reported when using losartan and / or hydrochlorothiazide alone. The overall incidence of adverse events, It reported in the appointment of the combination, It was comparable to that with placebo. The frequency of treatment discontinuation was also comparable to that of patients, placebo. In most cases, adverse reactions were mild, They were transient and did not require discontinuation of therapy.

In controlled clinical trials, dizziness was the only, drug-related, adverse reaction, whose frequency is higher than that for placebo longer, than 1 percent or more.

Losartan in combination with hydrochlorothiazide, generally, well tolerated in patients with hypertension and left ventricular hypertrophy. The most common adverse reactions were dizziness, weakness and fatigue.

During post-marketing experience with the drug were reported following additional adverse reactions.

Allergic reactions and immunopathological reactions: anaphylactic reactions, angioedema, incl. edema of the larynx and the glottis with the development of airway obstruction and / or facial edema, lips, throat and / or tongue, patients, taking losartan; some of these patients there were indications of the development of angioedema in history with other drugs, incl. ACE inhibitors. There are rare reports of the development of vasculitis (in t. no. Henoch-Schonlein) in patients receiving losartan.

From the digestive system: rarely – hepatitis, diarrhea (patients, taking losartan).

The respiratory system: possible cough (patients, taking losartan).

Dermatological reactions: hives, increased light- and photosensitivity.

From the laboratory parameters: in controlled clinical trials in patients receiving the drug Gizaar® standard clinically significant changes in laboratory parameters were noted infrequently. Hyperkalemia (potassium serum more 5.5 meq / l) I observed in 0.7 % patients, that did not require discontinuation of therapy. Increased ALT are rare and usually disappears after discontinuation of therapy.

Contraindications

- Anurija;

- Expressed by the human kidney (CC less than 30 ml / min);

- Expressed human liver;

- Up to 18 years (efficacy and safety have not been established);

- Hypersensitivity to any component of the drug;

- Hypersensitivity to sulfonamide derivative.

Tablets contain lactose, therefore, patients with rare hereditary intolerance to lactose, lactase deficiency or malabsorption of glucose-galactose should not take this drug.

With careful preparation should be applied in case of violation of water and electrolyte balance of blood, such as during diarrhea or vomiting (giponatriemiya, hypochloraemic alkalosis, gipomagniemiya, kaliopenia); in patients with renal insufficiency (CC 30-50 ml / min), with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney; for patients with diabetes; in patients with hypercalcemia, hyperuricemia and / or gout; in patients with a history of allergy, asthma; in systemic connective tissue diseases (incl. SLE); hypovolemia (incl. in patients receiving high doses of diuretics); and while the appointment of NSAIDs (incl. with inhibitors of COX-2).

Application of pregnancy and breastfeeding

Use of the drug is contraindicated in pregnancy Gizaar®.

Use of drugs, have a direct impact on the renin-angiotensin system, in II and III trimester of pregnancy can harm the developing fetus and even cause his death. Immediately after receiving Gizaara established pregnancy should stop.

Adequate and well-controlled clinical studies of the safety Gizaara during pregnancy was conducted.

In experimental animal studies, that the use of losartan may have teratogenic and cause the death of the fetus and newborn, probably due to the influence of the active substance on the renin-angiotensin system.

In fetal human kidney perfusion, which depends on the development of the renin-angiotensin system, It begins in II trimester; thus, the risk of malformations and fetal death increases with the use Gizaara in II and III trimesters of pregnancy.

Thiazides cross the placental barrier and are defined in the umbilical cord blood. The routine use of diuretics in pregnant healthy women is not recommended, tk. This increases the risk of the fetus such as fetal adverse events jaundice and neonatal jaundice, and his mother – thrombocytopenia.

There is no evidence, losartan is excreted in breast milk. However it is known, that thiazides are excreted in breast milk. Due to the risk of adverse events in infants in all cases should be made an informed decision about taking the drug during breastfeeding, taking into account the importance of therapy for mother.

In that case, if it is decided, it is necessary to take the drug Gizaar®, Breastfeeding should be discontinued.

Application for violations of liver function

The drug is contraindicated when expressed human liver.

Application for violations of renal function

The drug is contraindicated when expressed human kidney (CC less than 30 ml / min).

Cautions

Gizaar® can be administered in combination with other antihypertensive agents.

Lozartan

There are reports, that a number of patients, taking the drug, in connection with the suppression of the function of the renin-angiotensin system in renal function changes observed, including kidney failure; These changes were reversible and disappeared after discontinuation of therapy.

other facilities, acting on the renin-angiotensin system, may lead to an increase in the content of urea and creatinine in the blood of patients with bilateral renal artery stenosis and stenosis of the artery to a solitary kidney Similar effects were observed in patients receiving losartan; these changes were reversible renal function and disappeared after discontinuation.

Gidroxlorotiazid

As in the case of receiving any antihypertensives, Symptomatic hypotension may occur in some patients. Patients requires supervision for timely detection of clinical signs of impaired water and electrolyte balance, eg, Dehydration, giponatriemii, gipohloremicheskogo alkalosis, hypokalemia or hypomagnesemia, that may develop on the background of intercurrent diarrhea or vomiting. These patients need to control the level of serum electrolytes.

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

Thiazides may decrease the urinary excretion of calcium and episodic and cause a slight increase in serum calcium level. Marked hypercalcemia may be evidence of hidden hyperparathyroidism.

In connection with the effect of thiazide on calcium metabolism, taking them may distort the results of the research function of the parathyroid glands, so before the investigation of parathyroid function thiazide diuretic should be discontinued.

Increasing the level of cholesterol and triglycerides it may also be associated with thiazide diuretic therapy.

In some patients receiving thiazide diuretics can cause hyperuricemia and / or development of gout. Since losartan reduces uric acid levels, its combination with hydrochlorothiazide reduces the severity of hyperuricemia, caused by the diuretic.

Patients, receiving thiazides, hypersensitivity reactions may occur even if there is no indication of the presence of allergy or bronchial asthma in history. There are reports of acute development or progression of SLE in patients receiving thiazide diuretics.

In the analysis of the entire patient population, included in the LIFE study (Losartan Intervention For Endpoint reduction in hypertension – Impact of losartan on reducing the frequency of end points in hypertensive patients, n=9193), Treatment with losartan was accompanied by a decrease in the risk of reaching the primary composite endpoint (cardiovascular death, stroke, and myocardial infarction) on 13% (p=0.021) compared to atenolol. However, patients blacks, treated with atenolol, had a lower risk of events of the primary composite endpoint compared with Black patients, Accepted losartan (p=0.03).

Use in Pediatrics

Efficacy and safety of the drug in children under the age of 18 s is not installed.

Overdose

overdose of losartan limited data in humans. The most likely overdose symptoms are a marked reduction in blood pressure and tachycardia; aetiology can be a consequence parasympathetic (vagal) stimulation.

Treatment: in the case of symptomatic hypotension is a supportive therapy. Losartan and its active metabolite are output via hemodialysis

The most frequent symptoms of hydrochlorothiazide overdose are due to electrolyte deficiency (kaliopenia, chloropenia, giponatriemiya) and dehydration due to excessive diuresis. At the same time taking cardiac glycosides hypokalemia can exacerbate arrhythmias. Not installed, to what extent hydrochlorothiazide can be removed from the body by hemodialysis.

There is no data about specific treatment of overdose of the drug Gizaar®. Treatment is symptomatic and supportive. The drug should be discontinued, and the patient should be placed under observation. When, if the drug has recently adopted, recommended provocation of vomiting, as well as the elimination of dehydration, electrolyte abnormalities, hepatic coma and reducing blood pressure by standard techniques.

Drug Interactions

Lozartan

In clinical studies, the pharmacokinetics showed no clinically significant interaction of losartan with hydrochlorothiazide, digoksinom, varfarinom, cimetidine, fenoʙarʙitalom, ketoconazole and erythromycin.

The combination of losartan, as well as other means of, angiotensin II or blocking its effects, with potassium-sparing diuretics (eg, spironolactone, triamterene, amilorid), potassium-containing additives or potassium salts can lead to an increase in potassium level in serum.

NSAIDs (incl. selective COX-2 inhibitors) may reduce the effects of diuretics and other hypotensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists may be attenuated while the use of NSAIDs (incl. COX-2 inhibitors).

In some patients with impaired renal function, receiving NSAID therapy, (including COX-2 inhibitors), treatment of angiotensin II receptor antagonists can cause further deterioration in renal function. These effects are usually reversible.

Gidroxlorotiazid

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

With simultaneous application may require a dosage adjustment hypoglycemic agents (for oral and insulin).

In the application of hydrochlorothiazide with other antihypertensive agents observed an additive effect.

In the presence of anionic exchange resins hydrochlorothiazide absorption violated. Colestyramine or colestipol in single doses bind hydrochlorothiazide and reduce its absorption from the digestive tract to 85% and 43%, respectively.

The use of corticosteroids, ACTH leads to a marked decrease in the level of electrolyte, in particular can cause hypokalemia.

May reduce the severity of the response to administration of pressor amines (eg, epinephrine).

May increase the action of muscle relaxants nondepolarizing type of action (eg, tuʙokurarina).

Diuretics reduce the renal clearance of lithium and increase the risk of its toxic effect; the combined use of diuretics and drugs lithium is not recommended.

In some cases, NSAIDs (incl. selective COX-2 inhibitors), may reduce the diuretic, natriuretic and antihypertensive effects of diuretics.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored at a temperature of 15-30 ° C in the reach of children. Shelf life – 3 year.