GIZAAR Forte - instructions for use, doses, side effects, contraindications

Excipients: microcrystalline cellulose (Avicel PH102) 148.40 mg, lactose monohydrate 88.40 mg, corn starch pregelatinized starch 1500 47.86 mg, magnesium stearate 2.80 mg.

Film coating: giprolose 4.8 mg, hypromellose 4.8 mg, titanium dioxide (E171) 2.4 mg, carnauba wax 0.04 mg.

Description:Oval tablets covered with a film shell, white with engraving "745" on one side.

Pharmacotherapeutic group:Hypotensive combined agent (angiotensin II receptor antagonist [ARA II] + diuretic)

ATX: & nbsp

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

Pharmacodynamics:

Mechanism of action

Preparation Gisaar®Forte

Components of the preparation Gisaar®Forte have an additive antihypertensive effect, reducing the level of arterial pressure (BP) more than each of the components individually. It is believed that this effect is due to complementary action of both components. Due to the diuretic effect hydrochlorothiazide increases the activity of renin of blood plasma (ARP), stimulates the secretion of aldosterone, increases the concentration of angiotensin II and reduces the potassium content in the blood serum.The administration of losartan blocks all the physiological effects of angiotensin II and, due to the suppression of aldosterone effects, can help reduce the loss of potassium associated with taking a diuretic. Losartan has a moderate and transient uricosuric effect. Hydrochlorothiazide causes a slight increase in the concentration of uric acid in the blood. The combination of losartan and hydrochlorothiazide helps reduce the severity of hyperuricemia caused by a diuretic.

Losartan

Angiotensin II is a potent vasoconstrictor, the main active hormone renin-angiotensin-aldosterone systems (RAAS), as well as the decisive pathophysiological link in the development of hypertension (AH). Angiotensin II binds to AT 1 receptors found in many tissues (in the smooth muscle tissues of the vessels, in the adrenal gland, in the kidneys and in the heart) and performs several important biological functions, including vasoconstriction and aldosterone release. In addition, angiotensin II stimulates the proliferation of smooth muscle cells. AT₁-receptors - the second type of receptors with which angiotensin II binds, but its role in regulating the function of the cardiovascular system is unknown. Losartan-selective antagonist of AT₁-receptor angiotensin II, highly effective when administered orally. Losartan and its pharmacologically active carboxylated metabolite (E-3174) as in vitro, and in vivo block all the physiological effects of angiotensin II, regardless of its source or pathway of synthesis. Unlike some peptide angiotensin II antagonists losartan does not possess the properties of an agonist.

Losartan selectively binds to AT₁receptors and does not bind or block receptors of other hormones and ion channels, which play an important role in regulating the function of the cardiovascular system. Besides, losartan does not inhibit angiotensin-converting enzyme (ACE, kininase II), responsible for the destruction of bradykinin. Consequently, effects that are not directly related to AT blockade₁-receptors, such as increased bradykinin-mediated effects or development of edema (losartan 1.7%, placebo 1.9%), are not related to the action of losartan.

Hydrochlorothiazide

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

Hydrochlorothiazide is a diuretic and antihypertensive means.It affects the reabsorption of electrolytes in the distal tubules of the kidneys. Hydrochlorothiazide approximately equally increases the excretion of sodium and chlorine ions. Sodium-sulfur may be accompanied by a small loss of potassium and bicarbonate ions. When ingestion the diuretic effect develops within 2 hours, reaches a maximum on average after 4 hours and lasts from 6 to 12 hours.

Pharmacodynamics

The preparation Gisaar® Forte is a combined preparation of losartan and hydrochlorothiazide. In patients with hypertension and left ventricular hypertrophy losartan, including in combination with hydrochlorothiazide, reduces the risk of cardiovascular morbidity and mortality, as evidenced by the combined incidence of stroke and myocardial infarction, as well as the cardiovascular mortality in this category of patients.

Losartan

Losartan suppresses an increase in systolic and diastolic blood pressure (HELL) with infusion of angiotensin II. In the moment achievements the maximum concentration of losartan in the blood plasma (C_m_Oh) after taking losartan in a dose of 100 mg the above effect angiotensin II is suppressed by approximately 85%, and 24 hours after a single and multiple doses - by 26-39%.

During the administration of losartan, the elimination of negative feedback, consisting of angiotensin inhibition II secretion of renin, leads to an increase in ARP. The increase in ARP leads to an increase in the concentration of angiotensin II in the blood plasma. With long-term (6-week) treatment of patients with AG losartan at a dose of 100 mg / day there was a 2-3-fold increase in the concentration of angiotensin II in blood plasma at the time of reaching C_m_Oh losartan. In some patients, an even greater increase in the concentration of angiotensin II, especially with a short duration of treatment (2 weeks). Despite this, in the process of treatment antihypertensive effect and a decrease in the plasma aldosterone concentration occurred after 2 and 6 weeks of therapy, indicating an effective blockade of angiotensin receptors II. After cancellation of losartan, APP and angiotensin concentration II decreased within 3 days to the values observed before the start of losartan.Effect of Gisaar® Forte on ARP and angiotensin concentration II was similar to the observed effects when taking losartan in a dose of 50 mg.

Because the losartan is a specific antagonist AT₁receptors of angiotensin II, it does not inhibit ACE (kinase II) - an enzyme that inactivates bradykinin. A study comparing the effects of losartan in doses of 20 mg and 100 mg with the effects of an ACE inhibitor on the effect 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 response to angiotensin I and increased the severity of the effects caused by the action of bradykinin, without affecting the severity of the response to angiotensin II, which demonstrates the pharmacodynamic difference between losartan and ACE inhibitors. The concentration of losartan and its active metabolite in the blood plasma, as well as the antihypertensive effect of losartan increase with increasing dose of the drug. As losartan and its active metabolite are antagonists of angiotensin II receptors (ARA II), they both contribute to the antihypertensive effect.

In a study with a single dose of losartan in a dose of 100 mg, in which healthy volunteers (men) were included, taking the drug inward under high and low-fat diet conditions did not affect the glomerular filtration rate (GFR), the effective renal plasma flow and the filtration fraction. Losartan had a natriuretic effect that was more pronounced with a low-sal diet and, apparently, was not associated with the suppression of early sodium reabsorption in the proximal renal tubules. Losartan also caused a transient increase in the excretion of uric acid by the kidneys. In patients with AH, proteinuria (not less than 2 g / 24 h), without diabetes mellitus and taking losartan for 8 weeks at a dose of 50 mg with a gradual increase to 100 mg, there was a significant decrease in proteinuria (by 42%), fractional excretion of albumin and immunoglobulins (IgG). In these patients losartan stabilized GFR and reduced the filtration fraction.

In postmenopausal women, AH, who took losartan in a dose of 50 mg for 4 weeks, there was no effect of therapy on the renal and systemic levels of prostaglandins.

Losartan does not affect vegetative reflexes and does not have a lasting effect on the concentration of noradrenaline in the blood plasma.

In patients with AG losartan in doses up to 150 mg / day did not cause clinically significant changes in the concentration of fasting triglycerides, total cholesterol and high-density lipoprotein cholesterol. In the same doses losartan did not affect the concentration of glucose in the blood on an empty stomach.

Generally losartan caused a decrease in the concentration of uric acid in the blood serum (usually less than 0.4 mg / dL), which persisted with long-term treatment. In controlled clinical trials involving patients with AG cases of withdrawal of the drug due to an increase in the concentration of creatinine or the content of potassium in the blood serum is not documented.

In a 12-week parallel study, which included patients with left ventricular failure (II-IV functional class by classification NYHA), most of whom took diuretics and / or cardiac glycosides, compared the effects of losartan at doses of 2.5, 10, 25 and 50 mg / day 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 increased cardiac index and lowering wedge pressure in the pulmonary capillaries and decrease total peripheral vascular resistance, secondary systemic blood pressure and heart rate. The incidence of arterial hypotension in these patients depended on the dose of the drug. Neurohormonal effects included a decrease in the concentration of aldosterone and norepinephrine in the blood.

Pharmacokinetics:

Suction

Losartan

Ingestion losartan is well absorbed and metabolized by "primary passage" through the liver to form an active carboxylated metabolite and inactive metabolites. Systemic bioavailability of losartan in tablet form is approximately 33%. Medium FROM_m_Oh losartan and its active metabolite are reached after 1 hour and after 3-4 hours, respectively. When losartan was taken during the usual meal, there was no clinically significant effect on the profile of losartan concentration in the blood plasma.

Distribution

Losartan

Lozartan and its active metabolite bind to blood plasma proteins (mainly albumin) notless than 99%. The volume of distribution of losartan is 34 liters. Studies in rats have shown that losartan practically does not penetrate the blood-brain barrier.

Hydrochlorothiazide

Hydrochlorothiazide penetrates the placental (but not blood-brain barrier) and is excreted in breast milk.

Metabolism

Losartan

Approximately 14% of the dose of losartan for intravenous administration or ingestion is converted into its active metabolite. After ingestion or intravenous administration of radiolabeled radiolabel (¹⁴With losartan) the radioactivity of circulating blood plasma is primarily due to the presence in it of losartan and its active metabolite. Low conversion efficiency of losartan in its active metabolite was observed in approximately 1% of patients, participating in the study. In addition to the active metabolite, biologically inactive metabolites are formed, including the two main metabolites formed as a result of hydroxylation of the butyl side chain, and one secondary - N-2-tetrazole-glucuronide.

Excretion

Losartan

The plasma clearance of losartan and its active metabolite is about 600 ml / min and 50 ml / min, respectively.The renal clearance of losartan and its active metabolite is approximately 74 ml / min and 26 ml / min, respectively. When taking losartan, about 4% of the dose is excreted by the kidneys unchanged and about 6% of the dose is excreted by the kidneys as an active metabolite. Losartan and its active metabolite have linear pharmacokinetics when administered to losartan in doses up to 200 mg. After oral administration, the plasma concentrations of losartan and its active metabolite decrease polyexponentially with a finite half-life of about 2 and 6-9 hours, respectively. When the dosing regimen of the drug is 100 mg once a day, there is no significant accumulation in the blood plasma of either losartan or its active metabolite.

Excretion of losartan and its metabolites carried out kidney and through the intestines with bile. After oral administration ¹⁴With losartan in men, about 35% of radioactivity is found in urine and 58% in feces. After intravenous administration ¹⁴With losartan in men, approximately 43% of radioactivity is found in urine and 50% in feces.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized and is quickly excreted through the kidneys. When the plasma level of the drug was monitored for a minimum of 24 hours, the half-life period varied from 5.6 to 14.8 hours.At least 61% of the ingested dose is excreted unchanged for 24 hours.

Pharmacokinetics in specific patient groups

Losartan - hydrochlorothiazide

Elderly patients

The concentration of losartan and its active metabolite in blood plasma and the rate suction of hydrochlorothiazide in elderly patients with AG do not differ significantly from in young patients with AG.

Losartan

Floor

Values of losartan concentration in blood plasma in women with AG 2 times higher than the corresponding values for men with AG. The concentrations of active metabolite in men and women did not differ. This apparent pharmacokinetic difference, however, has no clinical significance.

Patients with impaired hepatic function

When losartan was administered orally to patients with mild and moderate alcoholic cirrhosis, the concentrations of losartan and its active metabolite in blood plasma were respectively 5 and 1.7 times higher than in young healthy male volunteers.

Patients with impaired renal function

Concentrations of losartan in blood plasma in patients with creatinine clearance (CC) above 10 ml / min did not differ from those in patients with unchanged renal function. Area under the curve "concentration-time" (AUC) losartan in patients on hemodialysis was approximately 2 times greater than in AUC losartan in patients with normal renal function. The concentrations of the active metabolite in the blood plasma did not change in patients with impaired renal function or patients on hemodialysis. Losartan and its active metabolite is not output by the hemodialysis procedure.

Indications:

- Arterial hypertension (patients who are shown combined therapy).

- Reducing the risk of associated cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy, manifested by a cumulative reduction in the incidence of cardiovascular mortality, stroke and myocardial infarction.

Contraindications:

- Hypersensitivity to any of the components of this drug.

- Hypersensitivity to other sulfonamide derivatives.

- Anuria.

- Severe violations of kidney function (creatinine clearance less than 30 ml / min).

- Severe liver dysfunction.

- Pregnancy and the period of breastfeeding.

- Age to 18 years (efficacy and safety of use not established).

- Simultaneous use with aliskiren in patients with diabetes mellitus (see INTERACTION WITH OTHER DRUGS).

- Hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

Carefully:

Bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney; hyperkalemia; condition after kidney transplantation (no experience of application); aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy; heart failure with concomitant severe renal insufficiency; heart failure with life-threatening arrhythmias; cardiac ischemia; cerebrovascular diseases; primary hyperaldosteronism; angioedema in history; acute attack of myopia and angle-closure glaucoma (hydrochlorothiazide).

Patients with reduced circulating blood volume (eg, receiving treatment with large doses of diuretics) - symptomatic arterial hypotension may occur.

Pregnancy and lactation:

Drugs that affect directly the RAAS,can cause serious damage and death of the developing fetus, therefore, when diagnosing pregnancy, the preparation Gisaar® Forte should be immediately canceled.

Although there is no experience using Gisaar® Forte in pregnant women, preclinical studies in animals have shown that the administration of losartan leads to the development of severe embryonic and neonatal injuries and fetal or progenital death. It is believed that the mechanism of these phenomena is due to the impact on the RAAS.

Renal perfusion in the fetus, depending on the development of RAAS, appears in the second trimester, so the risk to the fetus increases if the drug Gisaar® Forte is used in the second or third trimester of pregnancy.

The use of drugs that affect RAAS in the second and third trimester of pregnancy reduces the function of the kidneys of the fetus and increases the incidence and mortality of the fetus and newborns. The development of oligohydramnion can be associated with fetal lung hypoplasia and skeletal deformities. Possible adverse events in newborns include hypoplasia of the skull bones, anuria, arterial hypotension, renal failure and death.The above undesirable outcomes are usually due to the use of drugs that affect RAAS in the second and third trimester of pregnancy. Most epidemiological studies on the development of fetal anomalies after the use of antihypertensive drugs in the first trimester of pregnancy have not revealed differences between drugs that affect RAAS and other antihypertensive drugs. When prescribing antihypertensive therapy for pregnant women, it is important to optimize the possible outcomes for the mother and fetus.

If it is not possible to select alternative therapy instead of therapy with drugs that affect RAAS, it is necessary to inform the patient about the possible risk of therapy for the fetus. It is necessary to conduct periodic ultrasound examinations to assess the intra-amniotic space. If oligohydramnion is detected, stop taking Gisaar® Forte, unless it is vital to the mother. Depending on the week of pregnancy, appropriate fetal tests are necessary.Patients and physicians should be aware that the oligohydramnios may not be detected until irreversible damage to the fetus occurs. Careful observation of newborns whose mothers took Gisaar® Forte during pregnancy to control arterial hypotension, oliguria and hyperkalemia is necessary.

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

It is not known whether losartan with breast milk. Thiazides are excreted in breast milk. Since many drugs are excreted in breast milk and there is a risk of developing possible adverse effects in a breastfed infant,should decide whether to stop breastfeeding or to cancel the drug, taking into account the need for its reception for the mother.

Dosing and Administration:

The preparation Gisaar® Forte is taken internally, regardless of food intake. The preparation Gisaar® Forte can be taken in combination with other antihypertensive drugs.

Arterial hypertension

1 Gisaar tablet® Forte once a day. The preparation Gisaar® Forte is prescribed to patients without an adequate therapeutic response to taking 1 tablet of the drug Gisaar® (contains 50 mg of losartan + 12.5 mg of hydrochlorothiazide) once a day for 2-4 weeks. Typically, the antihypertensive effect is achieved within 3 weeks after the initiation of therapy. In the absence of a therapeutic effect, the dose of Gisaar® (50 mg + 12.5 mg) can be increased to 2 tablets once a day. The maximum dose is 2 tablets of the drug Gisaar® (50 mg + 12.5 mg) once a day or 1 tablet of the preparation Gisaar® Forte (100 mg + 12.5 mg).

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

1 tablet preparation Gisaar® Forte once a day. The preparation Gisaar® Forte is prescribed for patients who can not reach the target values of blood pressure on the background of taking 1 tablet of the drug Gisaar® (contains 50 mg of losartan + 12.5 mg of hydrochlorothiazide). If necessary, increase the dose to 2 tablets of the drug Gisaar® (50 mg + 12.5 mg) (total 100 mg of losartan and 25 mg of hydrochlorothiazide) once a day.

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

The preparation Gisaar® Forte (100 mg + 12.5 mg) should not be used for initial therapy in patients with impaired renal function of moderate severity (KK 30-50 ml / min).

The preparation Gisaar® Forte is not recommended for patients on hemodialysis. The preparation Gisaar® Forte should not be used in patients with severe renal dysfunction (CC less than 30 mL / min) (see CONTRAINDICATIONS).

Use in patients with reduced circulating blood volume

The preparation Gisaar® Forte (100 mg + 12.5 mg) should not be used for initial therapy in patients with reduced circulating blood volume.

Use in patients with impaired liver function

The preparation Gisaar® Forte is contraindicated in patients with severe impairment of liver function (see CONTRAINDICATIONS).

Application in elderly patients

Gisaar® Forte (100 mg + 12.5 mg) should not be used for initial therapy in elderly patients.

Side effects:

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 discontinuation of therapy.

In controlled clinical trials in the treatment of hypertension, dizziness was the only drug-related adverse reaction whose frequency exceeded that of placebo by more than 1%.

As shown in controlled clinical trials, losartan in combination with hydrochlorothiazide is generally well tolerated in patients with hypertrophy and left ventricular hypertrophy. The most frequent adverse reactions were systemic and non-systemic dizziness, weakness / increased fatigue. In the course of post-marketing use of the drug, clinical trials and / or post-marketing use of individual active components of the drug, the following additional adverse reactions were reported.

Violations from the blood and lymphatic system: thrombocytopenia, anemia, aplastic anemia, hemolytic anemia, leukopenia, agranulocytosis.

Immune system disorders: anaphylactic reactions, angioedema, including swelling of the larynx and vocal cords with the development of airway obstruction and / or swelling of the face, lips, pharynx and / or tongue in patients taking losartan, were rarely observed (> 0.01% and <0.1% of cases); some of these patients had indications of an angioedema development in the history of using other drugs, including ACE inhibitors.

Disorders from the metabolism and nutrition: anorexia, hyperglycemia, hyperuricemia, disturbances in the balance of blood electrolytes, including hyponatremia and hypokalemia.

Disorders of the psyche: insomnia, anxiety.

Impaired nervous system: dysgeusia, headache, migraine, paresthesia.

Disorders from the side of the organ of vision: xantopsy, transient disturbance of vision focusing.

Heart Disease: palpitation, tachycardia.

Vascular disorders: dose-dependent orthostatic effects, necrotic angiitis (vasculitis), cutaneous vasculitis.

Disturbances from the respiratory system, chest and mediastinal organs: cough, nasal congestion, pharyngitis, sinusitis (sinusitis), upper respiratory tract infections, adult respiratory distress syndrome (including pneumonitis and pulmonary edema).

Disorders from the gastrointestinal tract: dyspepsia, abdominal pain, esophageal reflux, gastrointestinal colic, diarrhea, constipation, nausea, vomiting, pancreatitis, sialadenitis.

Disorders from the liver and bile ducts: hepatitis, jaundice (intrahepatic cholestatic jaundice).

Disturbances from the skin and subcutaneous tissues: rash, skin itch, purpura (including purple Shenlaine-Genocha), toxic epidermal necrolysis, urticaria, erythroderma, photosensitivity, lupus-like syndrome.

Disturbances from the musculoskeletal and connective tissue: back pain, muscle cramps, muscle spasms, myalgia, arthralgia.

Disorders from the kidneys and urinary tract: glucosuria, renal dysfunction, interstitial nephritis, renal failure.

Violations of the genitals and breast: erectile dysfunction / impotence.

General disorders and disorders at the site of administration: pain in the chest, swelling, malaise, fever, weakness.

Laboratory and instrumental data: violations of the liver (rarely increased activity of alanine aminotransferase).

Laboratory indicators

In controlled clinical trials, with the use of the preparation Gisaar® Forte, clinically significant changes in standard laboratory parameters were rarely observed. Hyperkalemia (serum potassium> 5.5 meq / L) was observed in 0.7% of patients, however, in these studies, there was no need to discontinue Gisaar® Forte because of the occurrence of hyperkalemia.The increase in alanine aminotransferase activity was rarely observed and usually returned to normal after the abolition of therapy.

Overdose:

There is no data on the specific treatment of an overdose of Gisaar® Forte. Treatment is symptomatic and supportive. Gisaar® Forte must be discontinued, and the patient must be monitored. If the drug is taken recently, it is recommended to provoke vomiting, as well as to eliminate dehydration, water-electrolyte disorders, hepatic coma, and lowering blood pressure by standard methods.

Losartan

Information on overdose is limited. The most likely manifestation of an overdose is a marked decrease in blood pressure and tachycardia; Bradycardia can occur due to parasympathetic (vagal) stimulation. In the case of symptomatic arterial hypotension, maintenance therapy is indicated. Treatment: symptomatic therapy.

Lozartan and its active metabolite are not excreted by hemodialysis.

Hydrochlorothiazide

The most frequent symptoms of overdose are a consequence of deficiency of electrolytes (hypokalemia, hypochloraemia, hyponatremia) and dehydration due to excessive diuresis.With the simultaneous administration of cardiac glycosides, hypokalemia can aggravate the course of arrhythmias.

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

Interaction:

Losartan

In clinical studies on pharmacokinetic interactions of drugs, clinically significant interactions of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine, and phenobarbital have not been identified. Rifampicin, being an inducer of the metabolism of drugs, reduces the concentration of the active metabolite of losartan in the blood. In clinical studies, the use of two inhibitors of the isoenzyme P450 3A4: ketoconazole and erythromycin has been studied. Ketoconazole did not affect the metabolism of losartan to the active metabolite after intravenous administration of losartan. Erythromycin did not have a clinically significant effect when taking losartan inside. Fluconazole, the inhibitor of the isoenzyme P450 2C9, decreases the concentration of the active metabolite of losartan, however the pharmacodynamic significance of simultaneous application of losartan and inhibitors of the isoenzyme P450 2C9 has not been studied.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. These data suggest that the metabolism of losartan to the active metabolite is carried out by the P450 2C9 isoenzyme, rather than the P450 isoenzyme ZA4.

The simultaneous use of losartan, as well as other drugs blocking angiotensin II or its effects, with potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride), potassium-containing additives or potassium salts may lead to an increase in potassium in the serum.

As with the use of other drugs that affect the excretion of sodium, losartan can reduce the excretion of lithium. Therefore, with the simultaneous use of lithium and ARA II preparations, it is necessary to carefully monitor the concentration of lithium in the blood serum.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2), can reduce the effect of diuretics and other antihypertensive agents. As a result, the antihypertensive effect of APA II or ACE inhibitors may be weakened when used simultaneously with NSAIDs, including selective COX-2 inhibitors.

In some patients with impaired renal function (eg, in elderly patients or patients with dehydration, including those taking diuretics) receiving NSAID therapy, including selective COX-2 inhibitors, concomitant use of ARA II or ACE inhibitors may cause further impairment of function kidney, including the development of acute renal failure. These effects are usually reversible, so the simultaneous use of these medicines should be carried out with caution in patients with impaired renal function. Double blockade of RAAS with the use of ARA II, ACE inhibitors or aliskiren (renin inhibitor) is associated with an increased risk of arterial hypotension, syncope, hyperkalemia and renal dysfunction (including acute renal failure) compared with monotherapy. Regular monitoring of blood pressure, kidney function and electrolyte content in the blood are required for patients taking both the Gisaar® Forte and other drugs that affect RAAS. The preparation Gisaar® Forte should not be used simultaneously with aliskirenom in patients with diabetes mellitus.Avoid simultaneous use of the preparation Gisaar® Forte and aliskiren in patients with renal insufficiency (GFR less than 60 ml / min).

Hydrochlorothiazide

With the simultaneous use of hydrochlorothiazide with the following drugs, the following effects are described.

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

Hypoglycemic agents (for oral administration and insulin) - may be required

dosage correction of hypoglycemic agents.

Other antihypertensives additive effect.

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

Corticosteroids, corticotropin or glycyrrhizic acid (found in licorice root) - marked decrease in electrolytes, in particular, the risk of hypokalemia.

Pressor amines (e.g., epinephrine) - it is possible to reduce the severity of the response to the introduction of pressor amines, but does not exclude the possibility of their simultaneous application.

Muscle relaxants of nondepolarizing action type (eg, tubocurarine) - it is possible to enhance the effect of muscle relaxants.

Lithium- Diuretics reduce renal clearance of lithium and increase the risk of toxic action of lithium. Their simultaneous application 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 inhibitors of COX-2, can reduce the diuretic, natriuretic and antihypertensive effects of diuretics.

In some patients with impaired renal function (eg, in 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 acute renal failure. These effects are usually reversible. Therefore, the simultaneous use of these drugs should be conducted with caution in patients with impaired renal function.

Effect of the drug on the results of laboratory studies

In connection with the effect of thiazide diuretics on calcium metabolism, their reception may distort the results of the study of parathyroid function (see SPECIAL INSTRUCTIONS).

Special instructions:

Losartan-hydrochlorothiazide

Hypersensitivity reactions

Patients with an angioneurotic edema in the anamnesis (edema of the face, lips, pharynx / larynx and / or tongue) need control of the drug (see ADVERSE EFFECTS).

Impaired kidney and liver function

The preparation Gisaar® Forte is contraindicated for use in patients with severe impairment of liver function and severe impairment of kidney function (QC not more than 30 ml / min) (see CONTRAINDICATIONS).

Embryotoxicity

Losartan

Arterial hypotension and decrease in the volume of circulating blood (BCC)

In patients with reduced BCC or sodium content in the blood, developed due to intensive diuretic therapy, diets with restriction of table salt, diarrhea or vomiting, symptomatic hypotension may develop, especially after taking the first dose of Gisaar® Forte. Correction of such conditions should be done prior to the appointment of the preparation Gisaar® Forte.

Violation of the water-electrolyte balance

Violation of the water-electrolyte balance is characteristic of patients with renal insufficiency with diabetes mellitus or without diabetes mellitus, therefore careful monitoring of these patients is necessary. A careful control of the potassium content in the blood or QC is necessary, especially in patients with heart failure and QA 30-50 ml / min.

During treatment with Gisaar® Forte, it is not recommended to take potassium-sparing diuretics, potassium preparations or potassium-containing substitutes for edible salt.

Aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy

Like all drugs that have a vasodilating effect, ARA II should be administered with caution to patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Ischemic heart disease and cerebrovascular disease

Like all medications with a vasodilating effect, ARA II should be administered with caution to patients with coronary heart disease or cerebrovascular disease, as excessive reduction in blood pressure in this group of patients can lead to myocardial infarction or stroke.

Chronic heart failure (CHF)

As with the use of other drugs that have an effect on RAAS, patients with CHF and with or without renal dysfunction have a risk of developing severe arterial hypotension or acute renal failure.

Primary hyperaldosteronism

Since in patients with primary hyperaldosteronism, as a rule, there is no positive response to therapy with antihypertensive agents that act by inhibiting RAAS, the use of Gisaar® Forte is not recommended in this group of patients.

Impaired liver function

Data from pharmacokinetic studies indicate that the concentration of losartan in the blood plasma in patients with cirrhosis increases significantly,so patients with mild to moderate liver function disorders in the history of the drug Gisaar® Forte should be administered with caution. There is no experience with losartan in patients with severe hepatic impairment (more than 9 on the Child-Pugh scale), so Gisaar® Forte should not be used in this group of patients (see CONTRAINDICATIONS).

Impaired renal function

Due to inhibition of RAAS in some predisposed patients, renal function changes, including renal failure, were observed.

These changes in renal function may return to normal after discontinuation of treatment.

Some drugs that affect RAAS can increase the concentration of urea in the blood and serum creatinine in patients with bilateral stenosis of the renal arteries or stenosis of the renal artery of a single kidney. It has been reported that similar effects occur when taking losartan. Similar violations of kidney function can be reversible after the abolition of therapy. Losartan should be used with caution in patients with bilateral stenosis of the renal arteries or stenosis of the renal arterythe only kidney.

Hydrochlorothiazide

Arterial hyiotension and disturbance of water-electrolyte balance

When using antihypertensive drugs in some patients may develop symptomatic hypotension. Patients should be observed to detect clinical signs of water-electrolyte balance disturbance, for example, dehydration, hyponatremia, hypochloraemic alkalosis, hypomagnesemia or hypokalemia, which may develop against the background of concomitant diarrhea or vomiting. Such patients need regular monitoring of the content of serum electrolytes. Patients with edema may experience dilutional hyponatremia in hot weather.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. In some cases, it may be necessary to correct the dose of hypoglycemic agents, including insulin (see INTERACTION WITH OTHER MEDICINES). Thiazides can reduce the excretion of calcium by the kidneys and cause a short-term and insignificant increase in serum calcium. Expressed hypercalcemia may indicate latent hyperparathyroidism.Due to the influence of thiazides on calcium metabolism, their administration can distort the results of the study of parathyroid gland function, therefore, before the study of parathyroid function, the thiazide diuretic should be canceled.

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

In some patients, the use of thiazide diuretics can lead to hyperuricemia and / or gout development. Because the losartan reduces the concentration of uric acid, its simultaneous use with hydrochlorothiazide reduces the severity of hyperuricemia caused by a diuretic.

Impaired liver function

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, as this can lead to the development of intrahepatic cholestasis, and minor changes in the water-electrolyte balance can trigger the development of hepatic coma. The preparation Gisaar® Forte is contraindicated in patients with severe impairment of liver function.

Acute myopia and secondary closed angle glaucoma

Hydrochlorothiazide, being a sulfonamide derivative, can cause an idiosyncratic reaction in the form of acute transient myopia and acute closed-angle glaucoma. Symptoms of these disorders are an unexpected reduction in visual acuity or eye pain, which typically occurs within a few hours to several weeks after starting the drug. If therapy is not available, acute angle-closure glaucoma can lead to loss of vision. The main treatment consists in the fastest possible removal of hydrochlorothiazide. It should be borne in mind that if intraocular pressure remains uncontrolled, urgent surgical or surgical treatment may be required. The risk factors for the development of acute closed-angle glaucoma include information about allergies to sulfonamides or penicillin in the anamnesis.

Other effects

In patients taking thiazide diuretics, hypersensitivity reactions can occur even in the absence of an anamnesis of allergic reactions or bronchial asthma. Reported relapses or worsening of the severity of systemic lupus erythematosus in patients taking thiazide diuretics.

Special patient groups

Race

Analysis of the data of the entire population of patients included in the study LIFE on the study of the effect of losartan on the reduction in the frequency of development of the main composite criterion for evaluating the study in patients with hypertrophy and left ventricular hypertrophyn = 9193), showed that the ability of losartan in comparison with atenolol to reduce the risk of stroke and myocardial infarction, as well as to reduce the rate of cardiovascular mortality in patients with AH and left ventricular hypertrophy (by 13.0%, p = 0.021) does not apply to patients Negroid race, although both regimens effectively reduced blood pressure in these patients. In this study, the drug losartan in comparison with atenolol reduced the rate of cardiovascular morbidity and mortality in patients with AH and left ventricular hypertrophy of all races, except Negroid (n = 8660, p = 0.003). However, in this study, patients of the Negroid race who received atenolol, had a lower risk of developing the main composite test evaluation criterion (ie, a lower combined rate of cardiovascular mortality, stroke, and myocardial infarction) compared to patients of the same race who took losartan (p = 0.03).

Children and teens

The effectiveness and safety of Gisaar® Forte in children and adolescents under 18 years of age have not been established.

If newborns, whose mothers took Gisaar® Forte during pregnancy, develop oliguria or arterial hypotension, symptomatic therapy is needed to maintain blood pressure and renal perfusion. You may need a blood transfusion or dialysis to prevent the development of arterial hypotension and / or maintain kidney function.

Elderly patients

Clinical studies have not revealed any specific features regarding the safety and efficacy of Gisaar® Forte in elderly patients (over 65 years of age).

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

There have been no studies to assess the impact on the ability to drive vehicles and work with machinery. When driving vehicles or working with machinery, care should be taken because of the potential for developing dizziness or weakness (see ADVERSE EFFECTS).

Form release / dosage:

Film coated tablets 100 mg + 12.5 mg.

Packaging:For 10 or 14 tablets in a blister of PVC / A1 foil. 2 blisters for 14 tablets or 5 blisters for 10 tablets together with instructions for use in a cardboard bundle.

Storage conditions:At a temperature of no higher than 30 ° C. Keep out of the reach of children.

Shelf life:

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-001306/09

Date of registration:20.02.2009

Expiration Date:Unlimited

The owner of the registration certificate:Merck Sharp and Doum B.V.Merck Sharp and Doum B.V. Netherlands

Manufacturer: & nbsp

MERCK SHARP & DOHME, B.V. Netherlands

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp16.04.2017

Illustrated instructions

Instructions

GISAAR® Forte (Hyzaar® forte)