Hyzaar Forte Tablets 100mg 12.5mg N28
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Active ingredients
Losartan + Hydrochlorothiazide
Release form
Pills
Composition
Active ingredient: Losartan potassium, Hydrochlorothiazide (Hydrochlorothiazide) Concentration of the active substance (mg): 112.5
Pharmacological effect
An antihypertensive drug of combined composition. The active substances of the Hyzaar drug have an additive antihypertensive effect, reducing the level of hell to a greater extent than each of the components separately. due to the diuretic effect, hydrochlorothiazide increases plasma renin activity (arp), stimulates the secretion of aldosterone, increases angiotensin ii levels and decreases serum potassium levels. taking losartan blocks all the physiological effects of angiotensin ii and due to the suppression of the effects of aldosterone reduces the potassium loss caused by the diuretic. Losartan has a moderate and transient uricosuric effect. hydrochlorothiazide causes a slight increase in the level of uric acid in the blood; The combination of losartan and hydrochlorothiazide helps to reduce the severity of diuretic-induced hyperuricemia. Losartanlosartan is an angiotensin ii receptor antagonist. Angiotensin ii binds to the at1 receptor subtype, found in many tissues (for example, in vascular smooth muscle, adrenal gland, kidney, and heart) and causes a number of important biological effects, including vasoconstriction and the release of aldosterone. Angiotensin ii also stimulates the proliferation of smooth muscle cells. the role of the second type of angiotensin ii receptor, the at2 subtype, in the cardiovascular homeostasis is unknown. angiotensin ii binds selectively to at1 receptors. 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 route of synthesis. Unlike some angiotensin ii peptide antagonists, losartan does not have agonist effects. Losartan binds selectively to at1 receptors and does not bind or block the receptors of other hormones and ion channels that play an important role in regulating the function of the cardiovascular system. In addition, losartan does not inhibit APF, which contributes to the degradation of bradykinin.therefore, effects not directly related to the blockade of at1 receptors, in particular, enhancing the effects associated with bradykinin exposure or the development of edema (losartan 1.7%, placebo 1.9%) are not related to the effect of losartan. Losartan eliminates the negative feedback that in the suppression of renin secretion by angiotensin ii, which leads to an increase in arp. an increase in arp is accompanied by an increase in plasma angiotensin ii level. With prolonged (6-week) treatment of patients with arterial hypertension with losartan in a dose of 100 mg / day, at the time of reaching the maximum concentration of the drug in the blood plasma, a 2-3-fold increase in the level of angiotensin ii was observed. some patients showed an even greater increase, especially with a short duration of treatment (2 weeks). antihypertensive activity and a decrease in the concentration of aldosterone in blood plasma appear after 2-6 weeks of therapy, which indicates an effective blockade of angiotensin ii receptors. arp and angiotensin ii level are reduced to baseline values 3 days after losartan is withdrawn. The effect of gizaara on arp and angiotensin ii was comparable to that of 50 mg of losartan. Because losartan is a specific antagonist of the at1 receptor angiotensin ii, it does not inhibit apf (kininase ii), an enzyme that inactivates bradykinin. The results of a study comparing the effects of 20 mg and 100 mg of losartan and the APF inhibitor 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. These data confirm the specific mechanism of action of losartan. in turn, the inhibitor apf blocked the response to angiotensin i and increased the severity of the response to bradykinin, without affecting the severity of the response to angiotensin ii, which demonstrates the pharmacodynamic difference between losartan and inhibitors of the apf.concentration of losartan and its active metabolite in plasma, as well as antihypertensive The effect of losartan increases with increasing dose of the drug. Since losartan and its active metabolite are antagonists of angiotensin ii receptors, both of them contribute to the antihypertensive effect. In a single-dose study of 100 mg of losartan, which included healthy male volunteers, taking the drug in a high-salt diet did not affect glomerular filtration rate (SCF), effective renal plasma flow and kidney filtration fraction.losartan demonstrated a natriuretic effect, which was more pronounced on a low-salt 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 uric acid excretion by the kidneys. patients with arterial hypertension, proteinuria (> 2 g / day), not suffering from diabetes and taking losartan at a dose of 50 mg with a gradual increase to 100 mg, there was a significant decrease proteinuria at 42%. albumin fractional excretion also decreased significantly. in these patients, losartan stabilized scf and decreased filtration fraction. In postmenopausal women with arterial hypertension, who took losartan at a dose of 50 mg / day for 4 weeks, there was no effect of therapy on the renal and systemic prostaglandin levels. Losartan does not affect vegetative reflexes and does not have a lasting effect on the level of norepinephrine in the blood plasma. in patients with arterial hypertension, losartan in doses up to 150 mg / day did not cause clinically significant changes in the level of fasting triglycerides, total cholesterol and cholesterol-lpvp. In the same doses, losartan did not affect the fasting blood glucose level. In general, losartan caused a decrease in the serum uric acid level (usually less than 0.4 mg / dL), which was maintained during long-term therapy. in controlled clinical trials in which patients with arterial hypertension were included, no cases of drug withdrawal due to an increase in serum creatinine or potassium were registered. In a 12-week parallel placebo-controlled study in patients with left ventricular failure (ii-iv functional class by nyha), most of which received diuretics and / or digitalis, compared the effects of potassium losartan at doses of 2.5, 10, 25, and 50 mg / day. at doses of 25 mg and 50 mg / day, the drug had positive hemodynamic and neurohormonal effects that were observed throughout the study. hemodynamic effects included an increase in cardiac index and a decrease in wedging pressure in the pulmonary capillaries, as well as a decrease in opss, systemic mean hell, and heart rate.neurohormonal effects manifested as a decrease in the level of aldosterone and norepinephrine in the blood. in patients with arterial hypertension and left ventricular hypertrophy, losartan, often in combination with hydrochlorothiazide, reduces the risk of cardiovascular morbidity and mortality, which was proved by evaluating the combined frequency of stroke and myocardial infarction, as well as an indicator of cardiovascular mortality in this category of patients. hydrochlorothiazide mechanism of the antihypertensive effect of thiazides non-weight en. thiazides usually do not affect the normal level of ad.hydrochlorothiazide is a diuretic and antihypertensive agent. it affects electrolyte reabsorption in the distal tubules of the kidneys. hydrochlorothiazide approximately equally increases the excretion of sodium and chlorine. natriuresis may be accompanied by a small loss of potassium ions and bicarbonate. when taken in, the diuretic effect begins after 2 hours, reaches a maximum on average after 4 hours and lasts from 6 to 12 hours.
Pharmacokinetics
Absorption Losartan When ingested, losartan is well absorbed from the gastrointestinal tract, is metabolized during the first passage through the liver, as a result of which an active carboxylated metabolite and inactive metabolites are formed. The systemic bioavailability of losartan in tablet form is about 33%. Cmax of losartan and its active metabolite are reached after 1 h and 3-4 h, respectively. When taking losartan during a meal there was no clinically significant effect on plasma concentration profile of losartan. Losartan and its active metabolite have linear pharmacokinetics when taking losartan orally in doses up to 200 mg. Distribution Lozartan Losartan and its active metabolite bind to plasma proteins ( mainly with albumin) more than 99%. Vd losartan is 34 liters. Studies in rats have shown that losartan practically does not penetrate the BBB. Hydrochlorothiazide Hydrochlorothiazide penetrates the placental barrier, is excreted in breast milk. Does not penetrate the BBB. Metabolism Losartan About 14% of the dose of losartan, introduced in / in or inside, turns into its active metabolite.After oral administration and iv administration of losartan labeled with 14C, circulating plasma radioactivity is primarily associated with the presence of losartan and its active metabolite in it. In addition to the active metabolite, biologically inactive metabolites are formed as a result of hydroxylation of the butyl side chain, including two major metabolites and one minor, N-2-tetrazole-glucuronide. ExcretionLosartan 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 losartan is taken orally, about 4% of the dose is excreted in the urine unchanged, and about 6% of the dose is taken as an active metabolite. After ingestion, plasma concentrations of losartan and its active metabolite are reduced polyexponentially with a final T1 / 2 of approximately 2 hours and 6-9 h, respectively. With a single dose of 100 mg / day, neither losartan nor its active metabolite significantly accumulate in the blood plasma. Excretion of losartan and its metabolites occurs in the bile and urine. After ingestion of losartan, labeled with 14C, about 35% of the radioactivity is detected in the urine and 58% in the feces. After iv administration of losartan, labeled with 14C, approximately 43% of radioactivity is detected in the urine and 50% in the feces. Hydrochlorothiazide Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys. T1 / 2 varies from 5.6 to 14.8 h. At least 61% of the ingested dose was eliminated unchanged for 24 hours. Pharmacokinetics in special clinical situationsLosartan - hydrochlorothiazide Concentration of losartan and its active metabolite in plasma and absorption rate of hydrochlorothiazide in elderly patients with arterial hypertension does not significantly differ from these indicators in young patients with arterial hypertension. Losartan The concentration of losartan in the blood plasma was 2 times higher in women with arterial hypertension compared to with men suffering from hypertension. This apparent pharmacokinetic difference has no clinical significance. The concentrations of the active metabolite in men and women did not differ. In patients with mild and moderate alcoholic cirrhosis of the liver, the oral plasma levels of losartan and its active metabolite were 5–1.7 times higher, respectively,than young male volunteers. Plasma concentrations of losartan in patients with QA of more than 10 ml / min did not differ from those in those with unchanged renal function. AUC of losarathan in patients on hemodialysis was about 2 times greater than in patients with normal renal function. Plasma concentrations of the active metabolite do not change in patients with impaired renal function or patients on hemodialysis. Losartan and its active metabolite cannot be removed by hemodialysis.
Indications
Arterial hypertension. Reducing the risk of cardiovascular morbidity and mortality in patients with arterial hypertension and left ventricular hypertrophy.
Contraindications
Hypersensitivity, anuria, hypovolemia (including on the background of high doses of diuretics), hepatic and / or renal failure, pregnancy, lactation.
Precautionary measures
The drug should be stored at a temperature of 15-30 ° C out of the reach of children.
Use during pregnancy and lactation
Use of the drug Hyzaar is contraindicated in pregnancy. The use of drugs that have a direct effect on the renin-angiotensin system in the second and third trimesters of pregnancy can cause harm to the developing fetus and even cause its death. Immediately after the pregnancy is established, Gizaar’s reception should be discontinued. Adequate and strictly controlled clinical studies of the safety of Gizaar’s use in pregnancy have not been carried out. In experimental animal studies, it has been shown that losartan can have a teratogenic effect and cause death the effect of this active substance on the renin-angiotensin system. In the human fetus, renal perfusion, which depends on the development of renin-angiotensin a marketing system, begins in the II trimester; thus, the risk of impaired development and fetal death increases with the application of Hyzaar in the II or III trimesters of pregnancy. Thiazides penetrate the placental barrier and are determined in umbilical cord blood. Routine use of diuretics in pregnant healthy women is not recommended, because This increases the risk for the fetus of such adverse events as fetal jaundice and jaundice of the newborn, and in the mother - thrombocytopenia. There is no evidence that 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, a balanced decision on taking the drug during breastfeeding should be made in all cases, taking into account the importance of therapy for the mother. If it is decided that Hyzaar is necessary, breastfeeding should be stopped .
Dosage and administration
Hyzaar Forte is taken orally, 1 tablet / day, regardless of the meal. The maximum dose - 2 pills 1 time / day. The maximum hypotensive effect develops within 3 weeks after the start of treatment.
Side effects
In clinical studies with losartan / hydrochlorothiazide, no adverse events specific to this combination preparation were observed. The adverse reactions were limited to those already reported with losartan and / or hydrochlorothiazide alone. The cumulative incidence of adverse reactions reported with this combination was comparable to that used with placebo. The frequency of discontinuation of therapy was also comparable to that in patients receiving placebo. In most cases, adverse reactions were mild, transient, and did not require discontinuation of therapy. In controlled clinical trials, dizziness was the only one associated with taking the drug, an undesirable reaction, the frequency of which exceeded that when taking placebo more than 1 percent or more. in combination with hydrochlorothiazide, it is generally well tolerated in patients with arterial hypertension and left ventricular hypertrophy. The most frequent adverse reactions were dizziness, weakness and fatigue. During the post-marketing experience with the drug, the following additional adverse reactions were reported. Allergic reactions and immunopathological reactions: anaphylactic reactions, angioedema, including laryngeal and glottis edema with the development of airway obstruction and / or swelling of the face, lips, pharynx and / or tongue in patients taking losartan; some of these patients had indications of the development of angioedema in the history of using other drugs, including ACE inhibitors. There are rare reports of vasculitis development (includingSchoenlein-Henoch purpura) on the background of receiving losartan. On the part of the digestive system: rarely - hepatitis, diarrhea (in patients taking losartan). On the part of the respiratory system: cough is possible (in patients taking losartan). Dermatological reactions: urticaria, increased light - and photosensitivity. From the laboratory indicators: in controlled clinical trials on the background of Hyzaar administration, clinically significant changes in standard laboratory parameters were rarely observed. Hyperkalemia (serum potassium of more than 5.5 meq / l) was observed in 0.7% of patients, which did not require discontinuation of the drug. Increased ALT activity was rarely observed and usually disappeared after discontinuation of therapy.
Overdose
Data on overdose of losartan in humans is limited. The most likely symptoms of overdose are marked reduction in blood pressure and tachycardia; bradycardia may be due to parasympathetic (vagal) stimulation. Treatment: supportive therapy is indicated in the case of symptomatic arterial hypotension. Losartan and its active metabolite are not excreted by hemodialysis. The most frequent symptoms of an overdose of hydrochlorothiazide are due to electrolyte deficiency (hypokalemia, hypochloraemia, hyponatremia) and dehydration due to excessive diuresis. With simultaneous intake of cardiac glycosides, hypokalemia can aggravate the course of arrhythmias. It has not been established to what extent hydrochlorothiazide can be removed from the body using hemodialysis. There is no data on the specific treatment of Hyzaar overdose. Treatment is symptomatic and supportive. The drug should be discontinued, and the patient should be monitored. If the drug is taken recently, it is recommended provocation of vomiting, as well as the elimination of dehydration, electrolyte abnormalities, hepatic coma and reduction of blood pressure by standard methods.
Interaction with other drugs
Losartan In clinical studies, the pharmacokinetics did not reveal the presence of a cognitive trait. , amiloride), potassium-containing additives or potassium salts can lead to an increase in the level of potassium in the blood serum. NSAIDs (includingselective inhibitors of COX-2) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the hypotensive effect of angiotensin II receptor antagonists can be attenuated while being used with NSAIDs (including COX-2 inhibitors). In some patients with impaired renal function who received NSAID therapy (including COX-2 inhibitors), treatment with angiotensin receptor antagonists II may cause further impairment of renal function. These effects are usually reversible. Hydrochlorothiazide With simultaneous use of thiazide diuretics with barbiturates, opioid analgesics, ethanol, the risk of orthostatic hypotension may increase. If you use it simultaneously, you may need to adjust the dose of hypoglycemic agents (for oral administration and insulin). additive effect. In the presence of anionic exchange resins, the absorption of hydrochlorothiazide is impaired. Colestyramine or colestipol bind hydrochlorothiazide in single doses and reduce its absorption from the gastrointestinal tract by 85% and 43%, respectively. Using corticosteroids, ACTH leads to a pronounced decrease in electrolyte levels, in particular, can cause hypokalemia. , epinephrine). It is possible to enhance the effect of muscle relaxants of non-depolarizing type of action (for example, tubocurarine). Diuretics reduce the renal clearance of lithium and increase the risk of its toxic actions; Combined use of diuretics and lithium preparations is not recommended. In some cases, the use of NSAIDs (including selective COX-2 inhibitors) can reduce the diuretic, natriuretic and antihypertensive effects of diuretics.
special instructions
Hyzaar can be prescribed in combination with other antihypertensive drugs. LozartanThere are reports that a number of patients taking the drug, in connection with the suppression of the renin-angiotensin system, showed changes in renal function, including renal failure; these changes were reversible and disappeared after discontinuation of therapy. Other agents affecting the renin-angiotensin system,can lead to an increase in the urea and creatinine levels in the blood of patients with bilateral renal artery stenosis and single kidney artery stenosis. Similar effects have been observed in patients receiving losartan; These changes in renal function were reversible and disappeared after discontinuation of therapy. Hydrochlorothiazide As with any antihypertensive drugs, symptomatic arterial hypotension may be observed in some patients. Patients require monitoring in order to promptly identify the clinical signs of impaired water and electrolyte balance, for example, dehydration, hyponatremia, hypochloraemic alkalosis, hypomagnesemia, or hypokalemia that may develop during intercurrent diarrhea or vomiting. In such patients, control of serum electrolytes is necessary. Thiazide therapy can lead to impaired glucose tolerance. In some cases, it may be necessary to adjust the dose of hypoglycemic agents (including insulin). Thiazides may reduce urinary calcium excretion and cause an episodic and insignificant increase in serum calcium levels. Severe hypercalcemia may indicate a latent hyperparathyroidism. Due to the effect of thiazides on calcium metabolism, their reception may distort the results of the study of parathyroid function, so thiazide diuretic should be canceled before studying the functions of parathyroid glands. thiazide diuretics. In some patients, taking thiazide diuretics can lead to hyperuricemia and / or the development of gout. Since losartan reduces uric acid levels, its combination with hydrochlorothiazide reduces the severity of diuretic hyperuricemia. In patients receiving thiazides, hypersensitivity reactions can occur even if there is no indication of allergies or asthma in history. There are reports of the development of exacerbation or progression of SLE in patients receiving thiazide diuretics. When analyzing the entire population of patients included in the LIFE study (Losartan Intervention for Endpoint Reduction in Hypertensive Patients, n = 9193) , treatment with losartan was accompanied by a 13% reduction in the risk of reaching the primary combined endpoint (cardiovascular death, stroke and myocardial infarction) (p = 0.021) compared with atenolol.However, patients of the Negroid race who received atenolol had a lower risk of developing the events of the primary combined endpoint compared with black patients who took Losartan (p = 0.03). Use in pediatrics The efficacy and safety of the drug in children under the age of 18 years has not been established.