Expiration date: 12/2025

The composition and form of issue:

Tablets, film-coated. 1 tablet contains active substances: 

losartan potassium 100 mg

hydrochlorothiazide 12.5 mg

other ingredients: microcrystalline cellulose (Avicel PHI02) lactose monohydrate corn starch pregelatinization 1500 magnesium stearate 

shell film: hyprolose hypromellose titanium dioxide E171 beeswax Carnauba 

in blisters of PVC/aluminium foil of 10 or 14 pieces per pack carton 2 blisters to 14 PCs. or 5 blisters to 10 PCs

Description pharmaceutical form:

Tablets oval, film-coated white color, engraved with "745" on one side.

Pharmacokinetics:

Suction

Losartan. If ingestion losartan is well absorbed and undergoes metabolism at the first passage through the liver, resulting in the formation of the active carboxylated metabolite and inactive metabolites. The systemic bioavailability of losartan in the tablet form is approximately 33%. Mean Cmax of losartan and its active metabolite are achieved through 1 h and over 3-4 h respectively. While taking losartan with food no clinically significant effect on concentration profile of losartan in plasma have been identified.

Distribution

Losartan. Losartan and its active metabolite are associated with blood plasma proteins (mostly albumin) is more than 99%. Vd losartan is 34 l. Studies on rats have shown that losartan is not practically penetrate through the GEB.

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

Metabolism

Losartan. About 14% the dose losartan, injected or oral, is converted into its active metabolite. After oral and/in the introduction of losartan, labeled with 14C, circulating plasma radioactivity is primarily due to the presence in it of losartan and its active metabolite.

In addition to active metabolite, hydroxylation of butyl side chain, are biologically inactive metabolites, including 2 main and 1 secondary metabolite — N-2-tetrazole-glucuronide.

Excretion

Losartan. Plasma clearance of losartan and its active metabolite is about 600 ml/min and 50 ml/min, respectively. Renal clearance of losartan and its active metabolite is approximately 74 and 26 ml/min, respectively. While taking losartan inside about 4% dose appears kidneys in an unmodified form, and about 6% of dose as active metabolite. While taking losartan doses up to 200 mg of this compound and its active metabolite are linear farmakokinetiku.

Once inside the plasma concentrations of losartan and its active metabolite decline polyexponentially with the final T1/2 is approximately 2 and 6-9 hours, respectively. With a single daily dose of the drug in a dose of 100 mg, neither losartan nor its active metabolite do not accumulate significantly in plasma.

Elimination of losartan and its metabolites occurs in the bile and kidneys. After intake of losartan, labeled with 14C, about 35% of radioactivity found in the urine and 58% in the feces. After I/V administration of losartan, labeled with 14C, about 43% of radioactivity detected in the urine and 50% in the feces.

Hydrochlorothiazide. Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys. T1/2 ranges from 5.6 to 14.8 h. Not less than 61% of the oral dose excreted unchanged within 24 h.

A separate group of patients

Elderly patients (losartan+hydrochlorothiazide). Concentrations of losartan and its active metabolite in blood plasma and the rate of absorption of hydrochlorothiazide in elderly patients with arterial hypertension did not differ significantly from these parameters in young patients with arterial hypertension.

Gender (losartan). Concentrations of losartan in plasma was 2 times higher in women with arterial hypertension compared to men suffering from this disease. This apparent pharmacokinetic difference has no clinical significance. Concentrations of the active metabolite of men and women do not differ.

The liver and kidneys (losartan). When administered to patients with easy and moderate alcoholic cirrhosis of the liver concentrations of losartan and its active metabolite in blood plasma were, respectively, 5-1,7 times more than in young male volunteers.

Concentrations of losartan in plasma in patients with Cl creatinine >10 ml/min did not differ from those in individuals with preserved kidney function. When comparing AUC in patients with normal renal function, the AUC of losartan in patients, on hemodialysis, was approximately 2 times more. Plasma concentrations of the active metabolite is not changed in patients with impaired renal function or patients on hemodialysis. Losartan and its active metabolite cannot be removed by hemodialysis.

Description pharmacological action:

Components of the drug Hyzaar Forte have additive antihypertensive effect, reducing blood pressure to a greater degree than each component separately. Due to the diuretic effect, hydrochlorothiazide increases renin activity of blood plasma (ARP), stimulates aldosterone secretion, increases the level of angiotensin II and reduces the level of potassium in the blood serum. Taking losartan blocks all physiological effects of angiotensin II and by inhibiting the effects of aldosterone may help to reduce the potassium loss associated with taking a diuretic.

Losartan has a mild and transient uricosuric effect. Hydrochlorothiazide is a slight increase in uric acid in the blood the combination of losartan and hydrochlorothiazide helps to reduce severity of hyperuricemia caused by diuretic.

Hyzaar Forte is a combination of losartan and hydrochlorothiazide. In patients with hypertension and left ventricular hypertrophy, losartan including the combination with hydrochlorothiazide, reduces the risk of cardiovascular morbidity and mortality that has been proven through the assessment of the combined incidence of stroke and myocardial infarction and increased cardiovascular mortality in these patients.

Losartan

Angiotensin II is a powerful vasoconstrictor — the main active hormone of the renin-angiotensin system, as well as a crucial pathophysiological factor in the development of hypertension. Angiotensin II binds to AT1 receptors found in many tissues, for example in vascular smooth muscle, adrenal glands, kidneys and heart, and raises a number of important biological effects, including vasoconstriction and release of aldosterone. Angiotensin II also stimulates the proliferation of smooth muscle cells. The role of the second type of angiotensin II receptor (AT2-subtype) in cardiovascular homeostasis is unknown.

Angiotensin II selectively binds to AT1-receptors. Losartan and its pharmacologically active metabolite (E-3174) as in vitro and in vivo, inhibit all physiological effects of angiotensin II, regardless of the source or route of synthesis. Losartan is a synthetic drug and, in contrast to some peptide antagonists of angiotensin II agonist effects.

Losartan selectively binds to AT1-receptors, it does not bind or block other hormone receptors and ion channels, playing an important role in regulating functions of the SSS. In addition, losartan does not inhibit ACE, which promotes the degradation of bradykinin. Consequently, effects not directly associated with the blockade of AT1-receptors, in particular, strengthening effects associated with exposure to bradykinin or the development of edema (losartan 1.7%, the placebo to 1.9%), are not related to the action of losartan.

Losartan reduces negative feedback, which consists in the suppression of angiotensin II secretion of renin, leading to increased activity of ARP. Improvement BDA is accompanied by increased levels of angiotensin II in blood plasma. During long-term (6-week) treatment of patients with arterial hypertension with losartan at a dose of 100 mg/day, achieved in the blood plasma Cmax of the drug was observed 2-3-fold increase in the level of angiotensin II. Antihypertensive activity and a decrease in the concentration of aldosterone in the blood plasma appear after 2-6 weeks of treatment, indicating effective blockade of the angiotensin II receptor. PRA and angiotensin II levels decrease to baseline values 3 days after the cancellation of losartan. The effects of the drug Hyzaar Forte PRA and angiotensin II levels are comparable to those when taking 50 mg of losartan.

Because losartan is a specific antagonist of AT1 receptors of angiotensin II, it does not inhibit ACE (kininase II), the enzyme that inactivates bradykinin. The results of a study that compared the effect of 20 mg and 100 mg of losartan and the ACE inhibitor in the 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 ACE inhibitor blocked the response to angiotensin I and increased the severity of the response to bradykinin, without affecting the severity of response to angiotensin II, demonstrating the pharmacodynamic distinction between losartan and ACE inhibitors.

The concentration of losartan and its active metabolite in plasma and antihypertensive effect of losartan increases with increasing dose. Due to the fact that losartan and its active metabolite are antagonists of receptors of angiotensin II, they both contribute to the antihypertensive effect.

In a clinical study with a single admission 100 mg losartan, which included healthy volunteers-men, the drug in conditions of high and malosolenoj diet did not affect the glomerular filtration rate (GFR), effective renal blood flow and filtration fraction of the kidneys. Losartan showed a natriuretic effect which was more pronounced in the malosolevoj diet and, apparently, was not associated with early suppression of 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 arterial hypertension, proteinuria (>2 g/day), not diabetes mellitus and receiving for 8 weeks losartan at a dose of 50 mg with a gradual increase to 100 mg, there was a significant reduction of proteinuria by 42 %. Fractional excretion of albumin also decreased significantly. In these patients the losartan stabilized GFR, and decreased filtration fraction.

In women in postmenopausal period with arterial hypertension, taking losartan at a dose of 50 mg/day for 4 weeks, there were no effects of the therapy on kidney and systemic levels of GHGs. Losartan does not affect autonomic reflexes and has no long-lasting impact on the level of noradrenaline in plasma. In patients with arterial hypertension, losartan in doses up to 150 mg/day did not cause clinically significant changes in fasting triglycerides, total cholesterol and HDL cholesterol. In the same doses of losartan had no effect on glucose levels in fasting blood.

In General, losartan caused a decrease in serum uric acid (usually <0.4 mg/DL), maintained during long-term therapy. In controlled clinical studies that included patients with hypertension, cases of drug discontinuation because of increased creatinine or potassium blood serum is not registered.

In a 12-week parallel, placebo-controlled study in patients with left ventricular failure (II–IV functional class NYHA classification), most of whom were receiving diuretics and/or digitalis, compared the effects of losartan in a doses of 2, 5, 10, 25 and 50 mg/day. In doses 25 and 50 mg/day the drug had a positive hemodynamic and neurohormonal effects which were observed throughout the study. Hemodynamic effects included an increase in cardiac index and reduced jamming pressure in the pulmonary capillaries, and a decrease in systemic vascular resistance, secondary systemic blood pressure and heart rate. Neurohormonal effects were related to lower levels of aldosterone and norarenalina in blood.

Hydrochlorothiazide

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

Hydrochlorothiazide is a diuretic and antihypertensive agent. It affects the reabsorption of electrolytes in the distal renal tubule. Hydrochlorothiazide was equally increases the excretion of sodium and chlorine ions. Natriuresis may be accompanied by a small loss of potassium ions and bicarbonate.

If ingestion diuretic effect starts after 2 h, reaching a maximum after an average of 4 hours and lasts 6 to 12 h

Indications:

• arterial hypertension (in patients, which shows the combined therapy)
  
• reducing the risk of cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy.
  

Contraindications:

• hypersensitivity to any component of the drug
  
• hypersensitivity to sulfonamides derived
  
• anuria
  
• expressed by the human kidney (Cl creatinine <30 ml/min)
  
• marked disorders of liver function
  
• the age of 18 years (efficacy and safety not established).
  
• lactose intolerance, lactase deficiency or glucose-galactose malabsorption (Hyzaar Forte contains lactose).
  

Caution: patients with disorders of fluid and electrolyte balance of the blood, for example on the background of diarrhea or vomiting (hyponatremia, gipohloremichesky alkaloz, gipomagniemia, hypokalemia), renal insufficiency (Cl creatinine 30-50 ml/min), bilateral renal artery stenosis or stenosis of the artery only kidneys, diabetes mellitus, hypercalcemia, hyperuricemia and/or gout, allergic history and asthma, as well as in systemic connective tissue diseases (including systemic lupus erythematosus), hypovolemia (including against the background of high doses of diuretics) and also in concurrent use with NSAIDs, including COX-2 inhibitors.

Application of pregnancy and breast-feeding:

The use of the drug Hyzaar Forte is contraindicated in pregnancy!

The use of funds that have a direct effect on the renin-angiotensin system during the second and third trimester of pregnancy may harm the developing fetus or even cause his death. Right after established pregnancy, the drug Hyzaar Forte should be discontinued.

Despite the lack of data on the use of the drug Hyzaar Forte in pregnant women, animal studies have demonstrated that losartan can cause harm to the fetus and newborn and cause their death, which was probably related to the influence of the drug on the renin-angiotensin system. In the fetus of human kidney perfusion, which depends on the development of the renin-angiotensin system, begins in the second trimester, so the risk of developmental disorders and fetal death is increased by the use of the drug Hyzaar Forte during the second or third trimester of pregnancy.

Thiazides cross the placental barrier and are found in the blood of the umbilical cord. Routine use of diuretics in healthy pregnant women is not recommended because it increases the risk of fetal adverse events such as fetal jaundice and neonatal jaundice, and the mother — thrombocytopenia.

There is no evidence that losartan is excreted in breast milk. It is known that thiazides are allocated in breast milk. In connection with risk of development of adverse events in infants in all cases should be informed decision about taking the drug in the breast-feeding period taking into account the importance of therapy for the mother. In that case, if it is decided that you need to take Hyzaar Forte, breastfeeding should be discontinued.

Side effects:

In clinical studies with the combination of losartan+hydrochlorothiazide were observed adverse reactions that are specific for this combination drug. Side effects were limited to those reported with the use of losartan or hydrochlorothiazide alone. The total frequency of adverse reactions reported in the appointment of this combination, was comparable with that of the placebo. The frequency of discontinuation of therapy was also comparable with that in patients receiving placebo. In most cases, adverse reactions were mild, were transient in nature and did not require discontinuation of therapy.

In controlled clinical studies, dizziness was the only related to the drug, adverse reaction, the frequency of which was higher than when receiving placebo by more than 1% or more.

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

During post-marketing use of the drug have reported the following additional adverse reactions.

Hypersensitivity: anaphylactic reactions, angioedema including swelling of the larynx and glottis 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 there were indications for the development of angioneurotic edema in anamnesis if you are using other drugs, including ACE inhibitors there have been rare reports about the development of vasculitis, including purpura, Shenleyn-Schonlein purpura in patients receiving losartan.

From the digestive tract: there are rare reports of development of hepatitis, and diarrhea in patients treated with losartan.

On the part of the respiratory system: it was reported about cough during treatment with losartan.

The skin and subcutaneous fat: urticaria, increased light and photosensitivity.

Laboratory findings: in controlled clinical trials on the background of the drug Hyzaar Forte clinically important changes in standard laboratory parameters were rarely hyperkalemia (serum potassium >5.5 in mEq/l) was observed in 0.7% of patients that did not require discontinuation of the drug increase in activity of ALT occurred rarely and usually disappear after discontinuation of therapy.

Drug interactions:

Losartan. In clinical studies of pharmacokinetics showed no clinically significant drug interactions with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin.

The combination of losartan, like other means that block angiotensin II or its effects, of potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride), kalisoderjasimi supplements or potassium salts can lead to increased levels of potassium in the blood serum.

NSAIDs, including selective COX-2 inhibitors may reduce the effect of diuretics and other antihypertensive agents. Therefore, the hypotensive effect of receptor antagonists angiotensin II could weaken NSAIDs, including COX-2 inhibitors.

In some patients with compromised renal function who received therapy with NSAIDs, including COX-2 inhibitors, treatment with the receptor antagonists of angiotensin II can cause further deterioration of renal function. These effects are usually reversible.

Hydrochlorothiazide. When used together with hydrochlorothiazide the following drugs are described the following effects.

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

Hypoglycemic agents (oral and insulin) may require dosage adjustment of hypoglycemic agents.

Other antihypertensive agents — additive effect.

Cholestyramine and colestipol in the presence of anionic exchange resins absorption of hydrochlorothiazide is impaired. Cholestyramine and colestipol dose bind the hydrochlorothiazide and reduce its absorption in the digestive tract of 85% and 43% respectively.

Corticosteroids, ACTH — marked reduction in the level of electrolytes, in particular the risk of hypokalemia.

Pressor amines (e.g. epinephrine) — may reduce the intensity of the response to Pressor amines, but not excluding the possibility of their application.

Muscle relaxants non-depolarizing type of action (e.g. tubokurarin) — may increase the effect of muscle relaxants.

Lithium — diuretics reduce kidney klirens lithium and increase the risk of developing toxic action of lithium joint use is not recommended before prescribing lithium drugs you should refer to the instructions for use.

NSAIDs (including COX-2 inhibitors) — in some patients NSAIDs, including selective COX-2 inhibitors can reduce the diuretic, natriuretic and antihypertensive effects of diuretics.

Method of application and dose:

Inside.

Hyzaar Forte can be administered with or without food.

Blood hypercapnia. 1 tablet Hyzaar Forte 1 per day.

Hyzaar Forte is prescribed to patients without adequate therapeutic response to reception 1 tablet Hyzaar (contains 50 mg of losartan and 12.5 mg hydrochlorothiazide) within 2-4 weeks. Typically, the antihypertensive effect is achieved within 3 weeks after the start of therapy. In the absence of therapeutic effect dose of the drug Gizaar 50/12,5 mg may be increased to 2 tab. 1 time per day. The maximum dose of 2 tablet gizaar 50/12,5 mg 1 time per day or 1 tab. gizaar Forte (100/12,5 mg).

Reducing the risk of cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy. 1 tablet Hyzaar Forte 1 per day.

Hyzaar Forte is prescribed to patients who fail to achieve target values of blood pressure in patients receiving 1 tablet Hyzaar .

Overdose:

Symptoms

Losartan: data on overdose in humans are limited. The most likely manifestations of overdose are marked reduction in blood pressure and tachycardia, bradycardia may be the result of parasympathetic (vagal) stimulation. In the case of symptomatic arterial hypotension shows maintenance therapy. Losartan and its active metabolite are excreted through kidney dialysis.

Hydrochlorothiazide: the most common symptoms of overdose are the result of a deficiency of electrolytes (hypokalemia, gipohloremia, hyponatremia) and dehydration due to excessive diuresis. While receiving cardiac glycosides gipokaliemia may worsen arrhythmias.

Treatment. No data on the specific treatment of overdose of the drug Hyzaar® Forte. Treatment is symptomatic and supportive. The drug Hyzaar® Forte should be discontinued and the patient should be observed. If the drug passed recently, we recommend braving the vomit, as well as the elimination of dehydration, electrolyte imbalance, hepatic coma and decrease in blood pressure by standard methods. Is not established to what extent hydrochlorothiazide may be removed from the body by hemodialysis.

Precautions:

The drug Hyzaar Forte can be administered in combination with other antihypertensive agents.

Losartan

Violations of kidney function. There are reports that some patients who took the drug, in connection with the suppression of the function of the renin-angiotensin system were renal dysfunction, including renal failure, these disorders may be reversible and disappear after discontinuation of therapy.

Other drugs acting on the renin-angiotensin system can cause an increase in the content of urea and creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Similar effects were observed in patients receiving losartan these changes in renal function may be reversible and take place after discontinuation of therapy.

Hydrochlorothiazide

Hypotension and disruption of water and electrolyte balance. As in the case of receipt of any antihypertensive drugs, some patients may experience symptomatic hypotension. Patients should be observed in order to detect clinical signs of violations vodno-elektrolitnogo balance, such as dehydration, hyponatremia, gipohloremichesky alkalosis, hypomagnesemia or hypokalemia which can develop on the background of concomitant diarrhea or vomiting. In such patients requires monitoring of electrolytes in the blood serum.

Metabolic and endocrine effects. Tiazidami therapy may disturb glucose tolerance. In some cases, you may need to adjust the dose of hypoglycemic agents, including insulin.

Thiazides may decrease the excretion of calcium by the kidneys and cause intermittent and slight increase in calcium level of blood serum. Marked hypercalcemia may be evidence of hidden hyperparathyroidism.

In connection with the effect of thiazides on calcium metabolism, and it may distort the results of research of function of the parathyroid glands, therefore, before the study of parathyroid function thiazide diuretic should be abolished.

Increasing the level of cholesterol and blood triglycerides may also be associated with tiazidnami dioretikami therapy.

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

Other effects. In patients receiving thiazide diuretics, hypersensitivity reactions may occur even in the absence in anamnesis of indications of allergic reactions or bronchial asthma. There are reports of the development of exacerbation or progression of systemic lupus erythematosus in patients receiving a thiazide diuretic.

Race

Data analysis the entire population of patients included in the LIFE study (Losartan Intervention For Endpoint reduction in hypertension) — the impact of losartan on reducing the incidence of endpoints in hypertension (n=9193) — showed that the ability of losartan compared to atenolol reduce the risk of stroke and myocardial infarction, as well as to reduce the rate of cardiovascular mortality in patients with hypertension and left ventricular hypertrophy (13%, p=0,021) does not apply to patients of the Negroid race, although both treatment regimens effectively lowered blood pressure in these patients. Moreover, patients blacks treated with atenolol had a lower risk of developing events of the primary composite endpoint compared with similar patients taking losartan (p=0.03).