Composition, form of production and packaging
The tablets covered with a film shell of white color, oval, with a risk on one side and engraving "952" - on the other.
Losartan potassium 50 mg
Excipients: microcrystalline cellulose - 52.5 mg, lactose monohydrate - 25.5 mg, corn pregelatinized corn starch - 20.95 mg, magnesium stearate - 1.05 mg.
The composition of the shell: giprolose (with 0.3% silicon dioxide) - 1.8 mg, hypromellose - 1.8 mg, titanium dioxide - 0.9 mg, carnauba wax - 0.05 mg.
14 pcs. - blisters (1) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
The tablets covered with a film shell of white color, drop-shaped, with engraving "960" on one side and smooth on the other side.
Losartan Potassium 100 mg
Excipients: microcrystalline cellulose - 105 mg, lactose monohydrate - 51 mg, pregelatinized starch - 41.9 mg, magnesium stearate - 2.1 mg.
The composition of the shell: giprolose (with 0.3% silicon dioxide) - 3.6 mg, hypromellose - 3.6 mg, titanium dioxide - 1.8 mg, carnauba wax - 0.05 mg.
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (1) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2010.
Specific antagonist of angiotensin II receptor (type AT 1 ) for oral administration. Angiotensin II selectively binds to AT 1 -receptors found in many tissues (in the smooth muscle tissues of the vessels, in the adrenal, kidney and heart) and performs several important biological functions, including vasoconstriction and aldosterone release. Angiotensin II also stimulates proliferation of smooth muscle cells. Lozartan and its pharmacologically active metabolite (E 3174) both in vitro, both in vivo and in vivo, block all the physiological effects of angiotensin II, regardless of the source or route of synthesis. Unlike some peptide angiotensin II antagonists, losartan does not have the effects of an agonist.
Losartan selectively binds to AT 1 -receptors 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. In addition, losartan does not inhibit ACE, which is responsible for the destruction of bradykinin. Consequently, effects that are not directly related to the blockade of AT 1 -receptors, in particular, the enhancement of effects associated with bradykinin or the development of edema (losartan - 1.7%, placebo - 1.9%), are not related to the action of losartan.
With prolonged (6-week) treatment of patients with arterial hypertension losartan at a dose of 100 mg / day, there was a 2-3-fold increase in the level of angiotensin II at the moment of reaching the C max drug in blood plasma; in some patients, an even greater increase in losartan concentration was observed, especially with a short duration of treatment (2 weeks). In the course of treatment, antihypertensive activity and a decrease in plasma aldosterone concentration occurred at 2 and 6 weeks of therapy, indicating an effective blockade of angiotensin II receptors. However, after abolition of losartan, plasma renin activity and angiotensin II level decreased to the initial values вЂ‹вЂ‹observed 3 days prior to the start of the drug administration.
Since losartan is a specific antagonist of AT 1 -receptor angiotensin II, it does not inhibit ACE, kinase II is an enzyme that inactivates bradykinin. A study comparing the effects of 20 mg and 100 mg of losartan with the effects of an ACE inhibitor on the response to angiotensin I, angiotensin II, and bradykinin showed that losartan blocks the effects of angiotensin I and angiotensin II without affecting the effects of bradykinin, which is due to specific mechanism of action of losartan. In contrast, ACE inhibitors block the response of angiotensin I and increase the response to 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.Because losartan and its active metabolite are antagonists of angiotensin II receptors, they both determine the antihypertensive effect.
In a study with a single dose of 100 mg of losartan in healthy volunteers (men), the use of the drug both in patients who maintained a diet with limited salt content and patients consuming a lot of table salt did not affect the glomerular filtration rate, the effective renal plasma flow and the filtration fraction. Losartan has a natriuretic effect, which 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 arterial hypertension, proteinuria (more than 2 g / 24 h), not suffering from diabetes mellitus and taking losartan for 8 weeks at a dose of 50 mg to 100 mg, there was a significant decrease in proteinuria by 42%, fractional excretion of albumin and IgG. In these patients, losartan stabilized the glomerular filtration rate and reduced the filtration fraction.
In postmenopausal women with hypertension who took losartan potassium at a dose of 50 mg / day 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 level of norepinephrine in the blood plasma.
In patients with arterial hypertension, losartan at doses up to 150 mg / day does not cause clinically significant changes in the level of fasting triglycerides, total cholesterol (Xs) and Xc-HDL. In the same doses, losartan does not affect the fasting blood glucose level.
In general, losartan caused a decrease in serum uric acid level (usually less than 0.4 mg / dl), which persisted during prolonged therapy. In controlled clinical trials that included patients with hypertension, there were no cases of drug withdrawal due to an increase in serum creatinine or potassium levels.
When ingested, losartan is well absorbed from the gastrointestinal tract and is subjected to the effect of "first passage" through the liver, resulting in the formation of an active carboxylated metabolite and inactive metabolites. Systemic bioavailability of losartan is approximately 33%. The average C max of losartan and its active metabolite is reached after 1 h and 3-4 h respectively. When losartan was taken during a normal meal, there was no clinically significant effect on the profile of losartan concentration in the blood plasma.
Lozartan and its active metabolite bind to plasma proteins (mainly albumin) by more than 99%. V d of losartan is 34 liters. Studies in rats have shown that losartan practically does not penetrate the BBB.
Approximately 14% of the dose of losartan (with oral and / or induction) is converted to its active metabolite. After oral or intravenous administration of losartan labeled with 14 C, the radioactivity of circulating blood plasma is primarily associated with the presence of losartan and its active metabolite in it. Biologically inactive metabolites are also formed, incl. two basic, resulting from the hydroxylation of the butyl side chain, and one secondary is N-2-tetrazole-glucuronide.
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 unchanged in the urine and about 6% of the dose is excreted in the urine as an active metabolite. Losartan and its active metabolite have a linear pharmacokinetics with oral administration of losartan potassium in doses up to 200 mg.
After oral administration, the plasma concentrations of losartan and its active metabolite decrease polyexponentially with a finite T 1/2 of approximately 2 and 6-9 hours, respectively. When taking the drug at a dose of 100 mg 1 time / day, there is no significant cumulation in the plasma of either losartan or its active metabolite.
The excretion of losartan and its metabolites occurs with bile and urine. After ingestion of losartan labeled with 14 C, about 35% of the radioactive label is found in urine and 58% in feces. After intravenous administration of losartan labeled with 14 C, approximately 43% of the radioactive label is detected in the urine and 50% in the feces.
Pharmacokinetics in specific patient groups
The concentrations of losartan and its active metabolite in blood plasma in elderly people with arterial hypertension do not significantly differ from these indices in younger patients with arterial hypertension.
Concentrations of losartan in blood plasma were 2 times higher in women with arterial hypertension compared with men with arterial hypertension. The concentrations of active metabolite in men and women did not differ. This apparent pharmacokinetic difference is not clinically significant.
When losartan was administered orally to patients with cirrhosis of the liver of alcoholic origin, the concentrations of losartan and its active metabolite in blood plasma were found to be 5 and 1.7 times (respectively) mild and moderate in severity of gravity, respectively, than in young healthy male volunteers.
Concentrations of losartan in blood plasma in patients with creatinine clearance above 10 ml / min did not differ from those in individuals with normal renal function.When compared, the AUC value in patients on hemodialysis was approximately 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 in patients on hemodialysis. Lozartan and its active metabolite can not be removed by hemodialysis.
- arterial hypertension;
- reduction in the risk of associated cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy, manifested by a decrease in the combined incidence of cardiovascular mortality, stroke and myocardial infarction;
- protection of the kidneys in patients with type 2 diabetes mellitus with proteinuria - slowing the progression of renal failure, manifested by a decrease in frequency
hypercreatininemia, the frequency of end-stage renal disease, requiring hemodialysis or kidney transplantation,
mortality rates, as well as a decrease in proteinuria;
- Chronic heart failure with ineffective treatment with ACE inhibitors.
Kozaar is taken inside regardless of the food intake, it is possible to use both in the form of monotherapy, and in combination with other antihypertensive agents.
With arterial hypertension, the standard initial and maintenance dose for most patients is 50 mg 1 time / day. The maximum hypotensive effect is achieved 3-6 weeks after the start of therapy. In some patients, to achieve a greater effect, the dose may be increased to 100 mg 1 time / day.
In patients with reduced BCC (for example, when taking diuretics in high doses) the initial dose of the drug should be reduced to 25 mg 1 time / day.
There is no need to select an initial dose in the elderly and in patients with renal insufficiency, including patients on dialysis.
Patients with a history of liver disease are recommended to prescribe the drug in lower doses.
To reduce the risk of associated cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy, the standard initial dose of the drug is 50 mg 1 time / day. In the future, it is recommended to add hydrochlorothiazide at low doses or to increase the dose of Kozaar to 100 mg 1 time / day, taking into account the degree of BP reduction.
To protect kidney function in patients with type 2 diabetes and proteinuria, the standard initial dose of the drug is 50 mg 1 time / day. In the future, it is recommended to increase the dose of Kozaar to 100 mg 1 time / day, taking into account the degree of BP reduction. The cosaar can be prescribed together with other antihypertensive agents (diuretics, calcium channel blockers, alpha and beta adrenoblockers, central drugs), insulin and other hypoglycemic agents (sulfonylureas, glitazones and glucosidase inhibitors).
In chronic heart failure, the initial dose of Kozaar is 12.5 mg 1 time / day. Typically, the dose is titrated at a weekly interval (ie 12.5 mg / day, 25 mg / day, 50 mg / day) to the usual maintenance dose of 50 mg 1 time / day, depending on individual tolerability.
In controlled clinical trials of the drug in patients with essential hypertension, the only side effect associated with taking the drug was dizziness, which was observed more often than with placebo and occurred in? 1% of patients receiving Cozaar. Besides this, y? 1% of patients had orthostatic reactions, depending on the dose of the drug. Rarely, rash was reported, but its incidence was less than with placebo.
Controlled clinical studies have shown that Cosaar is generally well tolerated by patients with left ventricular hypertrophy, patients with type 2 diabetes and proteinuria. The most frequent side effects associated with taking the drug were systemic and non-systemic dizziness, asthenia / weakness, decreased blood pressure and hyperkalemia.
In the course of these studies, the following side effects were observed with the use of Coxaar (n = 2085) and placebo (n = 535) 1% of patients:
On the part of the body as a whole: pain in the stomach 1.7% (placebo 1.7%); weakness and fatigue 3.8% (placebo 3.9%), chest pain 1.1% (placebo 2.6%), edema 1.7% (placebo 1.9%)
From the cardiovascular system: increased heart rate 1% (placebo 0.4%); tachycardia 1% (placebo 1.7%).
From the digestive system: diarrhea 1.9% (placebo 1.9%); dyspepsia 1.1% (placebo 1.5%); nausea 1.8% (placebo 2.8%).
From the musculoskeletal system: back pain 1.6% (placebo 1.1%); muscle cramps 1% (placebo 1.1%).
From the side of the central nervous system: dizziness 4.1% (placebo 2.4%); headache 14.1% (placebo 17.2%); Insomnia 1.1% (placebo 0.7%).
On the part of the respiratory system: cough 3.1 (placebo 2.6%); edema of the nasal mucosa 1.3% (placebo 1.1%); pharyngitis 1.5% (placebo 2.6%); sinusitis 1% (placebo 1.3%); infections of the upper respiratory tract 6.5% (placebo 5.6%).
The following undesirable reactions were noted in a wide clinical practice.
Allergic reactions: patients with losartan rarely had angioneurotic edema, including laryngeal edema, glottis, causing airway obstruction, and / or edema of the face, lips, pharynx, and / or tongue. Some of these patients had a history of anginaevrotic edema with ACE inhibitors. Rarely reported on the occurrence of vasculitis, including purple Shenlaine-Genoh.
From the digestive system: hepatitis (rarely), a violation of the liver.
From the hemopoietic system: anemia, thrombocytopenia.
From the musculoskeletal system: myalgia; arthralgia; rarely rhabdomyolysis.
From the side of the central nervous system: migraine, rarely - dysgeusia.
From the respiratory system: cough.
Dermatological reactions: urticaria, itching, skin hyperemia.
On the part of laboratory indicators: in conducting controlled clinical trials in patients with essential hypertension, clinically significant changes in standard laboratory parameters were rarely associated with the use of Cosaar. 1.5% of patients had hyperkalemia (serum potassium> 5.5 meq / l). In a study in patients with type 2 diabetes mellitus with proteinuria, hyperkalemia developed in 9.9% of patients treated with Kozaar and 3.4% of patients treated with placebo. Elevated levels of ALT were noted in rare cases and usually returned to normal after withdrawal therapy.
In general, Kozaar is well tolerated, the side effects are mild and transient and do not require withdrawal of the drug. The total frequency of Cozaar's side effects is comparable to this indicator when taking placebo.
- Hypersensitivity to the components of the drug.
Caution should be given to patients with reduced BCC, for example, receiving treatment with diuretics in high doses (symptomatic hypotension may occur), as well as patients with a history of liver and kidney disease.
PREGNANCY AND LACTATION
The use of Cosaar during pregnancy is contraindicated.
The use of drugs acting on the renin-angiotensin system in the II and III trimesters of pregnancy can cause serious damage or even the death of the developing fetus, therefore, in determining the pregnancy, the Coxaar should be immediately discontinued. In the fetus, renal perfusion, depending on the development of the renin-angiotensin system, appears in the second trimester; The risk to the fetus increases if Cosaar is prescribed in the second or third trimester of pregnancy.
It is not recommended to take Cozaar during lactation. Experience with losartan in the period of breastfeeding is not, and it is not known whether losartan is excreted in breast milk. Because many drugs are excreted in breast milk and can have an adverse effect on infants, taking into account the need for the drug for the mother should decide whether to stop breastfeeding or to cancel the drug.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution should be prescribed to patients with a history of renal diseases.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution should be prescribed to patients in liver anamnesis.
APPLICATION FOR CHILDREN
Safety and efficacy in children under 18 years of age have not been established.
Can manifest symptoms such as a hypersensitivity angioedema.
In patients with reduced BCC (e.g., treated with large doses of diuretics) may occur symptomatic hypotension. Correction of such conditions should be carried out before or destination Cozaar begin treatment with a lower dose.
Disruption of water and electrolyte balance is characteristic of patients with renal insufficiency, diabetes or without diabetes, so you should be very careful when administering the drug in this category of patients. In clinical studies, involving patients with type 2 diabetes with proteinuria, the incidence of hyperkalemia was higher in the group receiving Cozaar than in the placebo group. Several patients had to discontinue treatment due to hyperkalemia occurred.
During treatment Cozaar patients should not take potassium supplements or substitutes containing potassium salt without prior approval of the physician.
These pharmacokinetic studies indicate that concentration of losartan in the blood plasma of patients with liver cirrhosis increases significantly, so patients with a history of liver disease drug should be administered at a lower dose.
Because of the inhibition of the renin-angiotensin system in certain susceptible patients had abnormal renal function, including renal failure; these changes may disappear after cessation of therapy.
Some drugs that affect the renin-angiotensin system may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. It reported the occurrence of such effects while taking COZAAR; changes in renal function may disappear at the termination of therapy.
Patients with dependent activity of the renin-angiotensin-aldosterone system renal function (ie with severe chronic heart failure) treatment with ACE inhibitors in some cases accompanied by the development of oliguria and / or progressive azotemia and acute renal failure (rarely), and / or conditions with a fatal outcome. About this outcome was reported in the treatment of this category of patients Cozaar.
Clinical studies have not revealed any specifics regarding the safety and efficacy of losartan in elderly patients.
Use in Pediatrics
Safety and efficacy in children under 18 years of age have not been established.
Data on overdose are limited. The most likely symptoms of overdose: marked reduction of blood pressure and tachycardia; bradycardia may occur as a result of parasympathetic stimulation.
Treatment: symptomatic therapy. Losartan and its active metabolite are not removed from the circulation during hemodialysis.
There were no clinically significant drug interactions with drugs such as hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, erythromycin and ketoconazole.
Rifampin and fluconazole reduce the level of the active metabolite. The clinical significance of these interactions have not been studied.
As with other means of blocking the formation of angiotensin II and its effects, concomitant administration of potassium-sparing diuretics (spironolactone, triamterene, amiloride), potassium supplements and salts containing potassium, may increase the level of potassium in serum.
As with other agents affecting the excretion of sodium, treatment with losartan may be accompanied by decrease in excretion and increased serum concentrations of lithium, however, while treatment with lithium preparations should control its serum concentration.
NSAIDs, including selective inhibitors of COX-2 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, including selective COX-2 inhibitors.
In some patients with impaired renal function, who were treated with NSAIDs, including selective inhibitors of COX-2, co-administration of angiotensin II receptor antagonists can cause a further deterioration of renal function. Normally, this effect is reversible.
Fluconazole, an inhibitor of cytochrome P450 2C9 isoenzyme, lowers plasma levels of the active metabolite of losartan and increases the concentration, however, the pharmacodynamic importance for this phenomenon has not been established. It is shown that persons who are not metabolising losartan's active metabolite, there is very rare and specific defect isoenzyme cytochrome P450 2C9.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The preparation should be stored in tightly closed containers, protected from light, out of reach of children at a temperature not higher than 30 В° C. Shelf life - 3 years.