Universal reference book for medicines
Product name: LOSAKOR (LOSACOR)

Active substance: losartan

Type: Angiotensin II receptor antagonist

Manufacturer: ADIPHARM (Bulgaria)
Composition, form of production and packaging
The tablets covered with a film membrane
from light yellow to yellow color, oval, slightly biconcave, with a facet.

1 tab.

Losartan potassium 12.5 mg

Excipients: cellactose (a mixture of lactose monohydrate and cellulose), pregelatinized starch, corn starch, microcrystalline cellulose, silicon dioxide colloidal anhydrous, magnesium stearate.

Sheath composition: hypromellose, talc, propylene glycol, dye quinoline yellow (E104), titanium dioxide (E171).

7 pcs.
- packings cellular planimetric (2) - packs cardboard.
10 pieces.
- packings cellular planimetric (3) - packs cardboard.
10 pieces.
- packings cellular planimetric (6) - packs cardboard.
10 pieces.
- packings cellular planimetric (9) - packs cardboard.
14 pcs.
- packings of cellular contour (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2011.

PHARMACHOLOGIC EFFECT

A hypotensive drug, is a specific receptor antagonist, angiotensin II (type AT1).
Angiotensin II selectively binds to AT1 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. Losartan and its pharmacologically active metabolite (E 3174) both in vitro 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 AT1 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 contributes to the degradation of bradykinin.Therefore, effects not directly related to AT1 receptor blockade, in particular, increased effects associated with bradykinin or angioneurotic edema (losartan 1.7%, placebo 1.9%), are not relevant to the action of losartan.
With prolonged (6-week) treatment of patients with arterial hypertension, losartan at a dose of 100 mg / day was observed 2-3-fold, an increase in angiotensin II activity at the time of reaching the maximum plasma concentration of the drug in the blood plasma;
in some patients there was an even greater increase in losartan concentrations, especially with a short duration of treatment (2 weeks). However, antihypertensive activity and a decrease in plasma aldosterone concentration were manifested at 2 and 6 weeks of therapy, which indicates an effective blockade of angiotensin II receptors. After abolition of losartan, the plasma renin activity and angiotensin II activity decreased to the baseline values ​​observed 3 days before the start of the drug administration.
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 by 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.

After a single oral intake, the hypotensive effect (systolic and diastolic blood pressure decreases) reaches a maximum after 6 hours, then gradually decreases within 24 hours.
The maximum hypotensive effect develops 3-6 weeks after the start of the drug. Stabilizes the concentration of urea in the blood plasma. Does not affect vegetative reflexes, and does not have a long-term effect on the concentration of norepinephrine in the blood plasma. In patients with arterial hypertension without concomitant diabetes mellitus with proteinuria (more than 2 g / day), the use of the drug significantly reduces proteinuria, albumin and immunoglobulin G excretion.
PHARMACOKINETICS

Suction

When ingested, losartan is well absorbed from the gastrointestinal tract and is subjected to the effect of "primary 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.
Distribution

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.
Metabolism

Approximately 14% of the dose of losartan (when taken orally and / in the introduction) 'turns into its active metabolite.
After oral or intravenous administration of losartan, labeled 14 C, the radioactivity of the circulating blood plasma is primarily due to 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.
Excretion

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 by the kidneys and about 6% of the dose is excreted by the kidneys as an active metabolite. Losartan and its active metabolite have a linear pharmacokinetics when administered 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 about 2 hours and 6-9 hours, respectively.
When a single admission of the drug in a dose of 100 mg, neither losartan nor its active metabolite significantly accumulate in the plasma.
The excretion of losartan and its metabolites occurs through the intestine and kidneys.
After ingestion of losartan, labeled. 14 C, about 35% of the radioactive label is found in urine and 58% in feces. After intravenous administration of losartan, labeled 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 patients 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.

The concentration of losartan in the blood plasma in patients with creatinine clearance (CC) above 10 ml / min did not differ from those in persons with normal renal function.
In patients who need hemodialysis, the AUC value is approximately 2 times higher than in patients with normal renal function. Plasma concentrations of 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.
INDICATIONS

- 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;

- diabetic nephropathy in hypercreatinemia and proteinuria (urine albumin and creatinine ratio more than 300 mg / g) in patients with type 2 diabetes and concomitant arterial hypertension (decreased progression of diabetic nephropathy to terminal chronic renal failure);

- Chronic heart failure with ineffective treatment with ACE inhibitors.

DOSING MODE

Inside, regardless of food intake, the tablets are swallowed, not liquid, squeezed with water.
Multiplicity of admission - 1 time / day.
With arterial hypertension, the average daily dose is 50 mg 1 time / day.
In some cases, to achieve a greater effect, the dose is increased to 100 mg in 2 divided doses or 1 time / day. The maximum dose is 100 mg / day. When appointing the drug to patients receiving diuretics in high doses, the initial dose of the drug should be reduced to 25 mg (1/2 tablespoons 50 mg) 1 time / day.
There is no need to select an initial dose in elderly patients and in patients with renal insufficiency, including patients on dialysis.

Patients with hepatic insufficiency (less than 9 on the Child-Pugh scale) and patients older than 75 years are recommended a lower initial dose of the drug - 25 mg (1/2 tablets 50 mg) 1 time / day.

Insufficient experience in the use of the drug in patients with severe hepatic insufficiency , so the drug is not recommended for this category of patients.

To reduce the risk of cardiovascular disease and mortality in patients with hypertension and left ventricular hypertrophy, usually the initial dose is 50 mg 1 time / day.
In the future, hydrochlorothiazide can be added in low doses and / or the dose of Losakor can be increased to 100 mg per day in 1 or 2 doses.
To protect kidney function in patients with type 2 diabetes and proteinuria, usually the initial dose is 50 mg 1 time / day.
In the future, it is recommended to increase the dose to 100 mg 1 time / day, taking into account the degree of BP reduction.
The initial dose for patients with heart failure is 12.5 mg 1 time / day.
Typically, the dose increases with a weekly interval (ie 12.5 mg / day, 25 mg / day, 50 mg / day) to an average maintenance dose of 50 mg 1 time / day, depending on the patient's tolerance.
SIDE EFFECT

Side effects of the frequency of occurrence are distributed as follows: very often (? 10%), often (? 1%, but <10%), infrequently (? 0.1%, but <1%), rarely (? 0.01%, but <0.1 %), very rarely (<0.01%), including individual messages.

In patients with essential hypertension, the only side effect associated with taking the drug was dizziness, which was more frequent than with placebo and occurred in more than 1% of patients receiving LOSACOR.
In addition, less than 1% of patients had orthostatic reactions depending on the dose
preparation.
Rarely, rash was reported, but its incidence was less than with placebo.
Losacore 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, marked decrease in blood pressure, hyperkalemia.
Side effects, occurring with a frequency of development of more than 1%

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%), peripheral edema 1.7% (placebo 1.9%) .

From the cardiovascular system: a palpitation of 1% (placebo 0.4%), tachycardia 1% (placebo 1.7%).

On the part of 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 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%), upper respiratory infections 6.5% (placebo 5.6%).

Side effects, occurring with a development rate of less than 1%

Allergic reactions: angioedema, including laryngeal edema, glottis, causing airway obstruction, and / or edema of the face, lips, pharynx and / or tongue.

From the side of the central nervous system: migraine.

From the musculoskeletal system: myalgia, arthralgia.

From the skin: urticaria, skin itching.

On the part of the digestive system: hepatitis, a violation of the liver.

On the part of the organs of hematopoiesis: anemia, thrombocytopenia.

From the respiratory system: cough.

Laboratory indicators: often - hyperkalemia (concentration of potassium in the blood plasma is more than 5.5 meq / l);
sometimes - an increase in the concentration of urea and residual nitrogen or creatinine in the blood serum; very rarely - a moderate increase in hepatic transaminase activity (ACT and ALT, hyperbilirubinemia.
In patients with dehydration (eg, receiving diuretic treatment in high doses), at the beginning of treatment with losartan, symptomatic arterial hypertension may occur.With cirrhosis, the concentration of losartan in the blood plasma increases significantly.

In general, the drug is well tolerated, the side effects are mild and transient and do not require withdrawal of the drug.
The total frequency of Loxacor's side effects is comparable to that of placebo.
CONTRAINDICATIONS

- severe hepatic insufficiency (more than 9 points on the Child-Pugh scale);

- lactose intolerance, lactase deficiency and glucose-galactose malabsorption;

- Pregnancy;

- lactation period;

- age up to 18 years;

- Hypersensitivity to the components of the drug.

With caution: arterial hypotension, reduced bcc, abnormal water-electrolyte balance, bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney, renal failure, liver failure (less than 9 on the Child-Pugh scale);
with simultaneous application
with the following drugs (beta-blockers, sympatholytics, diuretics, hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole, erythromycin, rifampin, fluconazole, lithium carbonate, potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium supplements and salts , containing potassium, NSAIDs, including selective inhibitors of COX-2).

PREGNANCY AND LACTATION

Losakor is contraindicated in pregnancy and lactation.
It is known that drugs acting directly on the renin-angiotensin-aldosterone system (RAAS), when used in the II and III trimesters of pregnancy, can cause developmental defects or even death of the developing fetus. Therefore, when diagnosing pregnancy, taking Losakor should be stopped immediately.
It is not known whether losartan is excreted in breast milk.
It is not recommended to take Losakor during lactation. If taking Losakor is necessary during lactation, then breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER

With caution: bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney, renal failure.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

With caution: hepatic insufficiency (less than 9 on the Child-Pugh scale).

Contraindicated:

- severe hepatic insufficiency (more than 9 points on the Child-Pugh scale).

Patients with hepatic insufficiency (less than 9 on the Child-Pugh scale) are 25 mg (1/2 tablets 50 mg) 1 time / day.

APPLICATION FOR CHILDREN

Contraindicated in children under 18 years .

APPLICATION IN ELDERLY PATIENTS

There is no need to select an initial dose in elderly patients.

Patients older than 75 years are recommended a lower initial dose of the drug - 25 mg (1/2 tablespoons of 50 mg) 1 time / day.

SPECIAL INSTRUCTIONS

Perhaps the manifestation of such a symptom of hypersensitivity as angioedema.

Patients with a reduced osmotically active extracellular cation (BCC) (eg, receiving treatment with large doses of diuretics) may experience symptomatic arterial hypotension.
Correction of such conditions should be done before the appointment of Lozakor or start treatment with a lower dose.
During the treatment period, the level of potassium in the blood should be monitored regularly;
especially in elderly patients, with violations of kidney function.
Violation of the water-electrolyte balance is characteristic of patients with renal insufficiency with diabetes mellitus or without diabetes mellitus, therefore, when prescribing a drug in this category of patients, special care should be taken.

In patients with cirrhosis of the liver, the concentration of losartan in the blood plasma is significantly increased, and therefore, in the presence of liver diseases in the history of the drug should be prescribed in lower doses.

Drugs that have an effect on RAAS can increase the concentration of urea in the blood and creatinine in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney.

During the treatment period, the potassium content in the blood should be regularly monitored, especially in elderly patients, with renal dysfunction.

Impact on the ability to drive vehicles and manage mechanisms

There were no special clinical studies to assess the effect of the drug on the ability to drive vehicles and work with machinery.
It should be borne in mind the possibility of drowsiness and dizziness, so you need to be careful when performing work that requires increased attention, especially at the beginning of treatment, with an increase in the dose of the drug and in the management of vehicles.
OVERDOSE

Information on overdose is limited.

Symptoms: The most likely symptoms of an overdose are a marked decrease in 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.
DRUG INTERACTION

Mutually enhances the effect of beta-blockers and sympatholytics.

The combined use of losartan with diuretics has an additive effect.

There were no clinically significant drug interactions with drugs such as hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, erythromycin and ketoconazole.
Rifampin and fluconazole reduce the concentration of the active metabolite. The clinical significance of these interactions have not been studied.
There is a report on the development of lithium toxicity with concomitant use with lithium carbonate. With simultaneous use of the angiotensin II receptor antagonist and lithium may increase the concentration of lithium in the blood plasma. Given this, it is necessary to weigh the benefits and risks of combined use of losartan with lithium therapy.
In case of necessity of joint application of preparations, it is necessary to regularly monitor the concentration of lithium in blood plasma.
As with other drugs which block the formation of angiotensin II and its effects kalyysberegayuschih concomitant administration of diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium supplements and salts containing potassium, can result in an increase in potassium in serum.
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 COX-2 inhibitors, the simultaneous use of the angiotensin II receptor antagonists can cause a further deterioration of renal function. Normally, this effect is reversible.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of reach of children at a temperature of no higher than 25 ° C.
Shelf life - 3 years.
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