Losartan - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate (milk sugar) - 114.63 mg, 149.50 mg or 270.60 mg, microcrystalline cellulose - 5.72 mg, 12.24 mg or 26.60 mg, croscarmellose sodium (impellose) - 4.29 mg , 9.18 mg or 15.20 mg, silicon dioxide colloid (aerosil) - 1.43 mg, 2.04 mg or 3.80 mg. magnesium stearate - 1.43 mg, 2.04 mg or 3.80 mg.

composition of the shell: for dosage of 12.5 mg and 25 mg - Opadrai II white (polyvinyl alcohol (131203) - 40.0%, titanium dioxide (E 171) - 25.0%, macrogol (polyethylene glycol) (E1521) - 20.2% talc (E553b) - 14.8%) - 2.983 mg or 3.975 mg emulsion simethicone 30% (water 50.0-69.5%, polydimethylsiloxane 25.5-33.0%, polyethylene glycol sorbitan tristearate 3.0-7, 0%, methyl cellulose 1.0-5.0%, silica gel 1.0-5.0%) 0.017 mg or 0.025 mg;

for a dosage of 50 mg - Opadrai II pink (polyvinyl alcohol (E1203) - 40.0%,titanium dioxide (E 171) - 24.18%, macrogol (polyethylene glycol) (E1521) - 20.2%, talc (E553b) - 14.8%, carmine red dye (E120) - 0.54%, aluminum varnish on the basis of the dye is the sunset yellow sunset yellow (E110) - 0.15%, the lacquer aluminum based on the dye red charming (E129) - 0.08%, the lacquer aluminum based on the dye quinoline yellow (E104) - 0.05%) - 9.923 mg, emulsion simethicone 30% (water 50.0-69.5%, polydimethylsiloxane 25.5-33.0%, polyethylene glycol sorbitan tristearate -3.0-7.0%, methylcellulose 1.0-5.0% , silica gel 1.0-5.0%) 0.077 mg.

Description:The film-coated tablets are white or white with a grayish shade of color (for a dosage of 12.5 mg and 25 mg) or pink (for a dosage of 50 mg), round, biconvex. Insignificant roughness of the surface is permissible. Color of tablets on a break - white or white with a yellowish shade.

Pharmacotherapeutic group:Angiotensin II receptor antagonist (AT1 subtype)

ATX: & nbsp

C.09.C.A.01 Losartan

C.09.C.A Angiotensin II antagonists

Pharmacodynamics:

Losartan is a specific antagonist of angiotensin II receptors (subtype AT₁) for oral administration. Does not inhibit kinase II - an enzyme that catalyzes the reaction of the conversion of angiotensin I into angiotensin II.

Angiotensin II selectively binds to AT₁receptors located in many tissues (in smooth muscle tissues of blood vessels, adrenal glands, nights and heart) and performs several important biological functions, including vasoconetics and the release of aldosterone. 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. Losartan selectively binds to the AT₁receptors, does not bind or block receptors of other hormones and ion channels, which play an important role in regulating the function of the cardiovascular system. Besides, losartan does not inhibit angiotensin-converting enzyme (ACE) - kininase II, and, accordingly, does not interfere with the destruction of bradykinin, therefore side effects mediated by bradykinin (eg, angioedema) are rare.

When losartan is used, the absence of negative feedback influence the secretion of renin leads to an increase in renin plasma activity.Increased renin activity leads to an increase in angiotensin II in blood plasma. However, antihypertensive activity and a decrease in plasma aldosterone concentration persist, indicating an effective blockade of angiotensin II reviewers. Losartan and its active metabolite have a greater affinity for the angiotensin I receptors than for angiotensin II receptors. The active metabolite is 10-40 times more active than losartan.

After a single oral intake, the antihypertensive effect (systolic and diastolic blood pressure decreases) reaches a maximum after 6 hours, then gradually decreases within 24 hours.

The maximum antihypertensive effect develops 3-6 weeks after the start of the drug.

In patients with 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.

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.

Losartan at a dose of 150 mg per day does not affect the concentration of triglycerides, total cholesterol and high-density lipoprotein cholesterol (HDL) in the blood serum in patients with hypertension. At the same dose losartan does not affect the concentration of glucose in the blood on an empty stomach.

Pharmacokinetics:

Suction

Ingestion losartan is well absorbed from the gastrointestinal tract (GIT) and at the same time is metabolized by "primary passage" through the liver by carboxylation with the participation of the CYP2C9 isoenzyme with the formation of an active metabolite.

Systemic bioavailability of losartan is approximately 33%. The time to reach the maximum concentration of losartan and its active metabolite is reached in the blood serum after approximately 1 hour and after 3-4 hours, respectively, after ingestion. Eating does not affect the bioavailability of losartan.

Distribution

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

Metabolism

Approximately 14% of losartan taken orally or intravenously is converted to an active metabolite. In addition to the active metabolite, pharmacologically inactive metabolites are formed, including the two main metabolites formed as a result of 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 administered orally, approximately 4% of the dose taken is excreted by the kidneys unchanged and about 6% is excreted by the kidneys in the form of an active metabolite. Losartan and its active metabolite have linear pharmacokinetics when administered to losartan in doses up to 200 mg. The half-life is 1.5-2 hours, and its main metabolite is 6-9 hours, respectively. When taking the drug at a dose of 100 mg per day, neither losartan, nor its active metabolite significantly not cumulate in blood plasma.

Losartan and its metabolites are excreted from the body through the intestines with bile and kidneys.

Pharmacokinetics in specific patient groups

In patients with alcoholic liver cirrhosis of mild and moderate severity, the concentration of losartan is 5 times, and that of the active metabolite is 1.7 times higher than in healthy male volunteers.

When the creatinine clearance (CK) is above 10 ml / min, the concentration of losartan in the blood plasma does not differ from that with normal kidney function.

In patients in need of hemodialysis, the area under the concentration-time curve (AUC) is approximately 2 times higher than in patients with normal function of the nights.

Neither losartan, nor its active metabolite is removed from the body by hemodialysis.

The concentrations of losartan and its active metabolite in blood plasma in elderly male patients with arterial hypertension do not differ significantly from the values of these parameters in young male patients with hypertension. Values of plasma concentrations of losartan in women with arterial hypertension are 2 times higher than the corresponding values in men with arterial hypertension. The concentrations of the active metabolite in men and women do not differ.This pharmacokinetic difference is not clinically relevant.

Indications:

- Arterial hypertension.

- Chronic heart failure (as part of combination therapy, with intolerance or ineffectiveness of angiotensin-converting enzyme inhibitors).

- Reducing the risk of developing cardiovascular diseases (including stroke) and mortality in patients with hypertension and left ventricular hypertrophy.

- Diabetic nephropathy or hypercreatininaemia and proteinuria (urine albumin and creatinine ratio more than 300 mg / day) in patients with type 2 diabetes and concomitant arterial hypertension (reduction in progression of diabetic nephropathy to terminal chronic renal failure).

Contraindications:Hypersensitivity to the components of the drug; severe hepatic insufficiency (more than 9 on the Child-Pugh scale); age to 18 years; simultaneous use with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and / or renal dysfunction; lactose intolerance, lactase deficiency or glucose-galactose malabsorption; pregnancy and the period of breastfeeding.

Carefully:Arterial hypotension; reduced volume of circulating blood (BCC); violation of water and electrolyte balance; bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney; kidney failure; hepatic failure (less than 9 on the Child-Pugh scale); hyperkalemia; hypertrophic obstructive cardiomyopathy; heart failure with life-threatening arrhythmias; heart failure with concomitant severe impairment of kidney function; cardiac ischemia; cerebrovascular diseases; primary girondosteronism; angioedema in history.

Pregnancy and lactation:

The use of losartan in pregnancy is contraindicated. 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 the death of the developing fetus. Therefore, when diagnosing pregnancy, losartan should be stopped immediately.

It is not known whether losartan with breast milk. It is not recommended to take losartan in the period of breastfeeding.If the drug is needed during lactation, then breastfeeding should be discontinued.

Dosing and Administration:

Inside, regardless of food intake, the frequency of intake is 1 time per day. Tablets are swallowed whole, not liquid, squeezed with water.

Arterial hypertension

With arterial hypertension, the standard initial and maintenance dose for most patients is 50 mg 1 time / day.

To achieve greater therapeutic affect, the dose is increased to a maximum daily dose of 100 mg once daily.

Chronic heart failure

The initial dose for patients with chronic heart failure is 12.5 mg once a day. Typically, the dose increases with a weekly interval (i.e., 12.5 mg / day, 25 mg / day and 50 mg / day) to an average maintenance dose of 50 mg 1 time per day, depending on the patient's tolerability.

Reducing the risk of developing cardiovascular diseases (including stroke) and mortality in patients with hypertension and left ventricular hypertrophy

The initial dose of the drug is 50 mg 1 time / day. In the future, you can add hydrochlorothiazide in low doses or increased dose of the drug Losartan up to 100 mg in one or two doses, taking into account the decrease in blood pressure.

Kidney protection in patients with type 2 diabetes and proteinuria

A drug Losartan prescribe in the initial dose - 50 mg once a day with a further increase in the dose to 100 mg / day (taking into account the degree of BP reduction) in one or two doses.

Special patient groups:

In patients with reduced BCC (for example, when taking diuretics in high doses), the recommended initial dose of the drug Losartan is 25 mg 1 time / day.

Patients with renal insufficiency and patients on dialysis

There is no need to select an initial dose in patients with renal insufficiency, including patients on dialysis.

Elderly patients

There is no need for a dose selection in elderly patients, although it is recommended to start treatment with a dose of 25 mg in patients older than 75 years.

Patients with hepatic insufficiency

Patients with a history of liver disease are recommended to prescribe the drug in lower doses. The use of losartan is contraindicated in patients with severe hepatic insufficiency, since there is no clinical experience in this group of patients (see "Contraindications").

Safety and efficacy of the drug in children under 18 years of age have not been established.

Side effects:

Lozaratna's side effects are usually transient and do not require drug withdrawal.

When Lozaratna was used to treat essential hypertension in controlled trials, only the incidence of dizziness differed from placebo by more than 1% (4.1% vs. 2.4%) among all adverse events.

A dose-dependent orthostatic effect, characteristic of antihypertensive agents, was observed in less than 1% of patients with losartan.

The frequency of adverse reactions was determined according to the following gradation (classification of the World Health Organization): very frequent (≥ 10%); frequent (≥ 1%; <10%); infrequent (≥ 0.1%, <1%); rare (≥ 0.01%, <0.1%); very rare, including individual messages (<0.01%); the frequency is unknown (if it is impossible to estimate from the available data).

Prevalence of adverse reactions based on placebo-controlled clinical trials and post-registration follow-up.

Arterial hypertension:

Impaired nervous system: frequent: dizziness; infrequent: drowsiness, headache, sleep disturbance.

Hearing impairments and labyrinthine disturbances: Frequent: Vertigo.

Heart Disease: infrequent: a feeling of heartbeat, angina.

Vascular disorders: infrequent: (orthostatic) hypotension (including dose-mediated orthostatic effects) (especially in patients with reduced bcc, for example, in patients with severe heart failure or patients treated with high doses of diuretics).

Disorders from the gastrointestinal tract: infrequent: abdominal pain, intestinal obstruction.

Disturbances from the skin and subcutaneous tissues: infrequent: rash.

Common disorders and disorders together: infrequent: asthenia, weakness, swelling. Influence on the results of laboratory and instrumental studies: frequent: hyperkalemia; rare: increased activity of alanine aminotransphrasis (usually after withdrawal of treatment).

Patients with arterial hypertension and left ventricular hypertrophy:

Impaired nervous system: frequent: dizziness.

Hearing impairments and labyrinthine disturbances: Frequent: Vertigo.

Common disorders and disorders together: frequent: asthenia, weakness. Chronic heart failure:

Disturbances from the blood system and lymphatic system: frequent: anemia.

Impaired nervous system: frequent: dizziness, infrequent: headache; rare: paresthesia.

Heart Disease: rare: fainting, atrial fibrillation, acute disturbance of cerebral circulation.

Vascular disorders: frequent (orthostatic) hypotension (including dose-mediated orthostatic effects) (especially in patients with reduced BCC, for example, in patients with severe heart failure or patients treated with high doses of diuretics).

Disturbances from the respiratory system, thorax and mediastinum: infrequent: shortness of breath, cough.

Disorders from the gastrointestinal tract: infrequent: diarrhea, nausea, vomiting.

Disturbances from the skin and subcutaneous tissues: infrequent: urticaria, itchy skin. rash.

Disturbances from the musculoskeletal and connective tissue: infrequent: muscle spasm.

Disorders from the kidneys and urinary tract: frequent: violations of the function of the nights. renal insufficiency.

Common disorders and disorders together: infrequent: asthenia, weakness.

Impact on laboratory and instrumental research results: frequent: increased concentrations of urea, creatinine and potassium in blood plasma: infrequent: hyperkalemia (often seen in patients taking losartan in a dose of 150 mg per day instead of 50 mg per day).

Arterial hypertension and type 2 diabetes mellitus with impaired renal function:

Impaired nervous system: frequent: dizziness.

General disorders and disorders at the site of administration: frequent: asthenia, weakness.

Effects on laboratory and instrumental results: frequent: hyperkalemia (in a clinical study conducted with patients with type 2 diabetes and nephropathy, hyperkalemia> 5.5 mmol / l developed in 9.9% of patients taking losartan in tablets, and in 3.4% of patients taking placebo), hypoglycemia.

Post-acquisition monitoring:

Disturbances from the blood system and lymphatic system: frequency unknown: anemia, thrombocytopenia.

Immune system disorders: rare: allergic reactions, anaphylactic reactions, Quincke's edema (including swelling of the larynx, vocal cords, face, lips, pharynx and / or tongue (which leads to a violation of airway patency), in some of these patients, Quincke's edema was noted earlier in connection with administration of other drugs including ACE inhibitors), vasculitis (including hemorrhagic vasculitis (Sheng-lien-Henoch disease)).

Disorders of the psyche: frequency is unknown: depression.

Impaired nervous system: frequency unknown: migraine, taste disorder.

Hearing impairments and labyrinthine disturbances: frequency unknown: tinnitus.

Disturbances from the respiratory system, thorax and mediastinum: frequency unknown: cough.

Disorders from the gastrointestinal tract: frequency unknown: diarrhea.

Disorders from the liver and bile ducts: rare: hepatitis; frequency unknown: impaired liver function, pancreatitis.

Disturbances from the skin and subcutaneous tissues: frequency unknown: urticaria, itching, rash, photosensitivity.

Disturbances from the musculoskeletal and connective tissue: frequency unknown: myalgia. arthralgia, rhabdomyolysis.

Violations of the genitals and dairy. frequency unknown: erectile dysfunction / impotence.

General disorders and disorders at the site of administration: frequency unknown: malaise. Influence on the results of laboratory and instrumental studies: the frequency is unknown: hyponatremia.

The following additional adverse reactions were more frequent in patients who received losartan, than in patients receiving placebo (exact rates are unknown): back pain, urinary tract infections and flu-like symptoms.

Disorders from the kidneys and urinary tract

As a consequence of inhibition of RAAS in patients at risk, impaired renal function including acute renal failure was noted. These changes on the part of the kidney function can be reversible in the case of timely withdrawal of treatment.

Overdose:

Symptoms: marked decrease in LD and tachycardia; Bradycardia can occur due to parasympathetic stimulation.

Treatment: forced diuresis, symptomatic therapy; losartan and its active metabolite are not removed from the bloodstream by hemodialysis.

Interaction:

There was no clinically significant interaction of losartan with hydrochlorohyazide, digoxin, warfarin, cimstidine, phenobarbital, ketoconazole and erythromycin. Reportedly rifampicin and fluconazole reduce the concentration of the active metabolite in the blood plasma. The clinical significance of these interactions is still unknown.

As with other agents that inhibit the formation of angiotensin II or its effect, the simultaneous use of losartan with potassium-sparing diuretics (eg, spironolactone, triamcrene amyloride), potassium preparations, salts containing potassium, increases the risk of hyperkalemia.

Non-steroidal anti-inflammatory drugs (NSAIDs). including selective inhibitors of cyclooxygenase-2 (COX-2), can reduce the effect of diuretics and other antihypertensive agents.Therefore, the antigaintensive effect of angiotensin II receptor antagonists (APA II) or AIIF inhibitors can be weakened when used simultaneously with NSAIDs. including selective inhibitors of COX-2. In some patients with impaired sleep (for example, in elderly patients and in patients with reduced circulating blood volume (BCC), including those taking diuretics) who have been treated with NSAIDs, including selective COX-2 inhibitors, concomitant use of ARA II or inhibitors ACE, can cause further impairment of kidney function until the development of acute renal failure. Usually, this effect is reversible. Thus, simultaneous therapy with NSAIDs should be conducted with caution in patients with impaired renal function.

Double blockade of RAAS with APA II receptor antagonists. ACE inhibitors or aliskiren (renin inhibitor), is associated with an increased risk of arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure) compared with myogeraphy. It is necessary to monitor blood pressure, the function of the nights and the content of electrolytes in the blood in patients taking losartan and other drugs that affect RAAS. Losartan It should not be used concomitantly with aliskiren in patients with diabetes mellitus.

It should avoid simultaneous use of losartan and aliskiren in patients with impaired renal function (glomerular filtration rate less than 60 ml / min).

With the simultaneous use of ARA II and lithium, an increase in the concentration of lithium in the blood plasma is possible. Given this, it is necessary to weigh the benefits and risks of the joint use of losartan with lithium preparations. In the case of simultaneous use of drugs, it is necessary to regularly monitor the concentration of lithium in the blood plasma. Fluconazole, inhibitor of the cytochrome P450 2C9 isoenzyme, reduces plasma concentrations of the active metabolite and increases the concentration of losartan, however, the pharmacodynamic significance of this phenomenon has not been established. It was shown that in patients not metabolizing losartan in the active metabolite, there is a very rare and specific defect in the isoenzyme P450 2C9.

Special instructions:

In patients with reduced BCC (eg, receiving treatment with high doses of diuretics), at the beginning of treatment with losartan, symptomaticarterial hypotension (it is necessary to correct the BCC before the appointment of losartan or start treatment with a lower dose).

Violation of the water-electrolyte balance is characteristic of patients with impaired renal function with diabetes mellitus or without diabetes mellitus, therefore careful monitoring of these patients is necessary.

During drug therapy losartan patients should not take potassium or potassium supplements without prior approval from the doctor. In patients with cirrhosis of the liver, the concentration of losartan in the blood plasma is significantly increased, in connection with which. In the presence of liver diseases in the history, it should be prescribed in lower doses.

During the treatment period, the potassium content in the blood should be regularly monitored, especially in elderly patients, if the function of the nights is disturbed.

Drugs that affect RAAS can increase the concentration of urea in the blood and serum creatinine in patients with bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney.

Safety and efficacy of the drug in children under 18 years of age have not been established.

Effect on the ability to drive transp. cf.and fur:There have been no special clinical studies but an evaluation of the effect of the drug on the ability to drive vehicles and work with machinery. It should be borne in mind the possibility of the appearance of drowsiness and dizziness, so you need to watch the caution when carrying out 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.

Form release / dosage:The film-coated tablets are 12.5 mg, 25 mg and 50 mg.

Packaging:

For 7 or 10 tablets in a contour mesh package.

By 1. 2, 3 or 4 contour squares with instructions for use in a cardboard pack.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:4 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002884

Date of registration:27.02.2015

Expiration Date:27.02.2020

The owner of the registration certificate:BIOKOM, CJSC BIOKOM, CJSC Russia

Manufacturer: & nbsp

BIOKOM, CJSC Russia

Information update date: & nbsp04.04.2018

Illustrated instructions

Instructions

Losartan (Losartan)