Lozarel - instructions for use, doses, side effects, contraindications

core pills: losartan potassium 50,000 mg, microcrystalline cellulose 60.0 mg, lactose monohydrate 28.520 mg, pregelatinized starch 20.0 mg, silicon dioxide colloidal anhydrous 0.480 mg, magnesium stearate 1,000 mg;

film shell: hypromellose 1.984 mg, giprolose 0,496 mg, macrogol 400 0,400 mg, titanium dioxide (E 171) 0,920 mg, talc 0,200 mg.

Description:

Round, biconvex tablets white or white with a yellowish tinge color, covered with a film membrane, with a risk on one side.

Pharmacotherapeutic group:angiotensin II receptor antagonist

ATX: & nbsp

C.09.C.A.01 Losartan

C.09.C.A Angiotensin II antagonists

Pharmacodynamics:

Losartan is a specific antagonist of angiotensin II (type AT₁) receptors.Angiotensin II selectively binds to AT₁ receptors located in many tissues (in the smooth muscle tissues of the vessels, in the adrenal gland, kidneys and heart) and causes vasoconstriction and release of aldosterone, proliferation of smooth muscles.

Research in vitro and in vivo proved that losartan and its pharmacologically active metabolite block all physiologically important effects of angiotensin II, regardless of the source or route of its synthesis. Does not inhibit kinase II - an enzyme that destroys bradykinin.

Reduces the overall peripheral vascular resistance (OPSS), concentration in the blood of aldosterone, blood pressure (BP), pressure in the "small" circle of the circulation; reduces afterload, has a diuretic effect. Prevents development of myocardial hypertrophy, increases exercise tolerance in patients with chronic heart failure (CHF).

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 in 3-6 weeks after regular intake of the drug.

It does not inhibit angiotensin-converting enzyme (ACE) and, accordingly, prevents the destruction of bradykinin, therefore, losartan is not associated with effects mediated by bradykinin (eg, angioedema). 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 excretion G.

Stabilizes the level of urea in the blood plasma. Does not affect vegetative reflexes, and does not have a long-term effect on the level of norepinephrine in blood plasma.

In a dose up to 150 mg once a day does not affect the level of triglycerides, total cholesterol and high-density lipoprotein cholesterol (HDL) in the blood serum in patients with hypertension. In the same dose, losartan does not affect the fasting blood glucose level.

Pharmacokinetics:

Suction

Ingestion losartan well absorbed, systemic the bioavailability of losartan is about 33%. Maximum the concentration of losartan and its active metabolite in blood plasma is reached after approximately 1 hour and 3-4 hours after oral administration, respectively. Eating does not affect the bioavailability of losartan.

Distribution

More than 99% of losartan and its active metabolite binds to plasma proteins, mainly albumin. The volume of distribution is 34 liters. Losartan practically does not penetrate the blood-brain barrier.

Metabolism

Losartan is metabolized at "primary passage" through the liver by carboxylation with the participation of predominantly isoenzymes of cytochrome P450 CYP2C9 and CYP3A4 with the formation of pharmacologically active carboxylated metabolite and inactive metabolites.

About 14% losartan with the use of intravenous or oral is converted into its active metabolite. In addition to the active metabolite, biologically inactive metabolites are formed, including two major metabolites that are formed as a result of the hydroxylation of butyl side chain, and one secondary - N-2tetrazol-glucuronide.

Excretion

The plasma clearance of losartan is 600 ml / min, its active metabolite is 50 ml / min. The renal clearance of losartan and its active metabolite is 74 ml / min and 26 ml / min, respectively. Approximately 4% of the accepted dose of the drug is excreted by the kidneys unchanged, about 6% in the form of an active metabolite. Losartan and its active metabolite have linear pharmacokinetics when administered orally at doses up to 200 mg.

After application inside plasma concentrations of losartan and its active metabolite decrease polyexponentially with a terminal half-life of losartan about 2 hours, and the active metabolite - about 6-9 hours. When using the drug at a dose of 100 mg per day, neither losartan, nor the active metabolite significantly does not accumulate in the blood plasma. Losartan and its metabolites are excreted with bile through the intestine (58%) and kidneys (35%).

Pharmacokinetics in specific patient groups

Elderly patients

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 men with arterial hypertension.

Floor

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 significant.

Impaired liver function

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. Patients with hepatic plasma insufficiency The clearance of losartan was 50% lower, and the bioavailability with oral administration was 2 times higher than in healthy volunteers.

Impaired renal function

In patients with mild (creatinine clearance (CC) 50-74 ml / min) and moderate (KK 30-49 ml / min) degree of renal dysfunction plasma concentration and area under the concentration-time curve of losartan and its active metabolite is increased by 50-90%. Neither losartan, nor its active metabolite is not removed from the body by hemodialysis. With renal failure, dose adjustment is not required (except for cases of dehydrated patients).

Indications:

- Arterial hypertension;

- Chronic heart failure (with ineffective treatment with ACE inhibitors);

- Nephropathy in type 2 diabetes mellitus (reduced risk of hypercreatininemia and proteinuria);

- Reducing the risk of developing cardiovascular complications and mortality in patients with hypertension and left ventricular hypertrophy.

Contraindications:

- Pincreased sensitivity to the components of the drug, as well as to other drugs that are sulfonamide derivatives;

- hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;

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

- simultaneous use with aliskirenom in patients with type 2 diabetes mellitus and renal insufficiency (Rate of glomerular filtration (GFR) of less than 60 ml / min / 1.73 m²) (see section "Interaction with other medicinal products");

- pregnancy, the period of breastfeeding;

- age to 18 years (efficacy and safety not established).

Carefully:

- Patients with moderate hepatic and / or renal insufficiency; after kidney transplantation (no experience of application);

- states, accompanied by decrease in the volume of circulating blood (BCC, including diarrhea, vomiting, use in patients on hemodialysis);

- violations of water-electrolyte balance; diet with restriction of consumption of table salt; bilateral stenosis of the renal artery or stenosis of the renal artery of the only kidney;

- cerebrovascular diseases;

- chronic heart insufficiency (IV functional class by classification NYHA);

- combination of heart failure with concomitant severe renal disease insufficiency, with life-threatening arrhythmias; cardiac ischemia;

- Stenosis of the aortic and mitral valves, hypertrophic obstructive cardiomyopathy;

- angioedema in history;

- primary hyperaldosteronism, diabetes mellitus (increased risk of developing hyperkalemia);

- a joint application with beta-blockers, inhibitors angiotensin-converting enzyme (ACE), potassium preparations.

Pregnancy and lactation:

Application of the drug Lozarel® in pregnancy it is contraindicated.

The use of the drug Lozarel® during pregnancy can lead to low salinity, delay intrauterine fetal development, premature birth, fetal death, as well as an increased risk of developing a newborn, arterial hypotension, anuria, reversible or irreversible renal failure, hypoplasia of the skull bones, limb contractures, deformities of the bones of the skull, hypoplasia of the lungs.

If during pregnancy, taking the drug Lozarel^® It is necessary to carry out a thorough ultrasound control of fetal development. When detecting anomalies (especially low blood pressure), it is necessary to stop using the drug.

It is not known whether the losartan in breast milk, therefore, it is necessary to stop breastfeeding during the treatment with the drug.

Dosing and Administration:

Inside, 1 time per day, regardless of food intake.

Arterial hypertension

Standard initial and The maintenance dose is 50 mg once a day. If necessary, the dose of the drug can be increased to a maximum daily dose of 100 mg.

In patients with reduced BCC (for example, against the background of large doses of diuretics) it is recommended to start therapy with Lozarel® with 25 mg (1/2 tablets 50 mg) once a day.

Chronic cardiac failure

The standard starting dose is 12.5 mg / day, followed by a weekly increase of 2 times (ie 12.5 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 150 mg / day) , depending on the individual tolerability of the drug.

The maximum daily dose of 150 mg (only for this indication).

To start therapy with Lozarel® in a reduced dosage (12.5 mg), it is recommended to use dosage forms with a lower active ingredient content (tablets of 25 mg with a risk).

Nephropathy in type 2 diabetes mellitus (reduced risk of hypercreatininemia and proteinuria)

The standard starting dose is 50 mg once a day. In the course of treatment, depending on the indices of blood pressure, it is possible to increase the daily dose of the drug to 100 mg once a day.

The maximum daily dose is 100 mg.

The drug Lozarel ® can be used in combination with other antihypertensive drugs (diuretics, blockers "slow" calcium channels, alpha and beta adrenoblockers, antihypertensive drugs central action), insulin and other hypoglycemic drugs (derivatives sulfonylureas, glitazones and glucosidase inhibitors).

Reducing the risk of cardiovascular complications and death the patients with hypertension and left ventricular hypertrophy

The standard initial dose of Lozarel® is 50 mg once a day; if necessary, an increase in the daily dose of the drug Lozarel® to 100 mg, taking into account the degree of reduction in blood pressure or the addition of hydrochlorothiazide in low doses, is possible.

The maximum daily dose is 100 mg.

Patients with impaired renal function (severe or moderate severity - creatinine clearance (CK) of less than 20 ml / min), with liver diseases in the anamnesis, dehydration, during dialysis, as well as patients older than 75 years

a lower initial dose of the drug is recommended - 25 mg (1/2 50 mg tablets) once a day.

Side effects:

Generally, losartan well tolerated by patients with arterial hypertension, adverse events are mild and transient and do not require withdrawal of the drug. The total frequency of side effects of losartan is comparable to this indicator when using placebo.

In clinical trials most frequent undesirable The phenomenon with the use of losartan was dizziness.

According to the World Health Organization (WHO), unwanted effects are classified according to their frequency of development as follows: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, < 1/10000, rarely (> 1/10000, <1/1000) and very rarely (<1/10000), including individual messages, the frequency is unknown (it is impossible to calculate according to available data).

On the part of the blood system and lymphatic system

often: anemia;

rarely: thrombocytopenia;

frequency is unknown: eosinophilia, purple Shenlaine-Genocha.

From the side of metabolism and nutrition

frequency is unknown: decline appetite, weight gain.

From the side of the cardiovascular system

often: pronounced decrease blood pressure, orthostatic hypotension (in patients with CHF);

infrequently: a feeling of palpitations, arrhythmias (including sinus tachy- and bradycardia, ventricular tachycardia, atrial fibrillation), angina pectoris;

frequency is unknown: nasal bleeding, myocardial infarction, cerebrovascular accident, atrioventricular blockade II degree.

From the digestive system

infrequently: nausea, vomiting, diarrhea, constipation, dyspepsia, pain in the abdomen;

rarely: abnormal liver function, hepatitis, pancreatitis;

frequency unknown: anorexia, dryness of the oral mucosa, toothache, flatulence, gastritis.

From the skin

infrequently: skin rash, itching of the skin, hives;

frequency is unknown: dry skin, subcutaneous hemorrhage, photosensitivity, alopecia, cellulite.

From the side of the musculoskeletal system

frequency is unknown: convulsions, myalgia, arthralgia, joint swelling, rhabdomyolysis, pain in the gluteus, back pain, chest pain.

From the nervous system

often: dizziness, asthenia;

infrequently: drowsiness, headache, sleep disturbance (including insomnia), depression, anxiety, memory disorders, peripheral neuropathy, hypoesthesia, tremor, ataxia, impaired coordination, confusion;

rarely: paresthesia;

frequency unknown: migraine.

From the sense organs

infrequently: a taste disorder (dysgeusia);

frequency is unknown: "ringing" in the ears, conjunctivitis, pain / sensation burn in the eye, visual impairment.

From the respiratory system

often: dry non-productive cough, edema of the mucous membrane of the nasal cavity;

infrequently: dyspnea;

frequency is unknown: obstruction nose, upper respiratory tract infection, pharyngitis, sinusitis, bronchitis.

From the genitourinary system

often: acute renal dysfunction, kidney failure;

frequency is unknown: imperative urges for urination, urinary tract infections, decreased libido, erectile dysfunction / impotence.

Allergic reactions

rarely: angioedema (including laryngeal edema and tongue causing obstruction respiratory tract and / or swelling of the face, lips, pharynx), vasculitis.

Laboratory indicators

often: hyperkalemia potassium in the blood plasma more than 5.5 mmol / l), hypoglycemia;

rarely: increase in concentration urea and residual nitrogen or creatinine in blood plasma, a moderate increase in the activity of "liver" transaminases, hyperbilirubinemia;

frequency is unknown: hyponatremia.

General disorders and disorders at the site of administration

often: weakness, increased fatigue.

Overdose:

Symptoms: marked decrease in blood pressure and tachycardia; As a result of parasympathetic (vagal) stimulation, a bradycardia can develop.

Treatment: forced diuresis, symptomatic therapy. Hemodialysis is ineffective, because losartan and its active metabolite are not eliminated from the body by hemodialysis.

Interaction:

There were no pharmacokinetic interactions of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin, lovastatin.

There are reports that rifampicin and fluconazole (inhibitors isoenzyme cytochrome P450 2C9) reduce the content of the active metabolite and increase the concentration of losartan in the blood plasma. The clinical significance of these interactions is still unknown.

It was shown that in patients not metabolizing losartan in the active metabolite, there is a very rare and specific defect of the cytochrome P450 2C9 isoenzyme. The simultaneous use of losartan, as well as other drugs that inhibit the enzyme angiotensin II or its effects, with potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride, eplerenone (a derivative of spironolactone)) and potassium preparations (potassium-containing additives) increases the risk of hyperkalemia.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2), acetylsalicylic acid in a dose above 3 g per day, may reduce the effectiveness of antagonists receptors of angiotensin II (APA II), ACE inhibitors, diuretics. The simultaneous use of ARA II with NSAIDs, including selective inhibitors of COX-2, especially in the presence of reduced renal function, can lead to impaired renal function, including acute renal failure and an increase in potassium levels in the blood plasma (hyperkalemia).These effects are usually reversible.

With the joint application of ARA II and lithium preparations it is possible to increase the concentration of lithium in blood plasma. If simultaneous application is necessary, the plasma concentration of lithium should be monitored regularly.

The combined use of losartan with diuretics has an additive effect. Strengthens (mutually) the effect of other antihypertensive drugs (diuretics, beta-blockers, sympatholytic drugs).

With simultaneous application ACE inhibitors and ARA II it is necessary to regularly monitor the kidney function, since it is possible to increase the frequency of side effects, such as a marked decrease in blood pressure, hyperkalemia, impaired renal function.

Simultaneous application ACE inhibitors with other drugs affecting the renin-angiotensin-aldosterone system (RAAS), including those with antagonists of ARA II and aliskiren, leads to an increase in the frequency of cases of pronounced decrease blood pressure, syncope, hyperkalemia, disorders of kidney function (including acute renal insufficiency), especially in patients with confirmed atherosclerosis, cardiac insufficiency or sugar diabetes with damage to target organs. The question of the application of the double blockade of RAAS should be decided in each case individually. Required monitor indicators blood pressure, kidney function, and the content of electrolytes of blood plasma when using losartan with other drugs that affect RAAS.

Simultaneous application ARA II (including losartan) with aliskirenom contraindicated in patients with type 2 diabetes mellitus and renal insufficiency (GFR less than 60 ml / min / 1.73 m²).

Special instructions:

The safety and efficacy of Lozarel® in children have not been established.

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

In patients with dehydration (eg, receiving treatment with high doses of diuretics or against a background of vomiting, diarrhea on salt-free diet), at the beginning of treatment with Lozarel®, symptomatic arterial hypotension (it is necessary to correct the disturbances of the water-electrolyte balance before starting Lozarel® or begin treatment with a lower dose).Water-electrolyte disturbances are characteristic for patients with renal dysfunction in combination with or without diabetes mellitus and require correction. In a clinical trial with participation of patients with type 2 diabetes mellitus with nephropathy, the incidence of hyperkalemia in the group receiving losartan, was higher than in the group receiving the placebo. It is necessary to regularly monitor the potassium content in the blood plasma, as well as QC, especially in patients with cardiac insufficiency and QC in the range of 30-50 ml / min.

In patients with hepatic insufficiency, the concentration of losartan in plasma increases blood, so it is necessary dosage adjustment of Lozarel®.

Patients with primary hyperaldosteronism usually do not respond to therapy with RAAS inhibitors, so the use of Lozarel® is not recommended.

In patients with ischemic damage to the blood vessels of the heart or brain expressed decrease in blood pressure can lead to a heart attack myocardium or ischemic stroke.

As with the use of other drugs that affect RAAS, when using Lozarel® in patients with cardiac insufficiency (with / without renal dysfunction), there is a risk of developing severe arterial hypotension and acute renal insufficiency.

There is no experience with losartan in patients with heart failure and concomitant severe renal dysfunction, in patients with severe cardiac insufficiency (IV functional class by classification NYHA), as well as in patients with cardiac insufficiency and clinically expressed life-threatening arrhythmias. Therefore, use of Lozarel® in such patients should be carried out with caution.

Care should be taken when using Lozarel® in patients with hypertrophic obstructive cardiomyopathy or hemodynamically significant stenosis of the aortic or mitral valve.

The drug Lozarel® and other antagonists of angiotensin II receptors are less effective in patients of the Negroid race, due to prevalence patients with arterial hypertension with low renin activity.

There is no need for special precautions when destroying an unused preparation.

Effect on the ability to drive transp. cf. and fur:

During the treatment with the drug Lozarel^® may arise dizziness, drowsiness, headache, so caution should be exercised when management of transport resources and other class activities that require concentration and speed of psychomotor reactions.

Form release / dosage:Tablets, film-coated, 50 mg.

Packaging:

10 tablets per blister of Al / Al.

For 3 or 9 blisters together with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-006796/09

Date of registration:26.08.2009 / 29.10.2014

Expiration Date:Unlimited

The owner of the registration certificate:Sandoz d.Sandoz d. Slovenia

Manufacturer: & nbsp

LEK d.d. Slovenia

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp22.10.2016

Illustrated instructions

Instructions

Lozarel® (Losarel®)