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

Excipients: lactose monohydrate (sugar milk) - 60,000 mg; cellulose microcrystalline - 15,000 mg; croscarmellose sodium - 4,000 mg; povidone-K25 - 3,600 mg; magnesium stearate - 0.900 mg.

Shell composition: polyvinyl alcohol - 1.407 mg; Macrogol-4000 - 0.969 mg; titanium dioxide - 0.624 mg.

Active substance: Losartan potassium - 50,000 mg.

Excipients: lactose monohydrate (sugar milk) - 103,000 mg; microcrystalline cellulose - 30,000 mg; croscarmellose sodium - 8,000 mg; povidone-K25 - 7,000 mg; magnesium stearate - 2,000 mg.

Shell composition: polyvinyl alcohol - 2,814 mg; macrogol-4000 -1.938 mg; titanium dioxide - 1.248 mg.

Active substance: Losartan potassium - 100,000 mg.

Excipients: lactose monohydrate (sugar milk) -190,100 mg; cellulose microcrystalline - 57,000 mg; croscarmellose sodium - 15,800 mg; povidone-K25 - 13,300 mg; magnesium stearate - 3,800 mg.

Shell composition: polyvinyl alcohol - 5,628 mg; macrogol-4000 -3.876 mg; titanium dioxide - 2.496 mg.

Description:

Cylindrical biconvex tablets covered with a film shell of white or almost white color, on a cross section are visible two layers - a core of white or almost white color and a film membrane.

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 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 (vascular smooth muscle, adrenal gland, kidneys and the heart) and performs several important biological functions, including vasoconstriction 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 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. 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 using losartan, the absence of negative feedback influence on renin secretion 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 are preserved, which indicates an effective blockade of angiotensin II receptors. 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 in 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 two major metabolites resulting from the hydroxylation of the butyl side chain, and one secondary -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 ingested, 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 renal function.

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 (decreased progressiondiabetic 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; lactose intolerance, lactase deficiency or glucose-galactose malabsorption; pregnancy and lactation.

Carefully:Arterial hypotension, reduced volume of circulating blood (BCC), violations of water-electrolyte balance, bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney, kidney failure, liver failure (less than 9 on the Child-Pugh scale).

Pregnancy and lactation:

The use of Losartan during 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 a pregnancy, taking 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 a greater therapeutic effect, the dose is increased to a maximum daily dose of 100 mg once a day.

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 (BP).

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 impairment, since there is no clinical experience with this group of patients (see Table 1).section "Contraindications").

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

Side effects:

The side effects of losartan are usually transient and do not require withdrawal of the drug.

When using losartan for the treatment of hypertension in controlled studies, among the side effects only the incidence of dizziness was different from placebo by more than 1%.

In addition, less than 1% of patients had orthostatic reactions, depending on the dose of the drug. Rarely (≥ 0.01% and ≤ 0.1% of cases) reported skin rash, but the incidence was less than with placebo.

Side effects, occurring with a frequency of more than 1%

General symptoms	Losartan (n=2085)	Placebo (n=535)
Asthenia, fatigue	3,8	3,9
Chest pain	1,1	2,6
Peripheral edema	1,7	1,9
From the side of the cardiovascular system
Heart palpitations	1,0	0,4
Tachycardia	1,0	1,7
From the gastrointestinal tract
Abdominal pain	1,7	1,7
Diarrhea	1,9	1,9
Dyspeptic disorders	1,1	1,5
Nausea	1,8	2,8
From the side of the musculoskeletal system
Pain in the back, legs	1,6	1,1
Cramps of the calf muscles	1,0	1,1
From the central nervous system
Dizziness	4?1	2,4
Headache	14,1	17,2
Insomnia	1,1	0,7
From the respiratory system
Cough, bronchitis	3,1	2,6
Nasal congestion	1,3	1,1
Pharyngitis	1,5	2,6
Sinusitis	1,0	1,3
Upper respiratory tract infections	6,5	5,6

Side effects, occurring with a frequency of less than 1%

From the cardiovascular system: Orthostatic hypotension (dose-dependent), epistaxis, bradycardia, arrhythmias, angina pectoris, vasculitis, myocardial infarction.

From the digestive system: anorexia, dryness of the oral mucosa, toothache, vomiting, flatulence, gastritis, constipation, hepatitis, a violation of liver function.

From the skin: dry skin, erythema, ecchymosis, photosensitivity, increased sweating, alopecia.

Allergic reactions: urticaria, skin rash, itching, angioedema (including swelling of the larynx and tongue, causing airway obstruction and / or swelling of the face, lips, pharynx).

On the part of the hematopoiesis system: anemia (a slight decrease in hemoglobin and hematocrit, an average of 0.11 g% and 0.09% volume, respectively, rarely having clinical significance), thrombocytopenia, eosinophilia, purpura Shenlen-Genocha.

From the musculoskeletal system: arthralgia, arthritis, pain in the shoulder, knee, fibromyalgia.

From the nervous system and sensory organs: anxiety, sleep disorders, drowsiness, memory impairment, peripheral neuropathy, paresthesia, hyposthenia, tremor, ataxia, depression, syncope, ringing in the ears, impaired taste, visual impairment, conjunctivitis, migraine.

From the genitourinary and reproductive system: imperative urges for urination, urinary tract infections, impaired renal function, decreased libido, impotence.

Other: gout.

Laboratory indicators: hyperuricemia (the content of potassium in the blood plasma is more than 5.5 mmol / l); increasing the concentration of urea and residual nitrogen and creatinine in the blood serum; a moderate increase in the activity of "hepatic" transaminases: aspartate aminotransferase (ACT) and alanine aminotransferase (ALT), hyperbilirubinemia.

Overdose:

Symptoms: marked decrease in blood pressure 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 hydrochlorothiazide,digoxin, warfarin, cimetidine, phenobarbital, ketoconazole, and erythromycin. Reportedly rifampicin and flucoidazole reduce the concentration of the active metabolite in the blood plasma. The clinical significance of these interactions is still unknown.

As with other agents which inhibit the formation of angiotensin II, or its effect, the simultaneous use of losartan potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium preparations, salts containing potassium, increases the risk of hyperkalemia.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2), can reduce the effect of diuretics or other antihypertensives. Therefore, the antihypertensive effect recipes antagonists to angiotensin II (ARAN) or angiotensin-converting enzyme (ACE) inhibitors may be attenuated while the use of NSAIDs, including selective COX-2 inhibitors. In some patients with impaired renal function (for example, in elderly patients and patients with reduced circulating blood volume (BCC), including those taking diuretics) who have been treated with NSAIDs,including selective COX-2 inhibitors, the simultaneous use of ARA II or ACE inhibitors, may cause further impairment of kidney function until the onset 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 the use of ARA II, ACE inhibitors or aliskiren (renin inhibitor) is associated with an increased risk of arterial hypotension, hyperkalemia and renal dysfunction (including the development of acute kidney failure) compared with monotherapy. It is necessary to monitor blood pressure, kidney function 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. If it is necessary to use drugs simultaneously, you should 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 a reduced BCC (eg, receiving treatment with high doses of diuretics), at the beginning of treatment with Losartan, symptomatic arterial hypotension may occur (it is necessary to correct bcc before losartan is administered or start treatment at 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 liver cirrhosis the concentration of losartan in plasma is significantly increased, and therefore, if a history of liver disease it should be administered at lower doses.

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

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

Form release / dosage:

Tablets, film-coated 12.5 mg, 50 mg and 100 mg.

Packaging:

For 10, 30 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

10, 20, 30, 40, 50, 60 or 100 tablets in cans of polyethylene terephthalate for medicines or polypropylene for drugs sealed with high-pressure polyethylene caps with a first opening control or polypropylene caps with a "push-turn" system, or lids from low-pressure polyethylene with control of the first opening.

One jar or 1, 2, 3, 4, 5, 6 or 10 contour squares, together with the instructions for use, are placed in a cardboard package (bundle).

Storage conditions:

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

Keep out of the reach of children.

Shelf life:3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002220

Date of registration:04.09.2013 / 25.01.2018

Expiration Date:04.09.2018

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Information update date: & nbsp04.04.2018

Illustrated instructions

Instructions

Losartan (Losartan)