Composition, form of production and packaging
The tablets covered with a film cover of yellow color, round, biconcave; the core is white or almost white in cross section.
1 tab.
Losartan Potassium 100 mg
Excipients: lactose monohydrate - 115 mg, microcrystalline cellulose - 40 mg, croscarmellose sodium - 11.2 mg, povidone (polyvinylpyrrolidone low molecular weight) - 9 mg, silicon dioxide colloid - 2 mg, magnesium stearate - 2.8 mg.
The composition of the film shell: (hypromellose - 4.8 mg, talc 1.6 mg, titanium dioxide 0.826 mg, macrogol 4000 (polyethylene glycol 4000) 0.72 mg, iron oxide yellow (iron oxide) 0.054 mg) or (dry film coating mixture, containing hypromellose (60%), talc (20%), titanium dioxide (10.33%), macrogol 4000 (polyethylene glycol 4000) (9%), iron oxide yellow (iron oxide) (0.67%)) - 8 mg.
15 pcs. - Cellular outline packaging (aluminum / PVC) (2) - cardboard packs.
30 pcs. - Cellular outline packaging (aluminum / PVC) (1) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Losartan is a specific antagonist of angiotensin II receptor (tyine AT1) for oral administration. Angiotensin II selectively binds to AT1 receptors found in many tissues (in smooth muscle tissues of blood vessels, in the adrenal gland, at night 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 angiotensia II, regardless of the source or route of synthesis. Losartan selectively binds to AT1 receptors: it 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 the angiotensin-converting enzyme (ACE), which contributes to the degradation of bradykinin, so 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 the concentration of 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. After abolition of losartan, the plasma renin activity and angiotensin II concentration decreased for 3 days to the initial values ​​observed before the drug was started.
Losartan and its active metabolite have a great affinity for the angiotensin II receptor (type AT1).
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.
The maximum antihypertensive effect develops in 3-6 weeks after the start of the drug.
In patients with arterial hypertension, proteinuria (more than 2 g per day), without diabetes mellitus, the use of the drug significantly reduces proteinuria, albumin excretion and immunoglobulin G (IgG).
In postmioseusual women with arterial hypertension who took losartan at a dose of 50 mg / day for 4 pedules, there was no effect of therapy on the renal and systemic levels of prostaglandins.
Losartan has no effect on autonomic 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 per day does not cause clinically significant changes in the concentration of triglycerides, total cholesterol and high-density lipoprotein cholesterol. In the same doses, losartan does not affect the concentration of glucose in the blood on an empty stomach.Losartan caused a decrease in serum uric acid concentration (usually less than 0.4 mg / dl), which persisted during prolonged therapy. In controlled clinical trials involving patients with hypertension, there were no cases of drug withdrawal due to an increase in creatinine or potassium in the blood serum.
PHARMACOKINETICS
Suction
When ingested, losartan is well absorbed from the gastrointestinal tract. Systemic bioavailability of losartan is approximately 33%, food intake does not affect the bioavailability of losartan. The average maximum concentrations of losartan and its active metabolite are reached after 1 hour and 3-4 hours, respectively.
Distribution
Lozartan and its active metabolite bind to plasma proteins (mainly albumin) by more than 99%. The volume of distribution of losartan is 34 liters. Losartan practically does not penetrate the blood-brain barrier.
Metabolism
Losartan is subjected to the effect of "primary passage" through the liver, is megabolized with the participation of the cytochrome P450 isoenzyme CYP2C9.Approximately 14% of the dose of losartan administered intravenously orally is converted to its active metabolite (EXP3174) with a carboxyl group. Biologically inactive metabolites are also formed: two major metabolites (as a result of hydroxylation of the butyl side chain) and a less significant N-2-tetrazole-glucuronide.
Excretion
The plasma clearance of losartan and its active metabolite is 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 within 6% of the dose is excreted by the kidneys as an active metabolite. Losartan and its active metabolite have a linear pharmacokinetics when administered to losartan in doses up to 200 mg. After ingestion, the plasma concentrations of losartan and its active metabolite decrease polyexponentially with finite T 1/2 approximately 2 and 6-9 hours, respectively.
The excretion of losartan and its metabolites occurs with bile and kidneys. After ingestion of losartan labeled with 14 C, about 35% of the radioactive label is found in urine and 58% in feces.
Pharmacokinetics in specific patient groups
The concentrations of losartan and its active metabolite in blood plasma in elderly male patients with arterial hypertension do not significantly differ from these indices in younger male 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 the Nazis with cirrhosis of the liver of an alcoholic genesis of mild and moderate severity, the concentrations of losartan and its active metabolite in blood plasma were 5 and 1.7 times (respectively) greater 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 patients with normal renal function. In patients in need of hemodialysis, the area under the concentration-time curve (AUC) is 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 are not removed from the bloodstream 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 total 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 the frequency of hypercreatininemnia, the frequency of the terminal stage of chronic renal failure (CRF), requiring hemodialysis or kidney transplantation, mortality rates, and a decrease in proteinuria;
- Chronic heart failure with ineffective treatment with ACE inhibitors.
DOSING MODE
Inside, regardless of food intake.
The drug can be taken as a monotherapy, or in combination with other antihypertensive drugs.
Arterial hypertension
The standard initial and maintenance dose for most patients is 50 mg once a day. The maximum antihypertensive effect is achieved in 3-6 weeks from the start of therapy.
In some patients, to achieve a greater effect, the dose may be increased to a maximum daily dose of 100 mg once daily.
In patients with a reduced volume of circulating blood (for example, when taking diuretics in high doses), the initial dose of the drug should be reduced to 25 mg once a day (see section "Special instructions").
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) during the hemodialysis procedure, as well as patients older than 75 years, arerecommended to prescribe the drug at a lower initial dose of 25 mg once a day.
Reduced 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 once a day. In the future, it is recommended to add hydrochlorothiazide or increase the dose of Losartan to 100 mg (taking into account the degree of decrease in blood pressure (BP)) in one or two doses.
Kidney protection in patients with type 2 diabetes and proteinuria.
The standard initial dose of the drug is 50 mg once a day. In the future, it is recommended to increase the dose of Losartan to 100 mg once a day, taking into account the degree of BP reduction. Losartan can be prescribed together with other antihypertensive drugs (diuretics, blockers of "slow" calcium channels, alpha and beta adrenoblockers, central-action antihypertensives), insulin and other hypoglycemic drugs (sulfonylurea derivatives, glitazones and glucosidase inhibitors).
Chronic heart failure
The initial dose of the drug is 12.5 mg once a day. As a rule, the dose is titrated at a weekly interval (ie 12.5 mg once a day, 25 mg once a day, 50 mg once a day) to the usual maintenance dose of 50 mg once a day, depending on the individual portability.
SIDE EFFECT
In most cases, losartan is well tolerated, the side effects are mild and transient and do not require withdrawal of the drug.
Side effects observed when taking the drug are classified into categories depending on the frequency of their occurrence: very often> 1/10 (10%); often> 1/100 (1%) <1/10 (10%); sometimes> 1/1000 (0.1%), <1/100 (1%): rarely> 1/10000 (0.01%), <1/1000 (0.1%); very rarely <1/10000 (0.01%), including individual events.
Side effects, occurring with a frequency of more than 1%
Common disorders: asthenia, weakness, fatigue, pain in the chest, peripheral edema.
From the cardiovascular system: a feeling of palpitation, tachycardia.
From the digestive system: abdominal pain, diarrhea, indigestion, nausea.
From the musculoskeletal system: pain in the back, legs, muscle cramps.
From the central nervous system (CNS): dizziness, headache, insomnia.
On the part of the respiratory system: cough, bronchitis, swelling of the nasal mucosa, pharyngitis, sinusitis, infections of the upper respiratory tract.
Side effects, occurring with a frequency of less than 1%
From the cardiovascular system: angina, symptomatic arterial hypotension (especially in patients with intravascular dehydration, for example, patients with severe heart failure or with the intake of diuretics in high doses), dose-dependent orthostatic hypotension, bradycardia. arrhythmias, myocardial infarction, vasculitis.
From the digestive system: anorexia, dryness of the oral mucosa, toothache, flatulence, gastritis, constipation, hepatitis, liver dysfunction, vomiting.
From the skin: dry skin, ecchymosis, erythema, photosensitization, increased sweating, alopecia.
Allergic reactions: urticaria, pruritus, skin rash, angioedema (including swelling of the larynx, vocal fold, causing airway obstruction, and / or swelling of the face, lips, pharynx and / or tongue).
On the part of the hemopoietic system: anemia, thrombocytopenia, eosinophilia, purpura Shenlaine-Genocha.
From the nervous system and sensory organs: anxiety, sleep disturbance. drowsiness, memory impairment, peripheral neuropathy, paresthesia, hypostasis. tremor, ataxia, depression, fainting, ringing in the ears, impaired taste, visual impairment, conjunctivitis, migraine.
From the musculoskeletal system: arthralgia, arthritis, pain in the shoulder and in the knee, fibromyalgia.
From the urinary system: mandatory urination, urinary tract infections, impaired renal function.
On the part of the reproductive system: decreased libido, impotence.
Other: exacerbation of the gout, nosebleeds.
From the laboratory indicators:
often - hyperkalemia (the content of potassium is more than 5.5 mmol / l);
infrequently - increased concentrations of urea, residual nitrogen, creatinine in the blood serum;
very rarely - a moderate increase in activity of grapaminaz (aspartate amipotransferase, alanine aminotransferase), hyperbilirubinemia.
Attention! If any of the side effects indicated in the manual are aggravated or you notice any other side effects, not listed and instructions, inform your doctor.
CONTRAINDICATIONS
- hypersensitivity to any of the components of the drug;
- pregnancy and the period of breastfeeding;
- age up to 18 years;
- refractory hyperkalemia;
- lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome;
- dehydration;
- severe hepatic insufficiency (no experience of application);
- simultaneous use with aliskiren in patients with diabetes mellitus and / or with impaired renal function (glomerular filtration rate less than 60 ml / min).
With caution: hepatic insufficiency (less than 9 Child-Pugh scores), arterial hypotension, reduced circulating blood volume (BCC), water-electrolyte balance disturbance, hyperkalaemia, bilateral renal artery stenosis or stenosis of the single kidney artery, renal failure, post-transplant conditions kidney, aortic and mitral stenosis, obstructive hypertrophic cardiomyopathy, angioedema in history, severe heart failure (NYHA functional class IV), ischemia eskaya heart disease, heart failure, life-threatening arrhythmias, cerebrovascular disease, primary aldosteronism, cardiac insufficiency with concomitant severe renal insufficiency.
PREGNANCY AND LACTATION
The use of Losartan during pregnancy is contraindicated.
Drugs that directly affect the renin-angiotensin-aldosterone system (RAAS), when applied in the second and third trimesters of pregnancy, can cause a developmental defect or even the death of a developing fetus. Therefore, when diagnosing a pregnancy, Losartan should be stopped immediately.
In experimental studies, it is shown that the drug causes developmental defects and leads to the death of the fetus or newborn. It is believed that the mechanism of such an effect is a pharmacologically mediated effect on RAAS. Renal perfusion of a human fetus, depending on the development of RAAS, begins in the second trimester. The risk to the fetus increases if losartan is taken in the second or third trimester of pregnancy. The use of angiotensin II receptor antagonists in the II or III trimesters of pregnancy has a toxic effect on the fetus (decreased kidney function, development of oligohydramnion, slowing ossification of the skull) and newborn (renal failure, arterial hypotension, hyperkalemia). If the drug Losartan was used in the second trimester of pregnancy and later, it is recommended that ultrasound of the skull bones be performed and the kidney function assessed.
It is not known whether losartan is excreted in breast milk. When using Losartan during breastfeeding, a decision should be made either to stop breastfeeding or to stop treatment with the drug, taking into account its importance for the mother.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution in kidney failure.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution in liver failure.
APPLICATION FOR CHILDREN
Contraindicated for children under 18 years.
APPLICATION IN ELDERLY PATIENTS
Patients over 75 years of age are recommended to prescribe the drug at a lower initial dose
SPECIAL INSTRUCTIONS
Allergic reactions. The patients receiving losartan rarely had anaphylactic reactions, angioedema, involving the larynx and pharynx, causing airway obstruction and / or swelling of the face, lips, throat and / or tongue. In some of these patients, there was a history of anginaevretric edema with other medications, including ACE inhibitors. Therefore, when administering the drug to patients with a history of angioneurotic edema requires special care.
Hypotension and disruption of water and electrolyte balance, or a decrease BCC.In patients with reduced BCC (e.g., treated with diuretics in high doses) can occur symptomatic hypotension. Correction of these states is necessary to carry losartan destination or start treatment with the drug at a lower dose (see. "Dosage and Administration" section). Disruption of water-electrolyte balance is typical for patients with renal insufficiency with type 2 diabetes, or non-diabetic, so when administering the drug for these patients requires special care due to the risk of hyperkalemia (see. Partition Side effects, Subpart From the laboratory indicators).
The treatment should regularly monitor the content of potassium in the blood, especially in elderly patients with renal dysfunction. During treatment with losartan patients you should not take drugs or potassium salt substitutes containing potassium without prior approval of the physician.
Aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy. As with all drugs with vasodilating activity, receptor antagonists to angiotensin II must be administered with caution to patients with aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.
Coronary heart disease and cerebrovascular disease.As with all drugs with vasodilating effect, angiotensin II receptor antagonists should be used with caution in patients with coronary artery disease or cerebrovascular disease, because an excessive fall in blood pressure in this group of patients can lead to myocardial infarction or stroke.
Chronic heart failure (CHF). As with other drugs that have an effect on the RAAS in patients with chronic heart failure and with or without renal impairment, there is a risk of severe arterial hypotension or acute renal failure.
There is no sufficient experience with losartan in patients with heart failure and concomitant severe renal impairment, in patients with heart failure styazheloy (IV NYHA functional class but classification), as well as in patients with heart failure and symptomatic life threatening arrhythmias. Therefore, losartan should be used with caution in these groups the Nazis.
Primary aldosteronism. Patients with primary gileraldosteronizmom usually not observed a positive response to the therapy of antihypertensive agents that act by inhibition of the RAAS, so the use of losartan is not recommended in this group of patients.
Abnormal liver function.These pharmacokinetic studies indicate that losartan in plasma concentration in patients with cirrhosis is significantly increased, so patients with liver diseases in history should be used drug in the lower dose (see. "Dosage and Administration" section).
Impaired renal function . As a consequence of inhibiting the RAAS in certain predisposed patients experienced changes in renal function, including renal failure. These changes may take place after the cessation of treatment.
Some drugs that affect the RAAS may increase the concentration of urea in the blood and serum kreatiiina in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Changes in renal function may be reversible after treatment. During treatment should regularly monitor the concentration kreatiiina serum at regular intervals.
Elderly patients. Clinical studies have not revealed any differences in safety and efficacy of losartan in elderly patients.
Effect on the vehicles ability to control mechanisms n
During the period of treatment must be careful when driving and occupation of other potentially hazardous activities that require high concentration and psychomotor speed reactions (dizziness, especially in patients taking medicines diurezicheekie and switched to the drug therapy).
OVERDOSE
Data on drug overdose is limited.
The most likely symptoms
Marked reduction in blood pressure and tachycardia, bradycardia may occur as a result of parasympathetic (vagal) stimulation.
Treatment
Forced diuresis, symptomatic therapy. Neither losartan or an active metabolite thereof is not excreted via hemodialysis.
DRUG INTERACTION
It can be administered with other antihypertensive agents.
No clinically significant interaction with losartan drugs as hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital, erythromycin and ketoconazole was observed.
Rifamiitsin fluconazole and reduce the level of the active metabolite. The clinical significance of these interactions is not established.
As with other means of blocking the formation of angiotensin II and its effects, the simultaneous use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride, eplerenone) or a means to enhance the potassium content (e.g., heparin), potassium supplements and salts containing potassium, may increase potassium in the blood serum.
As with other agents affecting the excretion of sodium, treatment with losartan may be accompanied by decrease in sodium excretion and increased serum concentrations of lithium, however, while treatment with lithium preparations should control its serum concentration.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors tsikpooksigenazy-2 (COX-2), can reduce the effect of diuretics or other antihypertensives. Therefore antigipertepzivny effect receptor antagonists to angiotensin II or ACE inhibitors may be attenuated while the use of HPVP, including with the selective COX-2 inhibitors.
Some patients with renal dysfunction who were treated with NSAID, co-administration apgiotenzina II antagonists can cause a further deterioration of renal function. Normally, this effect is reversible.
Other antihypertensive agents may increase the severity of antihypertensive effect of losartan. The simultaneous use of drugs (e.g., tricyclic antidepressants, neuroleptics, baclofen, amifostine), which lower blood pressure in a main or side effect, can increase the risk of hypotension.
Dual blockade of the RAAS using receptor antagonists to angiotensin II, ACE inhibitors or aliskiren is associated with increased risk of arterial hypotension, syncope, hyperkalemia, and renal dysfunction (including acute renal failure) as compared with monotherapy. It is necessary to carefully monitor your blood pressure, renal function and fluid and electrolyte balance in patients treated with losartan and other drugs that affect the RAAS. Losartan is not recommended for use in conjunction with aliskiren in patients with diabetes mellitus. Avoid the simultaneous application of the drug Aliskiren and losartan in patients with renal insufficiency (glomerular filtration rate of less than 60 ml / min).
In an application with fluvastatin (weak inhibitor of the CYP isozyme 2C9) exposure difference was revealed.
If you assigned losartan, and you are taking other medications, consult with your doctor about this.
TERMS OF RELEASE FROM PHARMACY
On prescription.
TERMS AND CONDITIONS OF STORAGE
Store in a dark place at a temperature not higher than 25 В° C. Keep out of the reach of children. Shelf life - 3 years.
