Lorista N 100 - instructions for use, dose, side effects, contraindications

Lorista® H 100 - a combined drug, which includes losartan and hydrochlorothiazide, which have an additive antihypertensive effect, lowering blood pressure (BP) more than each of the components individually.

Due to the diuretic effect hydrochlorothiazide increases the activity of renin of blood plasma (ARP), stimulates the secretion of aldosterone, increases the concentration of angiotensin II and reduces the concentration of potassium in the blood plasma.The administration of losartan blocks all the physiological effects of angiotensin II and, due to suppression of aldosterone effects, can help reduce the loss of potassium associated with taking a diuretic.

Losartan has a moderate and transient uricosuric effect. Hydrochlorothiazide causes a slight increase in the concentration of uric acid in the blood; The combination of losartan and hydrochlorothiazide helps reduce the severity of hyperuricemia caused by a diuretic.

Losartan

Losartan is a selective antagonist of angiotensin II receptors (type AT₁) for oral administration. In vivo and in vitro losartan and its pharmacologically active metabolite E-3174 block all physiologically significant effects of angiotensin II on AT₁-receptors regardless of the route of its synthesis: leads to an increase in renin plasma activity, reduces the concentration of aldosterone in the blood plasma. Losartan indirectly causes activation AT₁-receptors by increasing the concentration of angiotensin II.

Does not inhibit the activity of kininase II, an enzyme that is involved in the metabolism of bradykinin. Reduces the overall peripheral vascular resistance (OPSS), pressure in the "small" circle of blood circulation, reduces afterload on the myocardium, has a diuretic effect.Prevents development of myocardial hypertrophy, increases exercise tolerance in patients with chronic heart failure (CHF). The administration of losartan once a day leads to a statistically significant decrease in systolic and diastolic blood pressure (BP). Losartan evenly controls blood pressure throughout the day, while the antihypertensive effect corresponds to a natural circadian rhythm. Decrease in blood pressure at the end of the dose was about 70-80% of the maximum effect of losartan, 5-6 hours after ingestion. There is no withdrawal syndrome.

Losartan does not have a clinically significant effect on the heart rate (heart rate).

Losartan is effective in men and women, as well as in patients older than 65 years and over young patients younger than 65 years.

Hydrochlorothiazide

A thiazide diuretic whose diuretic effect is associated with a disruption of the reabsorption of sodium, chlorine, potassium, magnesium, water in the distal nephron; delays the excretion of calcium ions, uric acid. Has an antihypertensive effect, the effect of which is due to the expansion of arterioles.Virtually no effect on normal blood pressure. Diuretic effect occurs in 1-2 hours, reaches a maximum after 4 hours and lasts for 6-12 hours. The maximum antihypertensive effect occurs in 3-4 days, but it may take 3-4 weeks to achieve the optimal therapeutic effect.

Pharmacokinetics:

The pharmacokinetics of losartan and hydrochlorothiazide with simultaneous use of differs from that when applied in monotherapy.

Losartan

Absorption

Losartan is well absorbed from the gastrointestinal tract (GIT) when ingested. It is subject to significant metabolism during the "primary passage" through the liver, forming a pharmacologically active carboxylated metabolite (E-3174) and inactive metabolites. Bioavailability is approximately 33%. 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 albumins) by more than 99%. The volume of distribution of losartan is 34 liters. Very poorly penetrates the blood-brain barrier.

Metabolism

Lozartan is metabolized with the formation of active (E-3174) metabolite (14%) and inactive, including the two main metabolites formed by hydroxylation of the butyl group of the chain and a less significant metabolite, N-2tetrazol-glucuronide.

Excretion

The plasma clearance of losartan and its active metabolite is approximately 10 ml / sec (600 ml / min) and 0.83 ml / s (50 ml / min), respectively. The renal clearance of losartan and its active metabolite is about 1.23 ml / sec (74 ml / min.) And 0.43 ml / sec (26 ml / min.). The half-life (T_1/₂) of losartan and the active metabolite is 2 hours and 6-9 hours, respectively. Excreted mainly with bile through the intestine - 58%, kidneys - 35%. Do not cumulate.

When administered orally in doses up to 200 mg losartan and its active metabolite have linear pharmacokinetics.

Hydrochlorothiazide

After oral intake of hydrochlorothiazide is 60-80%. The maximum concentration in the blood plasma is reached after 1-5 h after ingestion. Relationship with blood plasma proteins - 64%.

Hydrochlorothiazide is not metabolized and is rapidly excreted through the kidneys. T_1/₂ is 5-15 hours. At least 61% of the dose taken inside is excreted unchanged for 24 hours.

It penetrates through the placental barrier and is excreted in breast milk.

Pharmacokinetics in selected patient groups

Losartan + hydrochlorothiazide

Elderly patients

The concentrations of losartan and its active metabolite in the blood plasma and the rate of absorption of hydrochlorothiazide in elderly patients with arterial hypertension do not significantly differ from these indices in patients of young age with arterial hypertension.

Losartan

The concentration of losartan in blood plasma was 2 times higher in women with arterial hypertension compared with men with arterial hypertension. This pharmacokinetic difference is not clinically significant. The concentration of active metabolite in men and women does not differ.

Dysfunction of the liver and kidneys

When losartan was administered orally to patients with mild and moderate alcoholic cirrhosis, the concentrations of losartan and its active metabolite in the blood plasma were 5 to 1.7 times higher, respectively, than in young male volunteers.

Concentrations of losartan in blood plasma in patients with creatinine clearance (CC) above 10 ml / min did not differ from those in patients with preserved renal function.When comparing the area under the curve "concentration-time" (AUC) in patients with normal renal function, AUC losartan in patients on hemodialysis, was approximately 2 times more. Plasma concentrations of the active metabolite do not change in patients with impaired renal function or patients on hemodialysis. Losartan and its active metabolite can not be removed by hemodialysis.

Indications:

- Arterial hypertension (patients who are shown combined therapy).

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

Contraindications:Hypersensitivity to any of the components of the drug (as well as hypersensitivity to other drugs being derivatives of sulfonamide), anuria, severe renal failure (creatinine clearance less than 30 ml / min), severe liver dysfunction, pregnancy, breastfeeding period, age to 18 years (efficacy and safety not established), lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

Carefully:

Disorders of water-electrolyte balance of blood (hyponatremia, hypochloraemic alkalosis, hypomagnesemia, hypokalemia), bilateral stenosis of the renal arteries, stenosis of the artery of a single functioning kidney, condition after kidney transplantation, hypercalcemia, hyperuricemia and / or gout, allergic history, bronchial asthma, systemic diseases connective tissue (including systemic lupus erythematosus), simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs), including an inhibitor cyclooxygenase-2 (COX-2), diabetes mellitus, impaired hepatic function, renal dysfunction (QC from 30-50 ml / min), hypovolemia (including against a background of high doses of diuretics), acute attack of closed-angle glaucoma.

Pregnancy and lactation:

Pregnancy

Application of Lorista® N 100 is contraindicated in pregnancy! The use of drugs that have a direct effect on the renin-angiotensin-aldosterone system (RAAS) when used in the II and III trimesters of pregnancy

may cause developmental defects or even intrauterine fetal death.Therefore, when pregnancy occurs, the use of Lorista® H 100 should be discontinued immediately.

Thiazide diuretics penetrate the placental barrier and are identified in the blood of the umbilical vein. The use of diuretics in pregnant women is not recommended, as this increases risk development in the fetus of embryonic jaundice and jaundice of newborns, and in the mother - thrombocytopenia.

The use of Lorista® H 100 is possible if the benefit to the mother exceeds the potential risk to the fetus / child.

Breast-feeding

There is no evidence that losartan is excreted in breast milk. It is known that thiazide diuretics are excreted in breast milk.

If you need to use Lorist® H 100 during lactation, breastfeeding should be discontinued.

Dosing and Administration:

The drug Lorista® H 100 can be combined with other antihypertensive agents.

Arterial hypertension

The recommended dose of Lorista® H is 100-1 tablet (100 / 12.5 mg) once a day. As a rule, the drug is prescribed in the absence of an adequate therapeutic effect of Lorist® H (50 / 12.5 mg).

The maximum antihypertensive effect is achieved within three weeks of therapy.In elderly patients, patients with impaired renal function (CK 30-50 ml / min), including patients on dialysis, correction of the initial dose is not required.

Reducing the risk of cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy

The initial and maintenance dose of losartan is 50 mg once a day.

Patients who failed to achieve target BP levels when using losartan 50 mg / day require treatment with a combination of losartan with low doses of hydrochlorothiazide (12.5 mg). If necessary, it is possible to increase the dose of losartan to 100 mg in combination with hydrochlorothiazide at a dose of 12.5 mg / day. The recommended dose of Lorist® H 100-1 tablet (100 / 12.5 mg) once a day.

The maximum daily dose is 1 tablet of Lorist® H 100.

Impaired renal function

Correction of the dose is not required.

Elderly patients

Correction of the dose is not required.

Side effects:

Classification of the frequency of development of side effects of the World Organization

Health (WHO):

Often >1/10

often from >1/100 to <1/10

infrequently from >1/1000 to <1/100

rarely from >1/10000 to <1/1000

very rarely from <1/10000, including individual messages

the frequency of the unknown can not be estimated from the available data.

From the immune system

rarely: anaphylactic reactions, angioedema (including swelling of the larynx and tongue causing airway obstruction and / or swelling of the face, lips, pharynx), urticaria rash;

On the part of the hematopoiesis system

infrequent: anemia, Shenlen-Henoch purpura, ecchymosis, hemolysis, agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, thrombocytopenia;

From the nervous system

often: headache, dizziness, insomnia, increased fatigue; infrequently: migraine, anxiety, confusion, depression, sleep disorders, memory impairment, drowsiness, nervousness, paresthesia, tremor, fainting;

FROMabout the cardiovascular system

often: orthostatic hypotension (dose-dependent), palpitations, tachycardia; infrequently: atrioventricular blockade of II degree, chest pain, myocardial infarction, arrhythmia; rarely: vasculitis;

From the respiratory system

often: cough, upper respiratory tract infections, sinusitis, swelling of the nasal mucosa, nasal congestion;

infrequently: pharyngitis, laryngitis, rhinitis, dyspnea, bronchitis, epistaxis;

From the digestive system

often: diarrhea, dyspepsia, nausea, vomiting, abdominal pain;

rarely: hepatitis, a violation of liver function;

From the genitourinary system

infrequent: urinary tract infection, frequent urination, nocturia, weakened libido, decreased potency, glucosuria;

From the sense organs

infrequent: blurred vision, burning sensation in the eyes, conjunctivitis;

From the skin

often: alopecia, dry skin, erythema, photosensitivity, increased sweating;

infrequently: urticaria, itchy skin;

From the side of the musculoskeletal system

often: myalgia, back pain;

infrequently: arthralgia;

Other

often: asthenia, weakness, peripheral edema; infrequently: anorexia, exacerbation of gout;

Laboratory indicators

often: hyperkalemia, a slight decrease in the concentration of hemoglobin and hematocrit;

infrequently: a moderate increase in the concentration of urea and creatinine in the blood plasma, hyperglycemia, hyperuricemia, violations of the water-electrolyte balance; rarely: increased activity of alanine aminotransferase (ALT);

very rarely: increased activity of aspartate aminotransferase (ACT) and concentration bilirubin.

Overdose:

Losartan

Symptoms: marked decrease in blood pressure, tachycardia; bradycardia due to parasympathetic (vagal) stimulation.

Treatment: forced diuresis, symptomatic therapy, hemodialysis is ineffective.

Hydrochlorothiazide

Symptoms: the most frequent symptoms are a consequence of disturbance of the water-electrolyte balance (hypokalemia, hypochloraemia, hyponatremia) and dehydration due to excessive diuresis. With the simultaneous use of cardiac glycosides, hypokalemia can aggravate the course of arrhythmias.

Treatment: symptomatic and supportive. It is not established to what extent hydrochlorothiazide can be removed from the body by hemodialysis.

There is no data on the specific treatment of Lorist's drug overdose® H 100. Treatment is symptomatic and supportive. Application of Lorista® H 100 should be discontinued and the patient should be monitored. AT if the drug Lorista® N 100 is adopted recently, it is recommended to provoke vomiting,as well as elimination of dehydration (recovery of circulating blood volume (BCC)), "hepatic" coma and pronounced BP reduction by standard methods.

Interaction:

Losartan

Clinical studies have not revealed clinically significant drug interactions with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin.

Rifampicin and fluconazole reduce the concentration of the active metabolite (this interaction is not clinically studied).

Simultaneous use with potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium preparations or potassium-containing substitutes for table salt, as well as the use of other drugs that increase the concentration of potassium in the blood plasma, increase 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, including losartan.

The antihypertensive effect of losartan, as well as other antihypertensive agents, can be reduced by applying indomethacin.

Double blockade of RAAS: a double blockade of the RAAS; addition to ACE inhibitor therapy angiotensin II receptor antagonist, is only possible in individual cases under careful control of renal function.

Patients with atherosclerosis, heart failure or diabetes with end-organ damage, dual blockade of the RAAS (while the use of angiotensin II receptor antagonists, ACE inhibitors or aliskiren) is accompanied by an increased incidence of hypotension, syncope, hyperkalemia, and renal dysfunction (including acute renal failure) in comparison with the use of the drug of one of the listed groups. It is possible to reduce the elimination of lithium ions. Therefore, with simultaneous use of angiotensin II receptor antagonists with lithium salts Serum concentrations of lithium should be carefully monitored.

Hydrochlorothiazide

With thiazide diuretics, such medicines as ethanol, barbiturates and narcotic drugs, may potentiate the risk of developing orthostatic hypotension.

Hypoglycemic agents for oral use (sulfonylurea derivatives) and / or insulin: may increase the hypoglycemic effect of hypoglycemic agents for oral and / or insulin intake in patients with diabetes mellitus; when they are used simultaneously, there may be an increase in glucose tolerance, which may require correction of doses of hypoglycemic agents for ingestion and / or insulin.

Other antihypertensives additive effect.

Kolestyramin and colestipol - in the presence of anion-exchange resins, hydrochlorothiazide absorption is impaired.

Glucocorticosteroids, adrenocorticotropic hormone (ACTH) - a marked decrease in the electrolyte content, in particular hypokalemia.

Pressor amines (e.g., epinephrine (adrenalin), norepinephrine (norepinephrine)) - a decrease in the severity of the therapeutic effect against the background of the use of pressor amines.

Muscle relaxants of a nondepolarizing action type (eg, tubocurarine chloride) - strengthening the effect of muscle relaxants.

Lithium - diuretics reduce renal clearance of lithium and increase the risk of toxic action of lithium; simultaneous use is not recommended.

Ethanol, barbiturates, narcotic analgesics or antidepressants: risk of orthostatic hypotension.

Drugs used to treat gout (probenecid, sulfinpyrazone and allopurinol) - correction of the dose of drugs of uricosuric action may be necessary, since hydrochlorothiazide can increase the serum concentration of uric acid. An increase in the dose of probenecid or sulfinpyrazone may be necessary. The simultaneous use of thiazide diuretics can increase the frequency of hypersensitivity reactions to allopurinol.

Cyclosporin

Simultaneous use with cyclosporine may increase the risk of hyperuricemia and lead to an exacerbation of gout.

Anticholinergic agents (for example, atropine, biperidene) - increase the bioavailability of thiazide diuretics by reducing gastrointestinal motility and the rate of gastric emptying.

Cytotoxic drugs (cyclophosphamide, methotrexate) - Thiazide diuretics can reduce renal excretion of cytotoxic drugs and enhance their myelosuppressive effect.

Salicylates - in the case of high doses of salicylates, hydrochlorothiazide can enhance their toxic effects on the central nervous system.

Methyldopa - There are limited data on the development of hemolytic anemia with the simultaneous use of hydrochlorothiazide and methyldopa.

Cardiac glycosides - induced by thiazide diuretics hypokalemia or hypomagnesemia can lead to arrhythmia.

Special instructions:

Losartan

Renal impairment

Against the background of the use of losartan, reversible renal dysfunction, including renal failure, that occur after the withdrawal of losartan is possible. Drugs that affect RAAS can lead to an increase in the concentration of urea and creatinine in the blood plasma in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney. These changes in kidney function may be reversible and occur after the withdrawal of therapy. In patients with impaired renal function receiving NSAID therapy (including COX-2 inhibitors), therapy with angiotensin II receptor antagonists can lead to further impairment of renal dysfunction, including acute renal failure, which is usually reversible, and also increase potassium concentration in blood plasma in patients with pre-existing renal dysfunction.This combination is recommended for use with caution, especially in elderly patients. Patients should receive a sufficient amount of fluid, as well as monitor kidney function before and after treatment with Lorist® H 100.

Hydrochlorothiazide

Arterial hypotension and disturbance of water-electrolyte balance As with any antihypertensive drug, symptomatic hypotension may occur in patients. Patients should be observed in order to detect clinical signs of water-electrolyte balance disorders, for example, dehydration, hyponatremia, hypochloraemic alkalosis, hypomagnesemia or hypokalemia, which may develop against the background of concomitant diarrhea or vomiting. Such patients need control of the content of plasma electrolytes.

Metabolic and endocrine effects

Therapy with thiazide diuretics can impair glucose tolerance. In some cases, dosage adjustment of hypoglycemic agents for oral and / or insulin administration may be required.

Thiazides can reduce the excretion of calcium by the kidneys and cause a short-term and insignificant increase in the calcium concentration in theblood plasma. Expressed hypercalcemia may indicate latent hyperparathyroidism. Due to the influence of thiazides on calcium metabolism, their use can distort the results of the study of parathyroid gland function, therefore, before the study of the function of parathyroid glands, the thiazide diuretic should be canceled.

Increasing the concentration of cholesterol and triglycerides of blood can also be associated with therapy with thiazide diuretics.

In some patients, the use of thiazide diuretics can lead to hyperuricemia and / or gout development. Because the losartan reduces the concentration of uric acid, its combination with hydrochlorothiazide reduces the severity of hyperuricemia caused by a diuretic.

Acute attack of closed-angle glaucoma

Hydrochlorothiazide is a sulfonamide, which can cause an idiosyncratic reaction leading to the development of an acute attack of closed-angle glaucoma. Symptoms include: sudden reduction in visual acuity or eye pain, which usually appears within a few hours or weeks of initiating hydrochlorothiazide therapy.In the absence of treatment, an acute attack of angle-closure glaucoma can lead to a permanent loss of vision.

Treatment: stop hydrochlorothiazide as soon as possible. If intraocular pressure remains uncontrolled, immediate medical treatment or surgery may be required. Risk factors for the development of an acute attack of closed-angle glaucoma are: an allergic reaction to sulfonamide or benzylpenicillin in the anamnesis. Other effects

In patients receiving thiazide diuretics, hypersensitivity reactions can be observed even in the absence of an anamnesis indicating the presence of allergic reactions or bronchial asthma. There are reports of the development of exacerbation or progression of systemic lupus erythematosus against the background of the use of thiazide diuretics.

Excipients

It should be borne in mind that the composition of auxiliary substances of the drug Lorista® H 100 lactose monohydrate enters, so the drug is contraindicated in patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome (see below).section "Contraindications").

Effect on the ability to drive transp. cf. and fur:Care must be taken when driving vehicles and working with other technical devices that require a high concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, film-coated, 12.5 mg + 100 mg.

Packaging:

For 10, 14 or 15 tablets in a blister of the combined material PVC / PVDC-aluminum foil.

1, 3, 5, 6 or 9 blisters (10 blisters blister), or 1,2,4 or 6 blisters (blister 14 tablets), or 1, 2, 4 or 6 blisters (15 blisters blister pack ) is placed in a pack of cardboard along with instructions for use.

Storage conditions:In a place protected from moisture, at a temperature of no higher than 30 ° C, in the original packaging. 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:LP-002022

Date of registration:05.03.2013

Date of cancellation:2018-03-05

The owner of the registration certificate:KRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Manufacturer: & nbsp

KRKA, dd, Novo mesto, AO Slovenia

Representation: & nbspKRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Information update date: & nbsphttp://grls.rosminzdrav.ru/Grls_View_v2.aspx?idReg=84302&t=

Illustrated instructions

Instructions

Lorista® N 100 (Lorista® H 100)