Losartan-N Canon, 25 mg+100 mg 30 pcs

Losartan-N Canon is a combination drug with an antihypertensive effect.

Lozartan is a highly effective selective angiotensin II receptor antagonist (type AT1) when taken orally. Angiotensin II is a potent vasoconstrictor, the main active hormone of the RAAS, and a crucial pathophysiological link in the development of arterial hypertension. Angiotensin II selectively binds to AT1 receptors located in many tissues (vascular smooth muscle cells, adrenal glands, kidneys, and heart) and has several important biological functions, including vasoconstrictor function and aldosterone release. In addition, angiotensin II stimulates smooth muscle cell proliferation.

Lozartan and its pharmacologically active metabolite (E-3174), both in vitro and in vivo, block all physiological effects of angiotensin II, regardless of the source or synthesis pathway. Unlike some peptide angiotensin II receptor antagonists, losartan has no agonist effects. Losartan selectively binds to AT1 receptors and does not bind to or block receptors of other hormones and ion channels that play an important role in the regulation of cardiovascular function. In addition, losartan does not inhibit ACE, which is responsible for bradykinin degradation. Consequently, effects not directly related to AT1-receptor blockade, including bradykinin-mediated effects and the development of peripheral edema (losartan 1.7%, placebo 1.9%), are not relevant to the action of losartan.

Decreases RPS, BP, norepinephrine and aldosterone blood concentrations, small circulatory pressure; decreases post-load, has diuretic effect. Prevents the development of myocardial hypertrophy, increases exercise tolerance in patients with chronic heart failure (CHF). Oral administration of losartan increases plasma renin activity (PAR), which leads to an increase in plasma angiotensin II.

After a single dose, the antihypertensive effect (decreases systolic and diastolic BP) reaches a maximum after 6 h, then gradually decreases within 24 h. During treatment, antihypertensive activity and decreased blood plasma aldosterone concentration were manifested after 2 and 6 weeks of therapy, indicating effective blockade of angiotensin II receptors. However, after discontinuation of losartan, plasma renin activity and angiotensin II levels decreased after 3 days to baseline values observed before initiation of therapy.

Both losartan and its active metabolite have higher affinity for AT1 receptors than for AT2 receptors. The active metabolite is 10-40 times more active than losartan.

Hydrochlorothiazide is a thiazide diuretic, the diuretic effect of which is associated with disruption of reabsorption of sodium, chloride, potassium, magnesium, water ions in the distal nephron; it delays the excretion of calcium ions, uric acid. It has an antihypertensive effect, which develops due to the expansion of the arterioles. It has practically no effect on normal blood pressure.

The diuretic effect occurs in 1-2 hours, reaches a maximum in 4 hours and lasts for 6-12 hours. Antihypertensive effect occurs within 3-4 days, but it may take 3-4 weeks to achieve optimal therapeutic effect.

Indications

– arterial hypertension (patients for whom combination therapy is indicated);

– reducing the risk of developing cardiovascular diseases and mortality in patients with arterial hypertension and left ventricular hypertrophy.

Pharmacological effect

Losartan-N Canon is a combination drug that has an antihypertensive effect.

Losartan is a highly effective orally selective angiotensin II receptor antagonist (AT1 type). Angiotensin II is a powerful vasoconstrictor, the main active hormone of the RAAS, and also a decisive pathophysiological link in the development of arterial hypertension. Angiotensin II selectively binds to AT1 receptors found in many tissues (vascular smooth muscle cells, adrenal glands, kidneys and heart) and performs several important biological functions, including vasoconstrictor function and aldosterone release. In addition, angiotensin II stimulates the proliferation of smooth muscle cells.

Losartan and its pharmacologically active metabolite (E-3174), both in vitro and in vivo, block all physiological effects of angiotensin II, regardless of the source or route of synthesis. Unlike some peptide angiotensin II receptor antagonists, losartan does not have agonist effects. Losartan selectively binds to AT1 receptors and does not bind or block receptors of other hormones and ion channels that play an important role in regulating the function of the cardiovascular system. In addition, losartan does not inhibit ACE, which is responsible for the destruction of bradykinin. Therefore, effects not directly related to AT1 receptor blockade, including effects mediated by bradykinin and the development of peripheral edema (losartan 1.7%, placebo 1.9%), are not related to the action of losartan.

Reduces peripheral vascular resistance, blood pressure, blood concentrations of norepinephrine and aldosterone, pressure in the pulmonary circulation; reduces afterload and has a diuretic effect. Prevents the development of myocardial hypertrophy, increases exercise tolerance in patients with chronic heart failure (CHF). When losartan is taken orally, plasma renin activity (PAR) increases, which leads to an increase in the content of angiotensin II in the blood plasma.

After a single dose, the antihypertensive effect (systolic and diastolic blood pressure decreases) reaches a maximum after 6 hours, then gradually decreases over 24 hours. During treatment, antihypertensive activity and a decrease in plasma aldosterone concentrations appeared after 2 and 6 weeks of therapy, indicating effective blockade of angiotensin II receptors. However, after discontinuation of losartan, plasma renin activity and angiotensin II levels decreased after 3 days to the initial values ​​observed before starting the drug.

Both losartan and its active metabolite have a higher affinity for AT1 receptors than for AT2 receptors. The active metabolite is 10-40 times more active than losartan.

Hydrochlorothiazide is a thiazide diuretic, the diuretic effect of which is associated with impaired reabsorption of sodium, chlorine, potassium, magnesium, and water ions in the distal nephron; delays the excretion of calcium ions and uric acid. It has an antihypertensive effect, which develops due to the expansion of arterioles. Has virtually no effect on normal blood pressure.

The diuretic effect occurs after 1-2 hours, reaches a maximum after 4 hours and lasts 6-12 hours. The antihypertensive effect occurs after 3-4 days, but 3-4 weeks may be required to achieve the optimal therapeutic effect.

Special instructions

Losartan

In patients with reduced blood volume (for example, receiving diuretics in high doses), symptomatic arterial hypotension may occur, therefore, before starting treatment, it is necessary to replenish the blood volume or begin treatment with Losartan-N Canon at a lower dose.

During the treatment period, potassium levels in the blood plasma and CK should be regularly monitored, especially in elderly patients and patients with impaired renal function. Drugs that affect the RAAS may increase serum urea and creatinine concentrations in patients with bilateral renal stenosis or arterial stenosis of a solitary kidney.

Caution should be exercised when prescribing the drug Losartan-N Canon to patients with a burdened allergic history (including patients in whom angioedema had previously developed when using other drugs, including ACE inhibitors), as well as patients with bronchial asthma.

In patients with liver cirrhosis, the concentration of losartan in the blood plasma increases significantly, and therefore, in the presence of a history of liver disease, the drug should be prescribed in lower doses.

There is no need for special selection of the initial dose for elderly patients.

The drug may increase plasma urea and creatinine concentrations in patients with bilateral renal artery stenosis or renal artery stenosis of a solitary kidney.

There is no experience with the use of losartan in patients after kidney transplantation.

Like all drugs that have a vasodilating effect, Losartan-N Canon should be prescribed with caution to patients with aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy.

In patients with severe chronic heart failure, the use of drugs that affect the RAAS can lead to severe hypotension and acute renal failure. There are isolated reports of the development of oliguria and/or increasing azotemia and acute renal failure, incl. with fatal outcome.

There is insufficient experience with the use of losartan in patients with heart failure with concomitant severe renal failure, in patients with severe chronic heart failure (NYHA functional class IV), in patients with heart failure with life-threatening arrhythmias. In these groups, the drug Losartan-N Canon should be used with beta-blockers with caution.

In patients with ischemic cerebrovascular diseases, an excessive decrease in blood pressure can lead to stroke. Medical supervision is recommended when titrating the dose.

Patients with primary hyperaldosteronism usually do not respond to therapy with antihypertensive agents that act through inhibition of the RAAS. Therefore, it is not recommended to use the drug Losartan-N Canon to treat such patients.

Hydrochlorothiazide

Hydrochlorothiazide may increase arterial hypotension and water-electrolyte imbalance (decrease in blood volume, hyponatremia, hypochloremic alkalosis, hypomagnesemia, hypokalemia), impair glucose tolerance, reduce calcium excretion in the urine and cause a transient, slight excess of calcium concentration in the blood plasma. Severe hypercalcemia may indicate latent hyperparathyroidism. Due to the effect of thiazides on calcium metabolism, their use may distort the results of studying the function of the parathyroid glands, therefore, before studying the functions of the parathyroid glands, the thiazide diuretic should be discontinued.

Increased blood cholesterol and triglyceride concentrations may also be associated with thiazide diuretic therapy.

In some patients, the use of thiazide diuretics may lead to hyperuricemia and/or exacerbation of gout.

Hydrochlorothiazide can cause an idiosyncratic reaction leading to the development of acute transient myopia and an acute attack of angle-closure glaucoma. Symptoms include: sudden decrease in visual acuity or eye pain, usually occurring within hours to weeks of starting hydrochlorothiazide therapy. If left untreated, an acute attack of angle-closure glaucoma can lead to permanent vision loss. It is necessary to stop taking hydrochlorothiazide as soon as possible. If intraocular pressure remains uncontrolled, emergency medication or surgery may be required. Risk factors for the development of an acute attack of angle-closure glaucoma are: a history of allergic reactions to sulfonamide derivatives and penicillins.

In patients receiving thiazides, hypersensitivity reactions may occur even in the absence of indications of allergies or a history of bronchial asthma.

There are reports of exacerbation or progression of systemic lupus erythematosus during the use of thiazide diuretics.

Impact on the ability to drive vehicles and operate machinery

Studies of the effect on the ability to drive vehicles and use equipment have not been conducted. However, caution must be exercised when driving or using machinery.

Active ingredient

Hydrochlorothiazide, Losartan

Composition

1 film-coated tablet contains:

Pregnancy

The drug Losartan-N Canon is contraindicated during pregnancy. At the same time, the degree of risk to the fetus in the first trimester is lower compared to the second and third trimesters, since renal perfusion in the fetus, depending on the RAAS, appears in the second trimester.

It is not recommended to prescribe the drug Losartan-N Canon in the first trimester. However, in those extremely rare cases (less than one woman in a thousand) when the use of all other antihypertensive drugs is impossible, the drug can be prescribed under close medical supervision, including weekly ultrasound of the fetus. If signs of oligohydramnios are detected, treatment with an angiotensin II receptor antagonist should be discontinued.

The use of angiotensin II receptor antagonists in the second or third trimesters of pregnancy has a toxic effect on the fetus (decreased renal function, development of oligohydramnios, slower ossification of the skull) and the newborn (renal failure, arterial hypotension, hyperkalemia).

Since drugs acting on the RAAS in the second and third trimesters of pregnancy can lead to developmental disorders and/or fetal death, if pregnancy is established, taking the drug Losartan-N Canon should be stopped immediately.

For newborns and infants who were exposed in utero to an angiotensin II receptor antagonist, it is recommended to conduct careful monitoring for timely detection of decreased blood pressure, oliguria, and hyperkalemia.

Thiazides penetrate the placental barrier and are detected in the umbilical cord blood. The use of diuretics in pregnant women is not recommended, because this increases the risk of developing such adverse events as fetal and neonatal jaundice, and in the mother – thrombocytopenia.

It is not known whether losartan is excreted in breast milk, however, thiazides are known to be excreted in breast milk. Due to the risk of adverse events in infants, Losartan-N Canon is contraindicated during breastfeeding. If it is necessary to use the drug, breastfeeding should be stopped.

Contraindications

– arterial hypotension;

– anuria;

– severe renal dysfunction (creatinine clearance less than 30 ml/min);

– hyperkalemia;

– refractory hypokalemia;

– dehydration (including due to the use of diuretics in high doses);

– severe liver dysfunction (more than 9 points on the Child-Pugh scale);

– Addison’s disease;

– simultaneous use with aliskiren in patients with diabetes mellitus and patients with renal failure (creatinine clearance less than 60 ml/min);

– pregnancy;

– period of breastfeeding;

– age under 18 years (efficacy and safety have not been established);

– hypersensitivity to the components of the drug and to other sulfonamide derivatives.

With caution

— disturbances of water and electrolyte balance (hyponatremia, hypochloremic alkalosis, hypomagnesemia, hypokalemia, hyperkalemia, hypercalcemia);

– decreased blood volume (including due to the use of diuretics in high doses);

– liver failure (less than 9 points on the Child-Pugh scale);

– renal dysfunction (creatinine clearance more than 30 ml/min);

— condition after kidney transplantation (no experience of use);

– bilateral renal artery stenosis or stenosis of the artery of a single kidney;

– IHD;

– aortic and mitral stenosis;

— hypertrophic obstructive cardiomyopathy;

– heart failure with concomitant severe renal failure;

— severe chronic heart failure (functional class IV according to the NYHA classification);

– heart failure with life-threatening arrhythmias;

– cerebrovascular diseases;

– diabetes mellitus;

– symptomatic hyperuricemia and/or exacerbation of gout;

– a burdened allergic history (in some patients, angioedema developed earlier when using other drugs, including ACE inhibitors);

– bronchial asthma;

– systemic connective tissue diseases (including systemic lupus erythematosus);

– acute myopia;

– secondary angle-closure glaucoma;

– simultaneous use of NSAIDs, incl. COX-2 inhibitors;

– simultaneous use of cardiac glycosides;

– old age.

Side Effects

WHO classification of the incidence of side effects: very often – ≥1/10 prescriptions (>10%); often – from ≥1/100 to 1% and <10%); uncommon - from ≥1/1000 to 0.1% and <1%); rarely - from ≥1/10,000 to 0.01% and <0.1%); very rarely - <1/10,000 prescriptions (<0.01%); frequency unknown - based on available data, it is not possible to determine the frequency of occurrence.

Losartan

From the hematopoietic system: infrequently – thrombocytopenia, anemia.

Allergic reactions: uncommon – itching, rash, urticaria, vasculitis, including Henoch-Schönlein purpura; rarely – anaphylactic reactions, angioedema, including swelling of the larynx and vocal cords with the development of airway obstruction and/or swelling of the face, lips, pharynx and/or tongue. Some of these patients have previously experienced angioedema while using other drugs, incl. ACE inhibitors.

From the nervous system: often – sleep disturbance, insomnia, headache, dizziness; uncommon – anxiety, drowsiness, memory disorders, peripheral neuropathy, paresthesia, hypoesthesia, tremor, migraine, ataxia, depression, panic, anxiety, loss of consciousness, acute cerebrovascular accident.

From the side of the organ of vision: infrequently – impaired visual acuity, conjunctivitis.

On the part of the hearing organ: infrequently – ringing in the ears.

From the cardiovascular system: infrequently – bradycardia, atrial fibrillation, atrial and ventricular fibrillation, tachycardia, ventricular tachycardia, angina pectoris, myocardial infarction, orthostatic hypotension, cerebrovascular disorders, fainting.

From the respiratory system: often – nasal congestion, sinusitis, sinusitis, cough; uncommon – upper respiratory tract infections, rhinitis, pharyngitis, laryngitis, dyspnea, bronchitis, nosebleeds.

From the digestive system: often – diarrhea, dyspepsia, cramps, abdominal pain, nausea; uncommon – taste disturbance, dry mouth, constipation, flatulence, gastritis, vomiting, anorexia, liver dysfunction; rarely – hepatitis.

From the skin and subcutaneous tissues: uncommon – alopecia, dermatitis, dry skin, skin hyperemia, photosensitivity, increased sweating.

From the musculoskeletal system: often – muscle cramps in the lower extremities, myalgia, back pain, chest pain, pain in the legs; uncommon – arthralgia, arthritis, arm pain, knee pain, shoulder pain, hip pain, muscle stiffness, fibromyalgia, rhabdomyolysis.

From the urinary system: infrequently – imperative urge to urinate, urinary tract infections, impaired renal function, acute renal failure.

From the genital organs and mammary gland: infrequently – decreased libido, impotence.

From laboratory parameters: often – hyperkalemia; infrequently – moderate increase in the concentration of urea and creatinine in the blood serum, hypoglycemia, hyponatremia, hyperuricemia; very rarely – increased activity of liver enzymes, hyperbilirubinemia.

Other: often – asthenia, increased fatigue.

Hydrochlorothiazide

From the hematopoietic system: rarely – thrombocytopenia, aplastic anemia, hemolytic anemia, leukopenia, agranulocytosis.

Allergic reactions: uncommon – itching, rash, urticaria; rarely – anaphylactic reactions.

From the nervous system: often – headache, dizziness; uncommon – sleep disturbance, paresthesia, depression.

From the side of the organ of vision: infrequently – impaired visual acuity, conjunctivitis, xanthopsia.

From the cardiovascular system: infrequently – chest pain, bradycardia, AV blockade of the second degree, angina pectoris, orthostatic hypotension, vasculitis.

From the respiratory system: rarely – respiratory distress syndrome (including pneumonitis and pulmonary edema).

From the digestive system: infrequently – constipation, diarrhea, pancreatitis, inflammation of the salivary glands, loss of appetite, anorexia, intrahepatic cholestasis; rarely – hepatitis.

From the skin and subcutaneous tissues: infrequently – alopecia, skin hyperemia, photosensitivity, increased sweating.

From the musculoskeletal system: infrequently – muscle cramps in the lower extremities, muscle weakness, arthralgia.

From the urinary system: infrequently – nocturia, interstitial nephritis.

From the genital organs and mammary gland: infrequently – impotence.

From laboratory parameters: often – hyperkalemia; uncommon – hypokalemia, hypomagnesemia, hypercalcemia, hypochloremic alkalosis, moderate increase in serum urea and creatinine concentrations, hyponatremia, hyperuricemia, glucosuria; very rarely – increased activity of liver enzymes, hyperbilirubinemia.

Other: infrequently – fever.

Hydrochlorothiazide/losartan combination

From the nervous system: often – dizziness.

From the digestive system: rarely – hepatitis.

From laboratory parameters: rarely – hyperglycemia, increased activity of liver enzymes.

Interaction

Losartan

Can be used simultaneously with other antihypertensive drugs.

There were no clinically significant drug interactions between losartan and hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin.

Rifampicin and fluconazole have been reported to reduce plasma concentrations of the active metabolite. The clinical significance of this interaction is not yet known.

As with the use of other drugs that block the formation of angiotensin II and its effects, the concomitant administration of potassium-sparing diuretics (spironolactone and eplerenone, triamterene, amiloride), potassium supplements and salts containing potassium may lead to an increase in the content of potassium ions in the blood serum.

Antihypertensive drugs may enhance the hypotensive effect of losartan.

The hypotensive effect of losartan can also be enhanced by tricyclic antidepressants, antipsychotics, baclofen, amifostine, which reduce blood pressure as a main or side effect and increase the risk of arterial hypotension.

With the simultaneous use of angiotensin II receptor antagonists and NSAIDs (including selective COX-2 inhibitors, acetylsalicylic acid as an anti-inflammatory agent), the hypotensive effect of losartan may be reduced. In patients with impaired renal function, the simultaneous use of angiotensin II receptor antagonists or diuretics and NSAIDs may cause further deterioration of renal function, incl. acute renal failure and increased potassium levels in the blood serum. This combination should be used with caution, especially in elderly patients.

With the simultaneous use of lithium preparations with ACE inhibitors, a reversible increase in the concentration of lithium in the blood serum and the development of toxicity were recorded; in very rare cases this has been observed with the use of angiotensin II receptor antagonists. Caution should be exercised when using lithium drugs concomitantly with losartan. If this combination is necessary, it is recommended to monitor the concentration of lithium in the blood serum.

Mutually enhances the effect of beta-blockers and sympatholytics; combined use of losartan with diuretics causes an additive effect.

Dual blockade of the RAAS (eg, by combining an angiotensin II receptor antagonist with an ACE inhibitor or aliskiren) in patients with established atherosclerosis, heart failure, or diabetes mellitus with target organ damage is associated with a higher incidence of hypotension, syncope, hyperkalemia, and renal dysfunction (including the development of acute renal failure) compared with using a single-component blockade of the RAAS. The issue of using double blockade of the RAAS should be decided in each case individually and with careful monitoring of blood pressure, water-electrolyte balance of the blood and renal function.

Hydrochlorothiazide

When used concomitantly with thiazide diuretics, drugs such as ethanol, barbiturates and narcotics may potentiate the risk of orthostatic hypotension.

When using hydrochlorothiazide simultaneously with hypoglycemic agents (oral and insulin), dose adjustment of the latter may be required. Metformin should be used with caution due to the risk of lactic acidosis due to possible renal failure associated with hydrochlorothiazide.

When used with other antihypertensive drugs, an additive effect is possible.

Corticosteroids, ACTH, when used simultaneously with hydrochlorothiazide, can cause an excessive decrease in electrolyte levels, in particular, hypokalemia.

When used simultaneously with hydrochlorothiazide, it is possible to reduce the severity of the response to pressor amines (for example, epinephrine, norepinephrine).

Hydrochlorothiazide enhances the effect of non-depolarizing muscle relaxants (for example, tubocurarine).

Diuretics reduce the renal clearance of lithium and increase the risk of lithium toxicity; simultaneous use is not recommended.

NSAIDs (including COX-2 inhibitors) may reduce the diuretic, natriuretic and antihypertensive effects of diuretics.

Concomitant use with drugs for the treatment of gout (probenecid, sulfinpyrazone, allopurinol) may require dose adjustment of these drugs, since hydrochlorothiazide can increase the concentration of uric acid in the blood serum, an increase in the dose of probenecid or sulfinpyrazone may be required. Concomitant use of thiazide diuretics may increase the incidence of hypersensitivity to allopurinol.

Anticholinergics (atropine, biperiden) increase the bioavailability of thiazide diuretics due to a decrease in gastrointestinal motility and the rate of gastric emptying.

Thiazides can reduce the renal excretion of cytotoxic drugs (cyclophosphamide, methotrexate) and stimulate their myelotoxic effect.

When salicylates are used in high doses, hydrochlorothiazide may enhance their toxic effect on the central nervous system.

Separately, cases of hemolytic anemia have been reported with the combined use of hydrochlorothiazide and methyldopa.

Co-administration with cyclosporine may increase the risk of hyperuricemia and gout-like complications.

Hypokalemia or hypomagnesemia caused by the use of thiazide diuretics may contribute to the development of cardiac arrhythmias when used together with cardiac glycosides.

Due to the risk of developing hypokalemia, caution is required when using Losartan-N Canon simultaneously with the following drugs that can cause torsades de pointes: antiarrhythmic drugs (for example, quinidine, hydroquinidine, disopyramide, amiodarone, sotalol); some antipsychotic drugs (eg, thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopiride, amisulpiride, tiapride, pimozide, haloperidol, droperidol); others (eg, bepridil, cisapride, difemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, terfenadine, vincamycin IV, sparofloxacin, moxifloxacin, astemizole).

Thiazide diuretics may increase serum calcium levels by reducing calcium excretion. If it is necessary to use calcium supplements, the dose is selected under the control of calcium levels in the blood serum.

Vitamin D increases the risk of hypercalcemia.

Due to their effect on calcium excretion, thiazides may interfere with the results of studies of parathyroid function.

Carbamazepine increases the risk of symptomatic hyponatremia. Serum sodium levels must be monitored.

With dehydration caused by taking diuretics, the risk of developing acute renal failure increases, especially when iodine-containing drugs are administered in high doses. Rehydration should be carried out before the administration of such drugs.

Concomitant use of hydrochlorothiazide with amphotericin B, corticosteroids, ACTH and laxatives may aggravate electrolyte imbalances, especially hypokalemia.

Overdose

Losartan

Symptoms: excessive decrease in blood pressure, tachycardia. Bradycardia may occur due to parasympathetic (vagal) stimulation.

Treatment: forced diuresis, symptomatic therapy. Hemodialysis is not effective.

Hydrochlorothiazide

Symptoms: The most common symptoms are the result of electrolyte deficiency (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. With simultaneous use of cardiac glycosides, hypokalemia may aggravate the course of arrhythmias.

Treatment: symptomatic therapy.

Storage conditions

In a dry place, protected from light, at a temperature not exceeding 25 ° C.

Shelf life

2 years.

Manufacturer

Kanonpharma production CJSC, Russia