Lotonel, tablets 10 mg 60 pcs

Pharmacotherapeutic group

Diuretic agent.

ATC code

C03CA04

Pharmacological properties

Pharmacodynamics

Torasemide is a “loop” diuretic. The main mechanism of action of the drug is due to the reversible binding of torasemide to the sodium/chlorine/potassium ion transporter located in the apical membrane of the thick segment of the ascending loop of Genle, which results in reduction or complete inhibition of sodium ion reabsorption and reduction of intracellular fluid osmotic pressure and water reabsorption. Torasemide blocks myocardial aldosterone receptors, reduces fibrosis and improves diastolic function of the myocardium.

Thorasemide causes hypokalemia to a lesser extent than furosemide due to its anti-aldosterone action, but it is more active and its effect is longer.

The diuretic effect develops about an hour after oral administration, reaching a maximum after 2-3 hours, and lasts up to 18 hours, which facilitates tolerance of therapy because there is no very frequent urination in the first hours after oral administration, which limits patient activity.

Thorasemide reduces systolic and diastolic blood pressure in lying and standing position.

The use of torasemide is the most reasonable choice for long-term therapy.

Pharmacokinetics

absorption

. After oral administration, torasemide is quickly and almost completely absorbed in the gastrointestinal tract. Food intake has no significant effect on absorption of the drug. Maximum concentration of thorasemide in blood plasma is noted 1-2 hours after oral administration. Bioavailability is 80-90 % with slight individual variations.

Distribution

The binding to plasma proteins is more than 99%. The volume of distribution in healthy volunteers and in patients with mild to moderate renal insufficiency or chronic heart failure is 12 to 16 liters. In patients with cirrhosis the volume of distribution is doubled.

Metabolism

Metabolized in the liver by cytochrome P450 system isoenzymes. Three metabolites (M1, M3 and M5) are formed as a result of sequential oxidation, hydroxylation or ring hydroxylation reactions, which bind to plasma proteins by 86 %, 95 % and 97 % respectively.

Elimation

The elimination half-life (T_1/2) of torasemide and its metabolites in healthy volunteers is 3-4 hours. Total clearance of torasemide is 40 ml/min, renal clearance – 10 ml/min. On average, about 83% of the taken dose is excreted by the kidneys: unchanged (24%) and as mainly inactive metabolites (M1 – 12%, M3 – 3%, M5 – 41%).

Pharmacokinetics in special groups of patients

. In renal failure, the T_1/2 of torasemide is unchanged; the T_1/2 metabolites M3 and M5 are increased. Torasemide and its metabolites are slightly excreted by hemodialysis and hemofiltration.

In case of hepatic insufficiency, plasma concentrations of thoracemide are increased due to decreased rate of metabolism of the drug in the liver.

In patients with cardiac or hepatic insufficiency the T_1/2 of thorasemide and the M5 metabolite are slightly increased and cumulation of the drug is unlikely.

The pharmacokinetic profile of thoracemide in elderly patients is similar to that in younger patients, except that there is a decrease in renal clearance of the drug due to the characteristic age-related impairment of renal function in elderly patients. Total clearance and T_1/2 are unchanged.

Indications

Edema, Heart failure, liver damage, hypertension (high blood pressure)

• edema syndrome of different genesis, including chronic heart failure, liver, lung and kidney disease
• arterial hypertension.
  

Active ingredient

Torasemide

Composition

active ingredient: thorasemide – 10.00 mg;

excipients: lactose monohydrate, 150.00 mg; corn starch, 35.00 mg; sodium carboxymethyl starch (sodium starch glycolate, type A), 2.00 mg; colloidal silicon dioxide, 1.50 mg; magnesium stearate, 1.50 mg.

How to take, the dosage

To be taken by mouth, once a day, without chewing, with plenty of water. The tablets can be taken at any convenient fixed time, regardless of meals.

Oedema syndrome in chronic heart failure

The usual starting dose is 10-20 mg once daily. If necessary, the dose may be doubled until the desired effect is achieved.

Oedematous syndrome in renal disease

The usual starting dose is 20 mg once daily. If necessary, the dose may be doubled until the desired effect is achieved.

Oedematous syndrome in liver disease

The usual starting dose is 5-10 mg once daily. If necessary, the dose may be doubled until the desired effect is achieved.

The maximum single dose is 40 mg and it is not recommended to exceed this dose (no experience with use).

The drug is used over a long period or until the edema disappears.

Arterial hypertension

The starting dose is 2.5 mg (1/2 tablet of 5 mg) once daily. If there is no therapeutic effect within 4 weeks, the dose is increased to 5 mg once daily. In the absence of adequate reduction of blood pressure when administered in a dose of 5 mg once daily for 4-6 weeks, the dose is increased to 10 mg once daily. If the 10 mg dose does not give the desired effect, a hypotensive drug of another group should be added to the treatment regimen.

Patients of advanced age do not require dose adjustment.

Interaction

In concomitant use of thorasemide with mineral and glucocorticosteroids, amphotericin B increases the risk of hypokalemia; with cardiac glycosides – the risk of glycoside intoxication due to hypokalemia (for high and low-polar cardiac glycosides) and prolongation of the elimination half-life (for low-polar cardiac glycosides) increases.

The administration of torasemide increases the concentration and risk of nephro- and ototoxic effects of cephalosporins, aminoglycosides, chloramphenicol, etacrynic acid, antibiotics, salicylates, cisplatin, platinum drugs, amphotericin B (due to competitive renal excretion).

Simultaneous or concomitant use of thorasemide with angiotensin-converting enzyme inhibitors (ACE) or angiotensin II receptor antagonists may lead to a sharp decrease in blood pressure. This can be avoided by reducing the starting dose of the ACE inhibitor or by reducing the dose of thorazemide (or temporarily cancelling it).

The nonsteroidal anti-inflammatory drugs, sucralfate decrease the diuretic effect of thorasemide due to inhibition of prostaglandin synthesis, impairment of plasma renin activity and excretion of aldosterone.

Torasemide increases the antihypertensive effect of hypotensive agents, neuromuscular blockade of depolarizing myorelaxants (suxamethonium) and reduces the effect of nondepolarizing myorelaxants (tubocurarin).

Thorasemide decreases renal clearance of lithium preparations and increases the likelihood of intoxication.

Thorasemide increases the effectiveness of diazoxide and theophylline, reduces the effectiveness of hypoglycemic agents, allopurinol.

Presor amines and thorasemide mutually reduce the effectiveness of each other.

Drugs that block tubular secretion increase the plasma concentration of thoracemide.

The simultaneous use of cyclosporine and thorasemide increases the risk of gouty arthritis due to the fact that cyclosporine may cause impaired renal urate excretion and thorasemide may cause hyperuricemia.

The concomitant use of probenecid or methotrexate may decrease the effectiveness of thoracemide (same secretion pathway). On the other hand, thorasemide may lead to decreased renal elimination of these drugs.

It has been reported that in patients at high risk of nephropathy who take oral thoracemide, renal dysfunction has been observed more frequently with radiopaque agents than in patients at high risk of nephropathy who received intravenous hydration before radiopaque agents were administered.

The bioavailability and, consequently, the effectiveness of thoracemide may be reduced when co-therapy with colestyramine.

Special Instructions

Patients with hypersensitivity to sulfonamides and sulfonylurea derivatives may have cross-sensitivity to thorasemide.
Patients receiving high doses of thorasemide for a long period are recommended a diet with sufficient table salt and the use of potassium preparations to avoid the development of hyponatremia, hypokalemia and metabolic alkalosis.
The risk of hypokalemia is highest in patients with cirrhosis, increased diuresis, with insufficient intake of electrolytes with food, and with concomitant use of corticosteroids or ACTH.
Increased risk of water-electrolyte balance disorders is noted in patients with renal insufficiency. During a course of treatment with LOTONEL® it is necessary to monitor periodically the electrolyte content in the blood plasma (including sodium, calcium, potassium, magnesium), acid-base status, residual nitrogen, creatinine, uric acid concentration and if necessary provide the appropriate corrective therapy (with higher frequency in patients with frequent vomiting and against the background of parenteral fluid administration).
In patients with developed water-electrolyte disturbances, hypovolemia or prerenal azotemia laboratory tests may include: hyper- or hyponatremia, hyper- or hypochloremia, hyper- or hypokalemia, acid-base balance disorders and increased plasma urea concentration. In case of such deviations from the laboratory values the use of LOTONEL® should be stopped until normal values are restored, and then the treatment with LOTONEL® should be resumed in a lower dose.
In case of the appearance or worsening of azotemia and oliguria in patients with severe progressive renal disease it is recommended to stop the treatment with LOTONEL®.
The dosage regimen of patients with ascites against the background of liver cirrhosis should be chosen under hospital conditions (disorders of water-electrolyte balance may lead to hepatic coma). Regular monitoring of blood plasma electrolytes is indicated for this category of patients.

LOTONEL® administration may cause aggravation of gout.
In patients with diabetes or impaired glucose tolerance it is necessary to periodic control of glucose concentration in blood and urine.
In unconscious patients with benign prostatic hyperplasia, urethral narrowing, diuresis control is necessary due to the possibility of acute urinary retention.
In patients with cardiovascular disease, especially those taking cardiac glycosides, diuretic-induced hypokalemia may cause arrhythmias.

Influence on driving and operating machinery

Patients should refrain during treatment from driving and engaging in other potentially dangerous activities requiring increased concentration and rapid psychomotor reactions (risk of dizziness and somnolence).

Synopsis

Round flat cylindrical white or almost white tablets with a bevel and a rib.

Contraindications

• high sensitivity to thorazemide or any of the drug components;
• allergy to sulfonamides (sulfonamide antimicrobials or sulfonylurea preparations);
• Renal failure with anuria;
• hepatic coma and precoma;
• refractory hypokalemia;
• refractory hyponatremia;
• hypovolemia (with or without arterial hypotension) or dehydration;
• acute urinary outflow disorders of any etiology (including unilateral urinary tract involvement);
• glycoside intoxication;
• acute glomerulonephritis;
• decompensated aortic and mitral stenosis;
• hypertrophic obstructive cardiomyopathy;
• increased central venous pressure (over 10 mmHg. syst.);
• arrhythmia;
• chronic renal failure with increasing azotemia;
hyperuricemia;
• age below 18 years (safety and efficacy not established);
• pregnancy;
• breastfeeding period;
• current use of aminoglycosides and cephalosporins;
• lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

With caution

• arterial hypotension;
• stenotic atherosclerosis of cerebral arteries;
• hypoproteinemia;
• urine outflow disorders (benign prostatic hyperplasia, urethral narrowing or hydronephrosis);
• Ventricular arrhythmia in the history;
• acute myocardial infarction (increased risk of cardiogenic shock);
• diarrhea;
• pancreatitis;
• hypokalemia;
• hyponatremia;
• diabetes mellitus (decreased glucose tolerance);
• podagra, predisposition to hyperuricemia;
• anemia;
• current use of cardiac glycosides, corticosteroids and adrenocorticotropic hormone (ACTH).

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Side effects

The incidence of side effects is classified according to the World Health Organization recommendations:

very common: ≥ 1/10 (˃ 10%);

often: ≥ 1/100 to ˂ 1/10 (˃ 1% and ˂ 10%);

infrequently: ≥ 1/1000 to ˂ 1/100 (˃ 0.1% and ˂ 1%);

rarely: ≥ 1/10000 to ˂ 1/1000 (˃ 0.01% and ˂ 0.1%);

very rare: ˂ 1/10000 (˂ 0.01%);

frequency unknown: frequency cannot be estimated from available data.

Blood and lymphatic system disorders:

frequency unknown – thrombocytopenia, leukopenia, agranulocytosis, aplastic or hemolytic anemia.

Disorders of the immune system:

Severe anaphylactic reactions up to and including shock, which to date have only been described following intravenous administration.

Metabolic and nutritional disorders:

infrequent – polydipsia;

frequency unknown – hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, hypochloremia, metabolic alkalosis, hypovolemia, dehydration (more often in elderly patients), which may lead to hemoconcentration with a tendency to develop clots).

Nervous system disorders:

often – headache, dizziness, drowsiness;

infrequent – cramps of the muscles of the lower extremities;

p> frequency unknown – confusion, fainting, paresthesias in the extremities (feeling of numbness, “creeping goose bumps” and tingling).

Visual disturbances:

frequency unknown – visual disturbances.

Hearing and labyrinth disorders:

frequency unknown – hearing impairment, tinnitus and hearing loss (usually reversible) usually in patients with renal failure or hypoproteinemia (nephrotic syndrome).
Cardiac disorders:

infrequent – extrasystole, arrhythmia, tachycardia, palpitations.

Vascular disorders:

frequency unknown – excessive decrease in blood pressure, orthostatic hypotension, collapse, deep vein thrombosis, thromboembolism, reduced circulating blood volume.

Disorders of the respiratory system, thorax and mediastinum:

infrequently – nasal bleeding.

Gastrointestinal disorders:

often – diarrhea;

infrequent – abdominal pain, flatulence;

frequency unknown – dry mouth, nausea, vomiting, loss of appetite, pancreatitis, dyspeptic disorders.

Liver and biliary tract disorders:

frequency unknown – intrahepatic cholestasis.

Dermal and subcutaneous tissue disorders:

infrequent – facial redness;

frequency unknown – skin itching, rash, urticaria, erythema polymorphic, exfoliative dermatitis, purpura, vasculitis, photosensitization.

Muscle, skeletal and connective tissue disorders:

frequency unknown – muscle weakness.

Disorders of the kidneys and urinary tract:

often – increased frequency of urination, polyuria, nycturia;

infrequent – frequent urge to urinate; <

frequent unknown – oliguria, urinary retention (in patients with urinary tract obstruction), interstitial nephritis, hematuria.

Reproductive system and mammary gland disorders:

frequency unknown – decreased potency.

General disorders and reactions at the site of administration:

infrequent – fever, asthenia, weakness, increased fatigue, hyperactivity, nervousness.

Laboratory and instrumental findings:

infrequent – hypercholesterolemia, hypertriglyceridemia;

frequency unknown – hyperuricemia, slightly increased plasma alkaline phosphatase activity, increased plasma creatinine and urea concentrations, increased plasma activity of some “hepatic” enzymes (e.g., gamma-glutamyltransferase), hyperglycemia, decreased glucose tolerance (possible manifestation of latent diabetes).

If any of the side effects listed in the instructions worsen, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose

Symptoms

High diuresis accompanied by decreased circulating blood volume and disturbed water-electrolyte balance of the blood, followed by a marked decrease in blood pressure, drowsiness and confusion, collapse. Gastrointestinal disorders may be observed.

Treatment

There is no specific antidote. Provocation of vomiting, gastric lavage, activated charcoal. Treatment is symptomatic, dose reduction or discontinuation of the drug and simultaneous replenishment of circulating blood volume and correction of water-electrolyte balance and acid-base status under control of plasma electrolyte content and hematocrit level. Hemodialysis is ineffective, as excretion of torasemide and its metabolites is not accelerated.

Pregnancy use

Torasemide has no teratogenic effect and fetotoxicity, it penetrates through the placental barrier, causing water-electrolyte metabolism disorders and thrombocytopenia in the fetus. Controlled studies on the use of thoracemide in pregnant women have not been conducted, the drug is not recommended for use during pregnancy. There is no data on excretion of thoracemide into breast milk, therefore if it is necessary to use thoracemide during lactation, breastfeeding should be stopped.

Similarities

Diuver, Trigrim, Torasemide-SZ, Lotonel, Torasemide