Lotonel, tablets 5 mg 60 pcs

Pharmacotherapeutic group

Diuretic agent.

ATX code

C03CA04

Pharmacological properties .

Pharmacodynamics

Thorasemide is a “loop” diuretic. The main mechanism of action of the drug is due to the reversible binding of thorasemide 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 a reduction or complete inhibition of sodium ion reabsorption and a decrease in 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.

Torasemide reduces systolic and diastolic blood pressure while lying and standing.

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

Pharmacokinetics

absorption

.After oral administration, thoracemide is rapidly 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. Sequential oxidation, hydroxylation or ring hydroxylation reactions produce three metabolites (M1, M3 and M5), which bind 86%, 95% and 97% to plasma proteins, 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 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 hepatic insufficiency, plasma concentration of torasemide is 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 torasemide 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, with the exception 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

Liver damage, Hypertension (high blood pressure), Heart failure, Edema

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

Active ingredient

Torasemide

Composition

active ingredient: thorasemide -5.00 mg;
excipients: lactose monohydrate – 75.00 mg; corn starch – 17.50 mg; sodium carboxymethyl starch (sodium glycolate starch, type A) – 1.00 mg; colloidal silicon dioxide – 0.75 mg; magnesium stearate – 0.75 mg.

How to take, the dosage

Enually, 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 obtained.

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 can be doubled until the desired effect is achieved.

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

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

Arterial hypertension

The starting dose is 2.5 mg (1/2 tablet of 5 mg) once a day. 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 a day for 4-6 weeks, the dose is increased to 10 mg once a day. If the 10 mg dose does not produce the desired effect, a hypotensive drug of another group should be added to the treatment regimen.

Elderly patients 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 lengthening 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 thoracemide 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 initial dose of ACE inhibitor or by reducing the dose of torasemide (or temporarily withdrawing it).

Non-steroidal anti-inflammatory drugs, sucralfate reduce the diuretic effect of torasemide due to inhibition of prostaglandin synthesis, disruption of plasma renin activity and aldosterone excretion.

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

Torasemide decreases renal clearance of lithium drugs and increases the likelihood of intoxication.

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

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

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

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

The simultaneous use of probenecid or methotrexate may decrease the effectiveness of thorasemide (same secretion pathway). On the other hand, thorasemide may result in decreased renal elimination of these drugs.

It has been reported that patients at high risk for nephropathy who take oral thorasemide were more likely to have renal dysfunction when administering radiopaque agents than patients at high risk for nephropathy who were given intravenous hydration before administration of radiopaque agents.

The bioavailability and, consequently, the efficacy of thoracemide may be reduced by co-therapy with colestiramine.

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 to avoid the development of hyponatremia, hypokalemia and metabolic alkalosis on a diet with sufficient content of table salt and use of potassium preparations.
The risk of hypokalemia is highest in patients with cirrhosis, increased diuresis, with insufficient intake of electrolytes with food, as well as with concomitant use of corticosteroids or ACTH.
A higher risk of electrolyte and water 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 number of times 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 therapy with LOTONEL® should be resumed in a lower dose.
When azotemia and oliguria appear or increase in patients with severe progressive renal disease it is recommended to stop the drug therapy 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). This category of patients should be regularly controlled for plasma electrolytes.

The use of Lotonel® may cause aggravation of gout.
In patients with diabetes or impaired glucose tolerance it is required periodic control of glucose concentration in blood and urine.
In unconscious patients with benign prostatic hyperplasia, ureteral narrowing it is necessary to control diuresis due to the possibility of acute urinary retention.
In patients with cardiovascular diseases, especially those who take cardiac glycosides, hypokalemia caused by diuretics may cause arrhythmias.

Influence on driving and operating machinery

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

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 (>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;
• urinary 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).

.

Side effects

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

very frequently: ≥ 1/10 (˃ 10%);

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

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

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

very rarely: ˂ 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:

Serious 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:

frequent – headache, dizziness, drowsiness;

infrequent – cramps of the muscles of the lower extremities;

frequency unknown – confusion, fainting, and 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:

Infrequent – nasal bleeding.

Gastrointestinal disorders:

frequent – diarrhea;

infrequent – abdominal pain, flatulence;

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

Liver and biliary tract disorders:

frequency unknown – intrahepatic cholestasis.

Skin 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:

frequently – increased frequency of urination, polyuria, nycturia;

infrequently – frequent urge to urinate;<

frequency 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

Extensive 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 simultaneously 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 are 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