Tor-lup

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TOR-LOOP (TOR-LOOP)

Composition:

Active substance: torasemide;

1 tablet contains 10 mg of anhydrous torasemide;

Excipients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white or almost white, oval-shaped, biconvex uncoated tablets, marked with "C" on one side and a break line between the markings "4" and "2" on the other side.

Pharmacotherapeutic group.

Medicinal products affecting the cardiovascular system. Diuretics. High-selectivity diuretics. Simple sulfonamide agents. ATC code C03CA04.

Pharmacological Properties

Pharmacodynamics

Torasemide acts as a saluretic diuretic, with its effect related to inhibition of renal reabsorption of sodium and chloride ions in the ascending limb of the loop of Henle. In humans, the diuretic effect rapidly reaches its maximum within the first 2–3 hours after both intravenous and oral administration and remains constant for approximately 12 hours. In healthy volunteers, administration of doses in the range of 5–100 mg resulted in a logarithmic dose-proportional increase in diuresis (loop diuretic activity). Increased diuresis was observed even in cases where other diuretics, such as distally-acting thiazide-type diuretics, had already failed to produce the desired effect, for example in renal insufficiency. Due to this mechanism of action, torasemide reduces edema. In heart failure, torasemide reduces disease symptoms and improves myocardial function by decreasing both preload and afterload. After oral administration, the antihypertensive effect of torasemide develops gradually, starting from the first week of treatment. Maximum antihypertensive effect is achieved no later than 12 weeks. Torasemide reduces arterial blood pressure by decreasing total peripheral vascular resistance. This effect is explained by normalization of disturbed electrolyte balance, primarily due to reduction of elevated levels of free intracellular calcium ions in arterial smooth muscle cells, which has been observed in patients with arterial hypertension. This effect likely reduces the heightened vascular sensitivity to endogenous vasoactive substances, such as catecholamines.

Pharmacokinetics

After oral administration, torasemide is rapidly and completely absorbed. Maximum plasma concentration (Cmax) is reached within 1–2 hours. Bioavailability is approximately 80–90%; under conditions of complete absorption, the maximum first-pass effect is 10–20%. Food reduces the rate (dynamic component) of torasemide absorption (Cmax decreases and tmax increases), but does not affect total absorption. Plasma protein binding of torasemide exceeds 99%; for metabolites M1, M3, and M5, binding is 86%, 95%, and 97%, respectively. The apparent volume of distribution (Vz) is 16 L. In humans, torasemide is metabolized to form three metabolites—M1, M3, and M5. There is no evidence for the existence of other metabolites. Metabolites M1 and M5 are formed by oxidation of the methyl group on the phenyl ring to a carboxylic acid; metabolite M3 is formed by ring hydroxylation. Metabolites M2 and M4, detected in animal studies, have not been identified in humans. The pharmacokinetics of torasemide and its metabolites are characterized by linear kinetics. This means that Cmax and the area under the plasma concentration-time curve (AUC) increase proportionally with dose. The terminal half-life (t1/2) of torasemide and its metabolites in healthy individuals is 3–4 hours. Total clearance of torasemide is 40 mL/min, and renal clearance is approximately 10 mL/min. In healthy volunteers, approximately 80% of the administered dose is excreted in urine as torasemide and its metabolites, in the following approximate proportions: torasemide – 24%, metabolite M1 – 12%, metabolite M3 – 3%, metabolite M5 – 41%. The main metabolite M5 has no diuretic activity, while the combined contribution of active metabolites M1 and M3 to the total pharmacodynamic effect is approximately 10%. In renal insufficiency, total clearance and t1/2 of torasemide remain unchanged, while t1/2 of M3 and M5 is prolonged. However, pharmacodynamic characteristics remain stable, and the severity of renal insufficiency does not affect the duration of action. In patients with hepatic dysfunction or heart failure, t1/2 of torasemide and metabolite M5 is slightly prolonged, but the amount of substance excreted in urine is nearly equal to that in healthy volunteers; therefore, accumulation of torasemide and its metabolites does not occur. Torasemide and its metabolites are poorly removed by hemodialysis and hemofiltration.

Clinical characteristics.

Indications.

Treatment of edema associated with congestive heart failure, kidney or liver diseases.

Treatment of essential hypertension either as monotherapy or in combination with other antihypertensive agents.

Contraindications.

• Hypersensitivity to the components of the drug or to sulfonamide derivatives.
• Renal failure associated with anuria.
• Renal failure with progressive azotemia.
• Significant impairment of urination, for example due to prostate hyperplasia.
• Renal failure following administration of drugs causing renal damage.
• Hepatic coma or precoma.
• Arterial hypotension, hypovolemia, hyponatremia, hypokalemia.
• Arrhythmia.
• Pregnancy and breastfeeding period.
• Rare hereditary intolerance to galactose, lactase deficiency, or glucose-galactose malabsorption.
• Concomitant use with aminoglycosides or cephalosporins.

Interaction with other medicinal products and other types of interactions.

Effect of torasemide on the efficacy of other medicinal products

In patients with essential hypertension, torasemide has been used concomitantly with beta-blockers, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors. No new or unpredictable adverse reactions were observed. The drug also enhances the antihypertensive effect of ACE inhibitors and other antihypertensive agents, which may lead to excessive reduction in arterial pressure during concomitant use.

In patients with congestive heart failure, torasemide has been used with digitalis preparations, ACE inhibitors, and nitrates. None of these combined uses were associated with unpredictable or new adverse reactions. When torasemide is used concomitantly with digitalis preparations, potassium deficiency caused by the diuretic may lead to increased or enhanced adverse effects of both drugs.

Administration of torasemide does not affect the protein binding of glyburide or warfarin, does not alter the anticoagulant properties of phenprocoumon (a coumarin derivative), and does not influence the pharmacokinetic characteristics of digoxin or carvedilol (a vasodilator/beta-blocker). When used concomitantly with spironolactone, torasemide reduces the renal clearance of the latter; however, this does not require dose adjustment of either drug.

In healthy volunteers, concomitant administration of torasemide was associated with a significant decrease in renal excretion of spironolactone and a corresponding increase in AUC. However, clinical experience indicates that dose adjustment of either of these drugs is not necessary.

Effect of other medicinal products on torasemide

Salicylates. When used concomitantly with high doses of salicylates, the toxic effect of salicylates is increased. Nonsteroidal anti-inflammatory drugs (including acetylsalicylic acid), when used concomitantly with this drug and other loop diuretics (e.g., furosemide), may impair renal function.

Indomethacin. When used concomitantly with indomethacin, the diuretic effect of torasemide is partially suppressed (only under conditions of limited sodium intake – 50 mEq/day); such effects were not observed under normal sodium intake (150 mEq/day).

Cimetidine and spironolactone. Cimetidine and spironolactone do not alter the efficacy of torasemide.

Digoxin. Digoxin may increase the AUC of torasemide by 50%, but dose adjustment is not required.

Cholestyramine. Concomitant administration of torasemide and cholestyramine in humans has not been studied, but animal studies have shown that coadministration of cholestyramine reduces the absorption of orally administered torasemide. If combined therapy with cholestyramine is necessary, the drugs should be administered at different times to avoid potential reduction in torasemide absorption.

Probenecid. Concomitant use of probenecid reduces the secretion of torasemide in the proximal tubules and its diuretic activity.

Lithium. Diuretics reduce the renal clearance of lithium, increasing its toxic effects, and may enhance the ototoxic effects of aminoglycosides and etacrynic acid, especially in patients with renal impairment. Studies on such interactions with torasemide have not been conducted.

Aminoglycoside antibiotics and etacrynic acid. Torasemide enhances the ototoxic and nephrotoxic effects of aminoglycoside antibiotics and etacrynic acid; it also enhances the nephrotoxic effects of cephalosporins, platinum compounds, and the adverse effects of theophylline and muscle relaxants. Potential interactions of torasemide with these medicinal products have not been studied.

Special precautions for use.

Warnings

Liver disease with cirrhosis and ascites. Torasemide should be used with particular caution in patients with liver diseases associated with cirrhosis and ascites, as sudden changes in water-electrolyte balance may lead to hepatic coma. Therapy with torasemide (as with other diuretics) in these patients should be conducted under hospital conditions. To prevent hypokalemia and metabolic alkalosis, the drug should be administered concomitantly with aldosterone antagonists or potassium-sparing agents.

Ototoxicity. Cases of ototoxicity (tinnitus and hearing loss) have been reported after torasemide administration, which were reversible; however, a direct causal relationship with the drug has not been established. Ototoxicity has also been observed in animal studies at very high plasma levels of torasemide.

Hypovolemia and electrolyte imbalance. When prescribing diuretics, clinical symptoms of electrolyte imbalance, hypovolemia, extrarenal azotemia, and other disturbances should be carefully monitored. These may manifest as dry mouth, thirst, weakness, lethargy, somnolence, agitation, muscle pain or cramps, myasthenia, arterial hypotension, oliguria, tachycardia, nausea, and vomiting. Excessive diuresis may lead to dehydration, reduction in circulating blood volume, thrombosis, and vascular embolism, especially in elderly patients.

In patients with disturbances in water-electrolyte balance, hypovolemia, or extrarenal azotemia, laboratory parameters may change: hypernatremia, hyponatremia, hyperchloremia, hypochloremia, hyperkalemia, hypokalemia, acid-base imbalance, and increased blood urea nitrogen. In such patients, the drug should be discontinued and therapy resumed only after resolution of adverse effects, starting with lower doses of torasemide.

Controlled studies conducted in the United States and European countries have shown that torasemide was administered to patients with arterial hypertension at doses of 5 or 10 mg daily. During one year of observation, no significant changes in mean serum potassium levels were observed. Dose-dependent hypokalemia was more frequently observed in patients with congestive heart failure, liver cirrhosis, or kidney disease receiving torasemide at doses higher than those used in antihypertensive studies.

In patients with cardiovascular diseases, diuretic-induced hypokalemia may be a risk factor for the development of arrhythmias, particularly in patients receiving digitalis.

The highest risk of hypokalemia occurs in patients with liver cirrhosis, those with increased diuresis, those on a salt-free diet, and those receiving concomitant corticosteroids or adrenocorticotropic hormone.

With prolonged use of torasemide, regular laboratory monitoring of electrolyte balance, particularly serum potassium levels, is required.

Safety measures

Before initiating treatment, existing hypokalemia, hyponatremia, or hypovolemia should be corrected.

With prolonged use of torasemide, regular monitoring of electrolyte balance, glucose, uric acid, creatinine, and blood lipids is required.

Patients with a tendency toward hyperuricemia and gout require special monitoring.

Patients with overt or latent diabetes mellitus should have carbohydrate metabolism monitored.

In patients with cardiovascular diseases, particularly those taking cardiac glycosides, hypokalemia induced by diuretics may increase the risk of arrhythmias. The risk of hypokalemia is higher in patients with liver cirrhosis, those with intense diuresis, those receiving inadequate electrolyte intake, and those taking corticosteroids or adrenocorticotropic hormone.

Laboratory data

Potassium. In studies involving patients with arterial hypertension, serum potassium levels were slightly reduced after 12 weeks of treatment with torasemide. In comparative studies with other diuretics, torasemide did not affect serum potassium levels. In long-term studies, torasemide did not significantly alter blood potassium levels.

Calcium. In healthy volunteers, single doses of torasemide increased urinary calcium excretion; however, serum calcium levels were slightly elevated during four six-week hypertension studies. In a long-term study in patients with congestive heart failure, the mean annual change in serum calcium was a decrease of 0.10 mg/dL (0.02 mmol/L). Hypocalcemia was not reported as an adverse reaction in 426 patients treated with torasemide for 11 months.

Magnesium. In healthy volunteers, single doses of torasemide increased urinary magnesium excretion, but serum magnesium levels were slightly elevated in four six-week hypertension trials. In hypertension studies, the mean annual change in serum magnesium was an increase of 0.03 mg/dL (0.01 mmol/L). One case of hypomagnesemia (1.3 mg/dL [0.53 mmol/L]) was reported as an adverse reaction among 426 patients receiving torasemide for an average of 11 months.

In a long-term clinical study using torasemide in patients with congestive heart failure, the annual change in serum magnesium increased by 0.2 mg/dL (0.08 mmol/L) (this value accounts for the use of magnesium-containing supplements by many patients). In a four-week study without magnesium supplementation, serum magnesium levels were below 1.7 mg/dL (0.70 mmol/L) in 6% and 9% of patients receiving 5 mg and 10 mg of torasemide, respectively.

Blood urea, creatinine, and uric acid. Torasemide causes small, dose-dependent increases in these parameters. In patients with arterial hypertension receiving 10 mg of torasemide daily for six weeks, mean increases were: serum urea – 1.8 mg/dL (0.6 mmol/L), creatinine – 0.05 mg/dL (4 µmol/L), and uric acid – 1.2 mg/dL (70 µmol/L). These parameters showed minimal changes during long-term treatment, and changes were reversible after discontinuation of therapy.

Symptomatic gout was reported in patients receiving torasemide, but the frequency was similar to that observed in patients receiving placebo.

Glucose. In patients with arterial hypertension receiving 10 mg of torasemide daily, a mean increase in serum glucose concentration of 5.5 mg/dL (0.3 mmol/L) was observed after six weeks of treatment, with a further increase of 1.8 mg/dL (0.1 mmol/L) the following year. Long-term studies showed that in patients with diabetes mellitus, mean glycemia values did not significantly change from baseline. Rare cases of hyperglycemia have been reported.

Serum lipids. In short-term controlled hypertension studies, daily doses of 5, 10, and 20 mg of torasemide were associated with increases in plasma total cholesterol of 4.4 and 8 mg/dL (0.10–0.20 mmol/L), respectively. These changes regressed during prolonged treatment.

In the same short-term hypertension studies, daily doses of 5, 10, and 20 mg of torasemide were associated with mean increases in plasma triglycerides of 16, 13, and 71 mg/dL (0.15–0.80 mmol/L), respectively.

Long-term trials with daily doses of 5 to 20 mg of torasemide showed no significant difference compared to baseline lipid levels after one year of treatment.

Others. During long-term studies in patients with arterial hypertension, torasemide was associated with a slight increase in mean hemoglobin and hematocrit, as well as red blood cell, platelet, and leukocyte counts, and serum alkaline phosphatase levels.

Although these changes were statistically significant, they had no medical consequences. In assessing liver enzyme levels in blood, no significant changes were observed except for an increase in alkaline phosphatase.

Use during pregnancy or breastfeeding.

Pregnancy. Reliable data on the effects of torasemide on the human embryo and fetus are lacking. Reproductive toxicity of torasemide has been demonstrated in animal experiments. Torasemide crosses the placental barrier. Therefore, torasemide should be used during pregnancy only if absolutely necessary and at the lowest effective dose. Diuretics are not suitable for standard treatment regimens for arterial hypertension or edema in pregnant women, as they may reduce placental perfusion and cause toxic effects on fetal development. If torasemide is used to treat pregnant women with heart or kidney failure, careful monitoring of electrolyte levels, hematocrit, and fetal development is required.

Lactation period. It has not yet been established whether torasemide passes into breast milk in animals or humans. A risk to newborns/infants cannot be excluded. Therefore, the use of torasemide during lactation is contraindicated. If torasemide must be used during this period, breastfeeding should be discontinued.

Fertility.

Studies on the effect of torasemide on fertility in humans have not been conducted. Animal experiments did not reveal any adverse effects of torasemide on fertility.

Ability to affect reaction speed when driving or operating machinery.

Even when used at recommended doses, torasemide may affect a patient's reaction speed and significantly impair the ability to drive or operate machinery. This is particularly relevant at the beginning of treatment, when increasing the dose, switching medications, or starting concomitant therapy. Therefore, extreme caution is required when driving or operating machinery during torasemide treatment.

Dosage and Administration.

Chronic heart failure.

The usual initial dose is 10–20 mg once daily.

If the desired diuretic effect is not achieved, the dose should be doubled (20–40 mg daily) until the desired effect is attained.

Chronic renal failure.

The usual initial dose is 20 mg once daily.

If the desired diuretic effect is not achieved, the dose should be doubled (40 mg daily) until the desired effect is attained.

Cirrhosis of the liver.

The usual initial dose is 5–10 mg once daily when used concomitantly with aldosterone antagonist agents or potassium-sparing diuretics. If the desired diuretic effect is not achieved, the dose should be doubled (10–20 mg daily) until the desired effect is attained.

There are no data regarding single doses exceeding 40 mg daily.

To split the tablet into two equal halves (to achieve a 5 mg dose), place the tablet on a hard surface and press downward with the thumbs on either side of the score line located on one side of the tablet. Tablets should be taken on an empty stomach, without chewing, and swallowed with a small amount of liquid. The bioavailability of torasemide is not affected by food intake. Tor-Lup is usually administered for a prolonged period or until edema subsides.

Patients with hepatic impairment. Treatment of such patients should be performed with caution, as increased plasma concentrations of torasemide may occur.

Elderly patients. No specific dose adjustment is required.

Essential hypertension. The usual initial dose is 5 mg once daily. If this dosage regimen does not provide adequate blood pressure reduction within 4–6 weeks, the dose should be increased to 10 mg once daily. If necessary, combination therapy with other antihypertensive agents should be considered.

Children.

Torasemide should not be used in children due to insufficient clinical experience.

Overdose.

The typical symptomatology is unknown. Overdose may cause pronounced diuresis, including the risk of excessive loss of water and electrolytes, somnolence, amnestic syndrome (a form of consciousness disturbance), symptomatic arterial hypotension, cardiovascular insufficiency, and gastrointestinal disturbances.

Treatment of overdose. There is no specific antidote. Symptoms of intoxication usually resolve with dose reduction or discontinuation of the drug, along with appropriate replacement of fluids and electrolytes (monitoring of blood electrolyte levels is required). Torasemide is not effectively removed from blood by hemodialysis. Treatment in case of hypovolemia: fluid volume replacement. Treatment in case of hypokalemia: administration of potassium supplements. Treatment of cardiovascular insufficiency: place the patient in a supine position and, if necessary, administer symptomatic therapy.

Anaphylactic shock (emergency measures). In case of skin reactions (such as urticaria or skin redness), patient agitation, headache, excessive sweating, nausea, cyanosis, venous catheterization should be performed; the patient should be placed in a horizontal position, free airway access ensured, and oxygen administered. If necessary, administer epinephrine, volume-expanding solutions, and glucocorticoid hormones.

Adverse Reactions

The following frequency criteria were used to assess adverse reactions: very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1000 to <1/100; rare: ≥1/10,000 to <1/1000; very rare: <1/10,000; frequency not known: cannot be estimated from available data.

Blood and lymphatic system disorders

Frequency not known: thrombocytopenia, leukopenia, anemia.

Immune system, skin and subcutaneous tissue disorders

Very rare: allergic reactions (including pruritus, rash), photosensitivity reactions.

Frequency not known: serious skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis).

Metabolism and nutrition disorders

Common: electrolyte imbalance (including hypovolemia, hyponatremia).

Uncommon: hypercholesterolemia, hyperlipidemia, polydipsia.

Frequency not known: worsening of metabolic alkalosis, hypertriglyceridemia.

Nervous system disorders

Common: headache, dizziness, somnolence.

Uncommon: leg cramps (particularly at the beginning of treatment).

Frequency not known: cerebral ischemia, paresthesia, confusion.

Eye disorders

Frequency not known: visual disturbances.

Ear and labyrinth disorders

Frequency not known: tinnitus, hearing loss.

Cardiac and vascular disorders

Uncommon: extrasystoles, palpitations, tachycardia, facial flushing.

Frequency not known: acute myocardial infarction, myocardial ischemia, angina pectoris, syncope, cerebral ischemia, embolism, hypotension.

Respiratory system disorders

Uncommon: epistaxis.

Gastrointestinal disorders

Common: gastrointestinal disturbances (including loss of appetite, stomach pain, nausea, vomiting, diarrhea, constipation).

Uncommon: abdominal pain, flatulence.

Frequency not known: dry mouth, pancreatitis.

Hepatobiliary disorders

Uncommon: increased blood levels of certain liver enzymes (gamma-glutamyl transferase).

Musculoskeletal and connective tissue disorders

Common: muscle cramps.

Renal and urinary disorders

Common: increased frequency of urination, polyuria, nocturia.

Uncommon: urinary urgency, urinary retention, bladder distension (in patients with benign prostatic hyperplasia, increased urine production may lead to urinary retention and excessive bladder distension).

Rare: increased plasma levels of urea and creatinine.

General disorders and administration site conditions

Common: increased fatigue, general weakness.

Uncommon: asthenia, thirst, increased activity, nervousness.

Laboratory test abnormalities

Uncommon: increased platelet count, increased levels of uric acid, glucose, and lipids (triglycerides, cholesterol) in blood.

Frequency not known: thrombocytopenia, leukopenia.

Other adverse reactions may include hypokalemia, hypovolemia, arterial hypotension, impotence, and shunt thrombosis.

Shelf life

3 years.

Storage conditions

Store in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging

10 tablets per blister, 3 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

Aurobindo Pharma Limited (Unit III), India.

Manufacturer's address

Survey No 313, 314, Block I, II, III, IV, Bachupally Village, Quthubullapur Mandal, Ranga Reddy District (A.P), India.

Marketing Authorization Holder

Aurobindo Pharma Ltd, India.

Address of Marketing Authorization Holder

Plot № 2, Maitrivihar, Ameerpet, Hyderabad - 500038, Telangana, India.