Proficor

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PROFIKOR® (PROFICOR®)

Composition:

Active substance: torasemide;

1 ml of injection solution contains torasemide calculated as 100 % dry substance – 5 mg;

Excipients: polyethylene glycol 400, tromethamine, sodium hydroxide, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear colorless solution practically free from mechanical particles. pH of the solution: 8.5–9.5.

Pharmacotherapeutic group. Diuretics. High-ceiling diuretics.

ATC code C03CA04.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Torasemide acts as a diuretic; its effect is associated with inhibition of renal reabsorption of sodium and chloride ions in the ascending limb of the loop of Henle.

Pharmacodynamic effects. In humans, the diuretic effect rapidly reaches its maximum within the first 2–3 hours after intravenous and oral administration, respectively, and remains consistent for approximately 12 hours. In healthy subjects, a logarithmic dose-proportional increase in diuresis was observed within the dose range of 5–100 mg (loop diuretic activity). Increased diuresis was observed even in cases where other diuretics, such as distally-acting thiazide-type diuretics, were no longer effective, for example in renal insufficiency. Due to this mechanism of action, torasemide leads to reduction of edema. In cases of heart failure, torasemide reduces disease symptoms and improves myocardial function by decreasing preload and afterload.

Pharmacokinetics

Absorption and distribution. The binding of torasemide to plasma proteins exceeds 99%; for metabolites M1, M3, and M5, binding is 86%, 95%, and 97%, respectively. The apparent volume of distribution (Vz) is 16 L.

Biotransformation. In the human body, torasemide is metabolized to form three metabolites, M1, M3, and M5. There is no evidence of other metabolites. Metabolites M1, M3, and M5 are formed through stepwise oxidation of the methyl group attached to the phenyl ring into a carboxylic acid; metabolite M3 is formed via hydroxylation of the ring. Metabolites M2 and M4, detected in animal experiments, have not been identified in humans.

Elimination. The terminal half-life (t1/2) of torasemide and its metabolites in healthy volunteers 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, with the following average percentage distribution: torasemide – approximately 24%, metabolite M1 – approximately 12%, metabolite M3 – approximately 3%, metabolite M5 – approximately 41%. The main metabolite M5 has no diuretic effect, while the combined contribution of the active metabolites M1 and M3 accounts for approximately 10% of the total pharmacodynamic effect. 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 unchanged, 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 practically not eliminated by hemodialysis or hemofiltration.

Linearity. The pharmacokinetics of torasemide and its metabolites are characterized by linear dependence. This means that the maximum plasma concentration and the area under the plasma concentration-time curve increase proportionally with the administered dose.

Clinical characteristics.

Indications.

Treatment of edema and/or effusions caused by heart failure, when intravenous administration of a medicinal product is required, for example, in case of pulmonary edema due to acute heart failure.

Contraindications.

Hypersensitivity to the active substance, sulphonilurea drugs, or to any of the excipients of the medicinal product. Renal failure with anuria. Hepatic coma or precoma. Arterial hypotension. Hypovolemia. Hyponatremia. Hypokalemia. Acute urinary obstruction, for example due to prostatic hyperplasia. Breastfeeding period.

Interaction with other medicinal products and other types of interactions.

Combinations not recommended

Torasemide, especially at high doses, may enhance the ototoxic and nephrotoxic effects of aminoglycoside antibiotics, such as kanamycin, gentamicin, tobramycin, and cytostatic agents—active platinum derivatives—as well as the nephrotoxic effects of cephalosporins.

Concomitant use of torasemide and lithium preparations may increase lithium plasma concentrations, potentially leading to enhanced effects and increased adverse reactions of lithium.

Combinations of medicinal products requiring caution

Torasemide enhances the effects of other antihypertensive agents, particularly angiotensin-converting enzyme inhibitors, which may result in excessive reduction of arterial blood pressure when used concomitantly. Concomitant use of torasemide with digoxin preparations may lead to potassium deficiency caused by diuretic use, potentially increasing and intensifying the adverse effects of both drugs. Torasemide may reduce the effectiveness of antidiabetic agents. Probenecid and nonsteroidal anti-inflammatory drugs (e.g., indomethacin, acetylsalicylic acid) may inhibit the diuretic and antihypertensive effects of torasemide. When treating with high-dose salicylates, torasemide may increase their toxic effects on the central nervous system. Torasemide may enhance the effects of theophylline and the action of curare-like medicinal agents. Laxatives, as well as mineralo- and glucocorticoids, may intensify potassium loss induced by torasemide. Torasemide may reduce the vasoconstrictive effects of catecholamines, such as epinephrine and norepinephrine.

Special precautions for use

Torasemide should not be prescribed in the following cases:

• Gout;
• Cardiac arrhythmias (e.g., sinoatrial block, second- and third-degree atrioventricular block);
• Pathological changes in acid-base metabolism;
• Concomitant therapy with lithium, aminoglycosides, or cephalosporins;
• Blood count abnormalities (e.g., thrombocytopenia or anemia) in patients without renal insufficiency;
• Renal dysfunction caused by nephrotoxic substances;
• Children and adolescents under 18 years of age.

Since treatment with torasemide may lead to increased blood glucose levels, patients with latent or manifest diabetes mellitus should undergo regular monitoring of carbohydrate metabolism. Particular attention should be paid, especially at the beginning of treatment and when treating elderly patients, to the emergence of symptoms of hemoconcentration and electrolyte depletion. During prolonged use of torasemide, regular monitoring of electrolyte balance, particularly serum potassium levels, is required. Additionally, regular monitoring of blood glucose, uric acid, creatinine, and lipid levels is recommended. Furthermore, periodic monitoring of complete blood count (erythrocytes, leukocytes, platelets) should be performed.

Consequences of misuse as a doping agent

The use of the medicinal product Proficor® may result in a positive doping test. The health consequences of misuse of Proficor® as a doping agent cannot be predicted, and in such cases, harm to health cannot be excluded.

Excipients

The medicinal product Proficor® contains less than 1 mmol of sodium (23 mg) per ampoule; therefore, this medicinal product can be considered practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy. Reliable data on the effects of torasemide in pregnant women are lacking. Reproductive toxicity of torasemide has been demonstrated in animal studies. Torasemide crosses the placental barrier. Proficor® is not recommended during pregnancy and in women of childbearing potential who are not using contraception. Therefore, torasemide should be used during pregnancy only if strictly indicated and at the lowest effective dose. Diuretics are not appropriate for standard treatment regimens of 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 failure or renal failure, careful monitoring of electrolytes, hematocrit, and fetal development is essential.

Breastfeeding period. It is currently unknown whether torasemide or its metabolites are excreted in human or animal breast milk. Risk to newborns or infants cannot be excluded. Therefore, the use of torasemide during lactation is contraindicated. The decision to discontinue breastfeeding or to discontinue/withhold treatment with Proficor® should be based on the benefits of breastfeeding for the child and the benefits of treatment for the mother.

Fertility. Studies on the effect of torasemide on fertility in humans have not been conducted. Animal studies have not shown any adverse effects of torasemide on fertility.

Ability to affect reaction speed when driving or operating machinery

Even when used correctly, torasemide may impair reaction speed when driving or operating machinery. This is particularly relevant at the beginning of treatment, when the dose is increased, when switching medications, or when concomitant therapy or alcohol consumption is involved. Therefore, caution is required when driving or operating machinery during treatment with torasemide.

Method of Administration and Dosage

Edema and/or effusions due to heart failure. Treatment should be initiated with a single dose of 2 mL of Prophicor® solution, equivalent to 10 mg of torasemide per day. If the effect is insufficient, the single dose may be increased to 4 mL of Prophicor® solution, equivalent to 20 mg of torasemide. If the effect remains inadequate, short-term therapy (for no more than 3 days) with a daily dose of 8 mL of Prophicor® solution, equivalent to 40 mg of torasemide, may be used.

Acute pulmonary edema. Treatment should begin with intravenous administration of a single dose of 4 mL of Prophicor® solution, equivalent to 20 mg of torasemide. Depending on the response, this dose may be repeated at 30-minute intervals. The maximum daily dose of 20 mL of Prophicor® solution, equivalent to 100 mg of torasemide, must not be exceeded.

Special patient groups

Elderly patients. Treatment in this patient group does not require special dose adjustment. However, no specific studies comparing elderly patients with younger patients have been conducted.

Patients with hepatic impairment. Torasemide is contraindicated in patients with hepatic coma or precoma (see section "Contraindications"). Treatment in this patient group should be performed with caution, as increased plasma concentrations of torasemide may occur (see section "Pharmacokinetics").

Method of administration

The injection solution should be administered intravenously, slowly. Intra-arterial administration is prohibited. Only clear, particle-free solutions should be administered. Prophicor® must not be used if signs of solution degradation are present (e.g., presence of suspended particles) or if the ampoule is damaged. Each ampoule is for single use only. Any unused solution must be immediately disposed of according to local regulations. Prophicor® must not be mixed with other medicinal products intended for intravenous injection and/or infusion (see section "Incompatibilities"). During prolonged treatment, intravenous administration should be replaced as soon as possible with oral administration, as intravenous administration of torasemide is not recommended for longer than 7 days.

Children

The safety and efficacy of Prophicor® in children and adolescents under 18 years of age have not been established. Therefore, torasemide should not be used in this age group (see section "Special precautions for use").

Overdose

Symptoms of intoxication

The typical clinical picture of overdose is not well defined. Overdose may cause pronounced diuresis, including the risk of excessive loss of water and electrolytes, somnolence, confusion, symptomatic arterial hypotension, circulatory collapse, 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 fluid and electrolyte replacement (monitoring is required). Torasemide is not removed from blood by hemodialysis. Treatment in case of hypovolemia: fluid volume replacement. Treatment in case of hypokalemia: administration of potassium supplements. Treatment in case of circulatory collapse: place the patient in a supine position and, if necessary, initiate symptomatic therapy.

Anaphylactic shock (immediate measures). At the first signs of skin reactions (e.g., urticaria or skin redness), patient agitation, headache, excessive sweating, nausea, or cyanosis, venous catheterization should be performed; the patient should be placed in a horizontal position, airway ensured, and oxygen administered. If necessary, intensive therapy should be continued (including administration of epinephrine, glucocorticoids, and circulating blood volume replacement).

Adverse Reactions

Listed below are adverse reactions that may occur during the use of the medicinal product Prophicor®. The following frequency categories were used to classify the incidence of adverse reactions:

Very common (≥1/10);
Common (≥1/100 to <1/10);
Uncommon (≥1/1,000 to <1/100);
Rare (≥1/10,000 to <1/1,000);
Very rare (<1/10,000);
Frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders: Very rare – haemoconcentration, thrombocytopenia, erythropenia and/or leukopenia (see section "Special precautions for use").

Immune system disorders: Very rare – allergic reactions. Following intravenous administration, acute, potentially life-threatening hypersensitivity reactions (anaphylactic shock) may occur, requiring immediate medical intervention.

Metabolism and nutrition disorders: Common – exacerbation of metabolic alkalosis, hyperkalemia, hypokalemia in case of concomitant low-potassium diet, vomiting, diarrhea, excessive use of laxatives, as well as in patients with chronic liver dysfunction. Depending on dosage and duration of treatment, disturbances in water-electrolyte balance such as hypovolemia, hypokalemia and/or hyponatremia may occur (see section "Special precautions for use").

Nervous system disorders: Common – headache, dizziness (especially at the beginning of treatment); rare – paresthesia; very rare – syncope, cerebral ischemia, confusion.

Eye disorders: Very rare – visual disturbances.

Ear and labyrinth disorders: Very rare – tinnitus, hearing loss.

Cardiac disorders: Very rare – myocardial ischemia, arrhythmia, angina pectoris, acute myocardial infarction.

Vascular disorders: Very rare – thromboembolic complications, arterial hypotension, circulatory disorders in the heart, and disturbances of central circulation.

Gastrointestinal disorders: Common – gastrointestinal disturbances (e.g., loss of appetite, stomach pain, nausea, vomiting, diarrhea, persistent constipation), especially at the beginning of treatment; rare – xerostomia; very rare – pancreatitis.

Hepatobiliary disorders: Common – increased blood concentration of certain liver enzymes (γ-glutamyl transferase).

Skin and subcutaneous tissue disorders: Very rare – allergic skin reactions (e.g., pruritus, rash, photosensitization), severe skin reactions.

Musculoskeletal and connective tissue disorders: Common – muscle cramps (especially at the beginning of treatment).

Renal and urinary disorders: Rare – in cases of impaired micturition (e.g., due to prostatic hyperplasia), increased urine production may be accompanied by urinary retention and bladder distension.

General disorders and administration site conditions: Common – increased fatigue, general weakness (especially at the beginning of treatment).

Investigations: Common – increased blood concentrations of uric acid and lipids (triglycerides, cholesterol) (see section "Special precautions for use"); rare – increased blood concentrations of urea and creatinine (see section "Special precautions for use").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibilities. Prophicor® must not be mixed with other medicinal products intended for intravenous injection and/or infusion.

Packaging. 2 ml or 4 ml in an ampoule; 5 ampoules per blister, 1 or 2 blisters per carton, or 100 ampoules per carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhym-Kharkiv".

Manufacturer's address and location of operations.
36 Severina Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.