INSTRUCTION

for medical use of the medicinal product

 TORICARD

Composition:

Active substance: torasemide;

1 tablet contains: torasemide 5 mg or 10 mg;

Inactive substances: lactose, monohydrate; microcrystalline cellulose; crospovidone; povidone; magnesium stearate, purified water.

Dosage form. Tablets.

Basic physical and chemical properties:

Toricard, 5 mg tablets: White to nearly white, oval tablets with a scoring line and marks "5" and "6" on one side and mark Н on another.

Toricard, 10 mg tablets: White to nearly white, oval tablets with a scoring line and marks "5" and "7" on one side and mark Н on another.

Pharmaceutical group. Diuretic drugs. Highly active diuretics.

ATC Code: C03C A04.

Pharmacological properties.

Pharmacodynamics.

Torasemide is a loop diuretic; at low doses, used for antihypertensive treatment, it induces a mild diuretic and saluretic action.  At higher doses, torasemide induces a brisk diuresis, which is dose dependant. Torasemide shows maximum diuretic activity in 2-3 hours after the intake, which remains constant for almost 12 hours.

Pharmacokinetics.

Torasemide is absorbed rapidly and almost completely after oral administration, and peak serum levels are reached after 1-2 hours after the intake. Systemic bioavailability makes 80-90% and does not depend on food intake. Torasemide binding to plasma proteins is more than 99%, metabolites M₁, M₃ and M₅ – 86%, 95% and 97% respectively. The distribution volume is 16 litres. Torasemide is metabolised to three metabolites, M₁, M₃ and M₅ by stepwise oxidation and hydroxylation. M₅ is pharmacologically inactive, and M₁ and M₃ metabolites account for about 10% of the pharmacological action of the drug. The terminal half-life of torasemide (t_1/2) and its metabolites is three to four hours in healthy volunteers. Total clearance of torasemide is 40ml/min and renal clearance about 10ml/min. About 80% of the dose is excreted as unchanged torasemide (24 %) and its metabolites: М₁ (12 %), М₃ (3 %) and М₅ (41 %). In patients with renal failure, elimination half-life of torasemide is unchanged, and elimination half-life of M₃ and M₅ metabolites is continued. Torasemide and its metabolites are barely excreted through haemodialysis or hemofiltration. In patients with impaired liver function or heart failure, the half-life period of torasemide and M₅ metabolite is slightly extended, however, the accumulations of torasemide and its metabolites are not observed.

Clinical particulars.

Indications.

Essential hypertension as monotherapy or combined therapy with other antihypertensive agents.

Treatment of oedema due to congestive heart failure; kidney or liver diseases.

Contraindications.

• Hypersensitivity to torasemide, sulphonylureas and other excipients of the drug.
• Renal failure with anuria.
• Hepatic coma or pre-coma.
• Arterial hypotension.
• Hypovolemia. Hyponatremia. Hypokalemia.
• Severe urination disorder, e.g., due to prostate hypertrophy.
• Lactation.
• The childhood period (under 18 years).

Interaction with other medicinal products and other forms of interaction.

When torasemide is used concomitantly with cardiac glycosides, potassium or magnesium deficiency may increase sensitivity of the cardiac muscle to such drugs. Concomitant administration of torasemide and mineralo- and glucocorticoids, and laxatives increases risk of potassium deficiency.

Torasemide enhances the action of other antihypertensive agents, including inhibitors of angiotensin-converting enzyme (ACE). Concomitant use with ACE inhibitors may result in severe hypotension. This may be avoided by lowering the starting dose of the ACE inhibitor or reducing the dose of torasemide 2-3 days before the use of ACE inhibitors.

Torasemide may decrease the vasoconstriction effect of adrenaline, noradrenaline.

Torasemide reduces the effect of antidiabetic agents.

Torasemide, especially at high doses, may potentiate the nephrotoxic and ototoxic effects of aminoglycoside antibiotics (e.g. kanamycin, gentamycin, and tobramycin), the toxic effects of platinum drugs and nephrotoxic effects of cephalosporins.

Torasemide increases the effects of theophylline and curare-containing muscle relaxants.

Probenecid and NSAIDs (e.g. indomethacin, propionic acid derivatives) inhibit the diuretic and hypotensive effect of torasemide.

Concomitant use of torasemide and lithium drugs may increase the lithium concentration in blood plasma and enhance cardio and neurotoxicity of the last one.

During the therapy with salicylates in high doses, torasemide may enhance their toxic effect on the central nervous system.

In case of concomitant therapy with colestyramine, absorption of torasemide may be lowered, and as a result, its action may be decreased.

Precautions for use.

Hypokalaemia, hyponatraemia, and hypovolaemia must be treated before the use of the drug.

During long-term treatment with torasemide, regular monitoring of the electrolyte balance (especially in patients who simultaneously intake digitalis glycosides, glucocorticoidsteroids, mineralocorticoidsteroids or laxatives), levels of glucose, uric acid, creatinine and lipids in blood, is recommended.

Careful monitoring of patients with a tendency for hyperuricaemia and gout development is recommended. Carbohydrate metabolism in patients with latent or manifest diabetes mellitus should be monitored.

Due to the lack of clinical use experience, torasemide should not be prescribed in pathological changes of acid-base balance; pathological changes in the blood, such as thrombocytopenia or anaemia in patients without renal failure; along with lithium, aminoglycosides, cephalosporins; with impaired renal function, caused by nephrotoxic agents; children; elderly patients (no recommendations for dosage).

Torasemide should be used with caution in patients with liver disease accompanied by cirrhosis and ascites, because sudden changes in water-electrolytic balance may lead to hepatic coma. For patients of this group, torasemide (and other diuretics) therapy should be carried out in a hospital. To prevent hypokalaemia and metabolic acidosis, the drug should be prescribed along with aldosterone antagonist-agents or agents that lead to the retention of potassium in the body.

After the torasemide intake cases of ototoxicity were observed (tinnitus and hearing loss), which were reversible, but a direct connection with the use of the drug was not revealed.

When diuretics are prescribed, it is necessary to control clinical symptoms of electrolyte imbalance, hypovolemia, extrarenal azotemia and other disorders, such as dry mouth, thirst, weakness, drowsiness, agitation, muscle pain or seizures, myasthenia gravis, hypotension, oliguria, tachycardia, nausea, and vomiting. Redundant diuresis may result in dehydration, reduced blood volume, blood clots and blood vessels embolism, especially in the elderly.

Patients with water-electrolytic imbalance should stop taking the drug. After elimination of adverse reactions the therapy should be resumed, starting with lower doses.

When the drug is prescribed, it is necessary to conduct regular laboratory monitoring of potassium indicators and other electrolytes in the blood serum.

Information about dosage for patients with renal or liver impairment is limited. The drug should be used with caution in patients with hepatic insufficiency, as it may increase plasma concentrations of torasemide.

The drug contains lactose; therefore, it should not be prescribed for patients with hereditary deficiency of lactase, galactose intolerance or with impaired metabolism of glucose / galactose.

Pregnancy and lactation.

There is no sufficient experience of clinical use of torasemide during pregnancy, so the drug can be prescribed during pregnancy only if the expected benefit for the pregnant woman outweighs the potential risk for the foetus (according to vital indications and at the lowest possible effective dose). It is unknown whether torasemide gets into breast milk, so during the treatment breast-feeding should be discontinued.

Effects on ability to drive and operate machinery.

The drug can influence human reaction rate, reducing it while driving vehicles or operating machines. Therefore, during the treatment it is necessary to be careful when driving vehicles and doing other potentially hazardous activities that require high concentration and speed of psychomotor reactions.

Routes of administration and dosage.

Tablets should be taken in the morning, regardless of the meal; not masticated; followed by a small amount of liquid.

The duration of treatment depends on the disease.

Essential hypertension: For adults the dose of 2.5 mg of torasemide a day is recommended. If after two months of therapy with the dose of 2.5 mg of torasemide the normalization of blood pressure is not reached, the dose can be increased up to 5 mg (once a day).The maximum effect is reached in 3 months after the beginning of the treatment. Doses greater than 5 mg do not contribute to the antihypertensive effect.

Oedema. Therapy should be started with a dose of 5 mg per day. Usually this dose is considered to be supportive. If the daily dose of 5 mg is insufficient, a daily dose of 10 mg should be prescribed. Depending on the severity of the patient's state, the daily dose can be progressively increased up to 20 mg of torasemide (once a day).

Patients with hepatic insufficiency. Treatment of these patients should be performed with caution because of possible increased concentration of torasemide in blood plasma.

Patients with liver cirrhosis. The total initial dose is 5-10 mg once a day in concomitant use with aldosterone antagonist-agents or with diuretics that lead to the retention of potassium in the body. In the absence of the necessary diuretic effect, the dose should be doubled (10-20 mg daily) to achieve the desired effect.

Patients with renal insufficiency. The total initial dose is 20 mg once a day.

In the absence of the necessary diuretic effect, the dose should be doubled (40 mg daily) to achieve the desired effect.

Elderly patients. Special adjustment of the dose is not necessary.

Children.

There are no clinical data on the efficacy and safety of the drug treatment of children. It is not recommended to prescribe the drug for patients in this age category.

Overdose.

No typical picture of intoxication is known. Overdose may cause severe diuresis, including the risk of excessive loss of water and electrolytes, drowsiness, amentive syndrome (a form of impaired consciousness), symptomatic arterial hypotension, cardiovascular insufficiency and digestive tract disorders.

Treatment. No specific antidote is known. Symptoms and signs of intoxication usually disappear after the reduction of the dose or cancellation of treatment with torasemide, and respective replacement of fluid and electrolytes (monitoring is required!). Torasemide is not excreted from blood by hemodialysis. Treatment in case of hypovolemia: replacement of fluid volume. Treatment in case of hypokalemia: prescribing potassium.

Anaphylactic shock (immediate action). At the first sings of skin reactions (such as, urticaria or redness of the skin), the excited state of the patient, headache, sweating, nausea, cyanosis, the vein catheterization is carried out; the patient is placed in a horizontal position, the free flow of air is ensured and oxygen is administered. If necessary, epinephrine, solutions that replace fluid volume and glucocorticoid hormones are administered.

Adverse reactions.

Metabolism disorders: increased metabolic alkalosis; muscle spasms (especially at the beginning of treatment); increased concentration of uric acid, glucose and lipids (cholesterol, triglycerides) in the blood plasma; hypokalaemia during the concomitant diet with low potassium conсentration, in vomiting, diarrhoea, after redundant use of laxatives and in patients with chronic liver failure. Depending on the dosage and duration of the therapy, the water-electrolytic imbalance, e.g. hypovolemia, hypokalemia, hyponatremia may be developed. In significant loss of fluid and electrolytes due to enhanced urination arterial hypotension, headache, asthenia, somnolence may occur, especially at the beginning of treatment and in elderly patients.

Cardiovascular disorders: thrombosis, arterial hypotension, cardiac and cerebral ischemia with possible development of cardiac arrhythmias, stenocardia, acute myocardial infarction and syncope.

Digestive tract disorders: loss of appetite, nausea, vomiting, stomach pain, indigestion and diarrhoea, constipation, flatulence and pancreatitis.

Renal and urinary system: increased serum creatinine and urea in blood serum; in patients with urination disorders, such as prostatic hypertrophy, urinary retention and possible bladder overdistention may occur; micturition reflex.

Hepatobiliary system: increased level of some liver enzymes (γ-glutamyl transpeptidase) in blood plasma.

Blood and lymphatic system: reduced amount of thrombocytes, red blood cells and/or leukocytes.

Skin and subcutaneous tissue: allergic reactions (e.g. itching, rash, exanthema, photosensitivity).

General disorders: headache, dizziness, confusion, increased fatigue, weakness (especially at the beginning of treatment), dry mouth, paresthesia of extremities, visual disturbances, tinnitus, hearing loss.

Storage life. 2 years.

Storage conditions. Store in the original package at temperature not exceeding 30 °С.

Keep out of reach of children.

Package. 10 tablets in a blister; 3 blisters in a carton box.

Terms of dispensing. On prescription.

Manufacturer.

Hetero Labs Limited.

Manufacturer’s registered address.

Unit-III, Formulations Plot №. 22-110 IDA, Jeedimeetla, Hyderabad 500 055 Telangana, India

Applicant.

Ananta Medicare Ltd.

Applicant’s registered address.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

Date of last review. 26.04.18