INSTRUCTION

for medical use of the medicinal product

TORICARD

Composition:

active substance: torasemide;

1 tablet contains: torasemide 5 mg or 10 mg;

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

Pharmaceutical form. Tablets.

Basic physical and chemical properties:

Toricard, 5 mg tablets: white to off-white, oval tablets with a scoreline and mark "5" and "6" on one side and mark “Н” on another.

Toricard, 10 mg tablets: white to off-white, oval tablets with a scoreline and mark "5" and "7" on one side and mark “Н” on another.

Pharmacotherapeutic group. Diuretics. Highly diuretics. Simple preparations of sulphonamides.

ATC Code: C03C A04.

Pharmacological properties.

Pharmacodynamics.

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

Pharmacokinetics.

Torasemide is absorbed rapidly and almost completely after oral administration, and peak serum levels are reached after one to two hours after 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, such as 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 subjects. 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 the presence of 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 not excreted by haemodialysis or hemofiltration, completely. In patients with impaired liver function or heart failure the half-life period of torasemide and M₅ metabolite is slightly extended, however accumulation of torasemide and its metabolites are not observed.

Clinical particulars.

Indications.

Treatment of essential hypertension (as monotherapy or combined therapy with other antihypertensive agents).

Treatment of oedema due to congestive heart failure, hepatic or renal diseases.

Contraindications.

• Hypersensitivity to active substance, sulphonylureas and other excipients of the drug.
• Renal failure with anuria.
• Hepatic coma and pre-coma.
• Hypotension.
• Hypovolemia. Hyponatremia. Hypokalaemia.
• Severe urination disorder, e.g., due to prostate hypertrophy.
• Pregnancy, lactation.
• Children (under 18 years).
• Co-administration of aminoglycoside antibiotics or cephalosporins or renal failure after using other drugs causing kidney damage.
• Arrhythmia.

Interaction with other medicinal products and other forms of interaction.

When torasemide is used simultaneously with cardiac glycosides, a potassium and/or magnesium deficiency may increase sensitivity of the cardiac muscle to such drugs. Co-administration of mineralo- and glucocorticoids and laxatives increases the 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 transient hypotension. This may be minimized 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 arterial responsiveness to presser agents e.g. 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, tobramycin), the toxic effects of platinum drugs and nephrotoxic effects of cephalosporins.

Torasemide increases the effects of theophylline and curare-like drugs.

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

Co-administration of torasemide and lithium drugs may increase the blood lithium concentration and enhance cardio and neurotoxicity.

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

Co-administration of colestyramine may decrease absorption of torasemide as a result its action becomes low.

Precautions for use.

Hypokalaemia, hyponatraemia, hypovolaemia and micturition disorders must be eliminated before using of the drug.

On long-term treatment with torasemide, regular monitoring of the electrolyte balance (especially in patients who are co-administrated with digitalis glycosides, glucocorticoid steroids, mineralocorticoid steroids or laxatives), glucose, uric acid, creatinine and lipids in the blood,and blood cells (erythrocytes, leukocytes and platelets) is recommended.

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

Due to the lack of experience of clinical use, torasemide is not recommended 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; impaired renal function caused by nephrotoxic agents; children; elderly patients (dosage recommendations are not available).

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 promoting the retention of potassium in the body.

After torasemide intake there were observed ototoxicity phenomena (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 azotaemia 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 cause dehydration, reduced blood volume, blood clots and embolism blood vessels, especially in the elderly.

Patients with water-electrolytic imbalance should stop taking the drug. After elimination of adverse effects the therapy should be resumed from the 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 hepatic impairment is limited. For patients with hepatic insufficiency the drug should be used with caution, as it may increase plasma concentrations of torasemide.

The drug contains lactose. Therefore, the drug should not be administered to patients with hereditary deficiency of lactase, galactose intolerance or with impaired metabolism of glucose / galactose.

If intolerance to certain sugars has been identified, a doctor should be consulted before taking this medicinal product.

Pregnancy and lactation.

There is no sufficient experience of clinical use of torasemide during pregnancy. Whilst studies in the rat have shown no teratogenic effect, malformed foetuses have been observed after high doses in pregnant rabbits. Torasemide penetrates the foetal membrane and causes electrolyte disturbances. There is also a risk of neonatal thrombocytopenia. No studies have been conducted on excretion in breast milk. Consequently, torasemide is contraindicated in pregnancy and lactation.

Effects on ability to drive and use machines.

The drug can influence on human reaction rate. The drug reduces reaction rate when driving vehicle or operating machines. Therefore, in the course of treatment you must be careful when driving vehicle and doing other potentially hazardous activities that require high concentration and speed of psychomotor reactions.

Method of administration and dosage.

The tablets should be taken with a small amount of liquid in the morning, regardless of meals; do not masticate.

The duration of treatment depends on the course of 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 torasemide 2.5 mg the normalization of blood pressure is not reached, the dose can be increased up to 5 mg (once a day).The maximum effect is exhibited in 3 months after beginning the treatment. Doses higher 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 and renal impairment. Information on dose adjustment for patients with hepatic and renal impairment is limited. Treatment of patients with hepatic impairment should be performed with caution due to potential increased concentration of torasemide in blood plasma. Torasemide is contraindicated for patients with hepatic coma or precoma (see section "Contraindications").

Elderly. A special dose adjustment is not required.

Children.

There are no clinical data on the efficacy and safety of the drug for treatment of children. It is not recommended for patients of 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 hypotension, hypovolemia, hyponatremia, hypochloraemic alkalosis, hemoconcentration, loss of consciousness, cardiovascular failure and gastrointestinal disorders.

Treatment. No specific antidote is known. Symptoms and signs of overdose require the dose reduction or withdrawal of torasemide, and simultaneous replacement of the fluid and electrolytes (monitoring is required!). Torasemide is not excreted from blood by haemodialysis. Treatment in case of hypovolemia: replacement of the fluid volume. Treatment in case of hypokalaemia: prescribing potassium.

Anaphylactic shock (immediate action). At the first sings of skin reactions (such as, urticarial or redness of the skin), the excited state of patient, headache, sweating, nausea and 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 replacing the 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 in concomitant diet with low potassium content, in vomiting, diarrhea, after redundant use of laxatives and in patients with chronic liver failure. Depending on the dosage and duration of therapy, the water-electrolytic imbalance, e.g. hypovolaemia, hypokalaemia, hyponatremia may be developed. The potential hypotension, headache, asthenia, somnolence, especially at the beginning of treatment and in elderly patients, may occur in significant loss of fluid and electrolytes due to enhanced urination.

Cardiovascular disorders: thrombosis, hypotension, cardiac and cerebral ischemia with potential development of cardiac arrhythmias, stenocardia, acute myocardial infarction, syncope, extrasystole, palpation, tachycardia.

Gastrointestinal disorders: loss of appetite, nausea, vomiting, stomach pain, indigestion and diarrhea, constipation, flatulence, pancreatitis, xerostomia (dry mouth).

Renal and urinary system disorders: increased serum creatinine and urea in serum; in patients with urination disorders, such as prostatic hypertrophy, urinary retention and over-distention of the bladder, uresiesthesia.

Hepatobiliary system disorders: increased level of some liver enzymes (γ-glutamyltranspeptidase) in blood plasma

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

Skin and subcutaneous tissue disorders: allergic reaction (e.g. itching, rash, exanthema, photosensitivity), severe skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis).

Musculoskeletal system and connective tissue disorders: muscle spasms.

Nervous system disorders: headache, dizziness, weakness, paraesthesiae, confusion, drowsiness, increased activity, nervousness.

Respiratory system disorders: nosebleeds.

Eye disorders: visual disorders.

Ear disorders: tinnitus, deafness.

General disorders: increased fatigue, asthenia, thirst.

Shelf-life. 2 years.

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

Keep out of the reach of children.

Packaging. 10 tablets in a blister. 3 blisters in a carton box.

Terms of dispensing. On prescription.