Trental^® 400 (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmfirma Sotex, CJSC (Russia)

Manufactured By

Zentiva, Private Limited (India)

Contact Information

PharmFirma Sotex ZAO (Russia)

ATC Code

C04AD03 (Pentoxifylline)

Active Substance

Pentoxifylline (Rec.INN registered by WHO)

Dosage Form

Trental® 400

Prolonged-release film-coated tablets, 400 mg: 20 or 60 pcs.

Dosage Form, Packaging, and Composition

Prolonged-release film-coated tablets white, oblong, biconvex; with the engraving “ATA” on one side.

Excipients: hydroxyethylcellulose, talc, povidone K25, magnesium stearate.

Shell composition hypromellose (HPMC 2910), titanium dioxide (E171), talc, macrogol 8000.

10 pcs. – blister packs (2) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.

The pack may have self-adhesive sticker(s) for first opening control.

Clinical-Pharmacological Group

Vasodilator drug

Pharmacotherapeutic Group

Peripheral vasodilators; purine derivatives

Pharmacological Action

The drug Trental^® 400 reduces blood viscosity and improves the rheological properties of blood (fluidity) by improving impaired erythrocyte deformability, reducing platelet and erythrocyte aggregation, lowering fibrinogen concentration, reducing leukocyte activity and decreasing leukocyte adhesion to the vascular endothelium.

The active substance of the drug Trental^® – Pentoxifylline – is a xanthine derivative. Its mechanism of action is associated with inhibition of phosphodiesterase and accumulation of cAMP in vascular smooth muscle cells and in blood cells.

Exerting a weak myotropic vasodilatory effect, Pentoxifylline slightly reduces total peripheral vascular resistance and slightly dilates coronary vessels.

Pentoxifylline has a weak positive inotropic effect on the heart.

Improves microcirculation in areas of impaired blood circulation.

Treatment with the drug Trental^® 400 leads to improvement of symptoms of cerebral circulation disorders.

In occlusive diseases of peripheral arteries, the use of the drug Trental^® 400 leads to an increase in walking distance, elimination of night cramps in the calf muscles and disappearance of pain at rest.

Pharmacokinetics

Absorption

After oral administration, Pentoxifylline is almost completely absorbed. The absolute bioavailability of the original substance is 19±13%.

The prolonged release of pentoxifylline allows maintaining its constant (peakless) concentration in the blood, which ensures better tolerability of the drug in this dosage form.

Metabolism

Pentoxifylline undergoes a “first-pass” effect through the liver. The concentration of the main active metabolite 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (metabolite I) in blood plasma is 2 times higher than the concentration of the original pentoxifylline. Metabolite I is in reversible biochemical redox equilibrium with pentoxifylline. Therefore, Pentoxifylline and metabolite I are considered together as an active unit. As a result, the availability of the active substance is significantly greater.

Pentoxifylline is completely metabolized in the body.

Excretion

The T_1/2 of pentoxifylline after oral administration is 1.6 h. More than 90% is excreted by the kidneys in the form of unconjugated water-soluble metabolites.

Pharmacokinetics in special clinical cases

In patients with impaired renal function, the excretion of metabolites is slowed down.

In patients with impaired liver function, the T_1/2 of pentoxifylline is prolonged and its absolute bioavailability increases.

Indications

• Occlusive disease of peripheral arteries of atherosclerotic or diabetic origin (for example, intermittent claudication, diabetic angiopathy);
• Trophic disorders (for example, trophic ulcers of the legs, gangrene);
• Cerebral circulation disorders (consequences of cerebral atherosclerosis, such as decreased concentration, dizziness, memory impairment), ischemic and post-stroke conditions;
• Circulatory disorders in the retina and choroid of the eye;
• Otosclerosis, degenerative changes against the background of pathology of the blood vessels of the inner ear and hearing loss.

ICD codes

Dosage Regimen

The drug is taken orally. The tablets should be swallowed whole with a sufficient amount of water during or immediately after a meal.

The dose is set by the doctor in accordance with the individual characteristics of the patient.

The recommended dose of the drug is 400 mg (1 tab.) 2-3 times/day. The maximum daily dose is 1200 mg (3 tab.).

In patients with impaired renal function (creatinine clearance below 30 ml/min) the dose may be reduced to 400-800 mg (1-2 tab.)/day.

Dose reduction taking into account individual tolerance is necessary in patients with severe liver dysfunction.

Treatment may be started with low doses in patients with low blood pressure, as well as in patients at risk due to possible blood pressure reduction (patients with severe coronary artery disease or with hemodynamically significant stenoses of cerebral vessels). In these cases, the dose may be increased only gradually.

Adverse Reactions

Below are the adverse reactions that have been observed in clinical studies and during post-marketing use of the drug (frequency unknown).

From the nervous system headache, dizziness, aseptic meningitis, convulsions.

Mental disorders agitation, sleep disorders, anxiety.

From the heart tachycardia, arrhythmia, decreased blood pressure, angina pectoris.

From the vessels flushing of the skin, bleeding (including bleeding from the skin vessels, mucous membranes, stomach, intestines).

From the digestive system xerostomia (dry mouth), anorexia, intestinal atony, feeling of pressure and fullness in the stomach area, nausea, vomiting, diarrhea, constipation, hypersalivation (increased salivation).

From the liver and biliary tract intrahepatic cholestasis, increased activity of liver transaminases, increased activity of alkaline phosphatase.

From the hematopoietic system leukopenia/neutropenia, thrombocytopenia, pancytopenia, hypofibrinogenemia.

From the organ of vision visual impairment, scotoma.

From the skin and subcutaneous tissues skin itching, skin rash, erythema (redness of the skin), urticaria, increased brittleness of nails, edema.

From the immune system anaphylactic/anaphylactoid reactions, angioedema, anaphylactic shock, bronchospasm.

Contraindications

• Hypersensitivity to pentoxifylline, other methylxanthines or to any excipient of the drug;
• Massive bleeding (risk of increased bleeding);
• Extensive hemorrhage in the retina (risk of increased bleeding);
• Cerebral hemorrhage;
• Acute myocardial infarction;
• Pregnancy (insufficient data);
• Breastfeeding period (insufficient data);
• Age under 18 years.

With caution the drug should be used in patients with severe cardiac arrhythmias (risk of worsening arrhythmia); arterial hypotension (risk of further decrease in blood pressure); chronic heart failure; peptic ulcer of the stomach and duodenum; impaired renal function (creatinine clearance less than 30 ml/min) (risk of accumulation and increased risk of adverse reactions); severe liver dysfunction (risk of accumulation and increased risk of adverse reactions); after recent surgical interventions; with an increased risk of bleeding (for example, in case of disorders of the blood coagulation system (risk of developing more severe bleeding)); with simultaneous use with anticoagulants (including indirect anticoagulants [vitamin K antagonists]); simultaneous use with platelet aggregation inhibitors (clopidogrel, eptifibatide, tirofiban, epoprostenol, iloprost, abciximab, anagrelide, NSAIDs [except selective COX-2 inhibitors], acetylsalicylic acid, ticlopidine, dipyridamole); simultaneous use with hypoglycemic agents for oral administration and insulin; simultaneous use with ciprofloxacin; simultaneous use with theophylline.

Use in Pregnancy and Lactation

The drug is not recommended for use during pregnancy, because there is insufficient data.

Pentoxifylline penetrates into breast milk in small amounts. If it is necessary to use the drug during lactation, breastfeeding should be discontinued (taking into account the lack of experience of use).

Use in Hepatic Impairment

With caution the drug should be used in patients with severe liver dysfunction (risk of accumulation and increased risk of adverse reactions).

Use in Renal Impairment

With caution the drug should be used in patients with impaired renal function (creatinine clearance less than 30 ml/min) (risk of accumulation and increased risk of adverse reactions.

Pediatric Use

Contraindicated for use under the age of 18 years (safety and efficacy of pentoxifylline in children have not been sufficiently studied).

Geriatric Use

In elderly patients, a reduction in the dose of the drug may be required (increased bioavailability and decreased elimination rate of pentoxifylline).

Special Precautions

Treatment should be carried out under blood pressure control.

In patients with diabetes mellitus taking hypoglycemic agents, prescribing the drug in high doses may cause severe hypoglycemia (correction of doses of hypoglycemic agents and glycemic control may be required).

When prescribing the drug Trental^® 400 simultaneously with anticoagulants, monitoring of the blood coagulation system parameters is necessary.

In patients who have recently undergone surgery, regular monitoring of hemoglobin and hematocrit is necessary.

In patients with low and unstable blood pressure, the dose of pentoxifylline must be reduced.

In elderly patients, a reduction in the dose of the drug may be required (increased bioavailability and decreased elimination rate of pentoxifylline).

Smoking may reduce the therapeutic effectiveness of the drug.

Use in pediatrics

The safety and efficacy of pentoxifylline in children have not been sufficiently studied.

Effect on ability to drive vehicles and mechanisms

Considering possible side effects (for example, dizziness), caution should be exercised when driving vehicles and engaging in potentially hazardous activities.

Overdose

Symptoms dizziness, nausea, vomiting of “coffee grounds” type, drop in blood pressure, tachycardia, arrhythmia, redness of the skin, loss of consciousness, chills, areflexia, tonic-clonic convulsions. If the above disorders occur, the patient should urgently consult a doctor.

Treatment symptomatic therapy. When the first signs of overdose appear (sweating, nausea, cyanosis), the drug should be discontinued immediately. If the drug has been taken recently, measures should be taken to prevent further absorption of the drug by its removal (gastric lavage) or by slowing absorption (for example, taking activated charcoal). Special attention should be paid to maintaining blood pressure and respiratory function. For convulsive seizures, diazepam is administered. A specific antidote is unknown.

Drug Interactions

Antihypertensive agents

Pentoxifylline increases the risk of arterial hypotension when used simultaneously with antihypertensive agents (for example, ACE inhibitors) or other drugs with a potential antihypertensive effect (for example, nitrates).

Drugs affecting the blood coagulation system

Pentoxifylline may enhance the effect of drugs affecting the blood coagulation system (direct and indirect anticoagulants, thrombolytics, antibiotics such as cephalosporins). When using pentoxifylline and indirect anticoagulants (vitamin K antagonists) together, cases of enhanced anticoagulant effect (risk of bleeding) have been observed in post-marketing studies. Therefore, at the beginning of pentoxifylline administration or when changing its dose, it is recommended to monitor the degree of anticoagulant effect in patients taking this combination of drugs, for example, to conduct regular INR monitoring.

Cimetidine

Cimetidine increases the concentration of pentoxifylline and active metabolite I in blood plasma (risk of adverse reactions).

Other xanthines

Concomitant administration with other xanthines may lead to excessive nervous excitement.

Hypoglycemic agents (insulins and hypoglycemic agents for oral administration)

The hypoglycemic effect of insulin or hypoglycemic agents for oral administration may be enhanced with the simultaneous use of pentoxifylline (increased risk of hypoglycemia). Strict monitoring of the condition of such patients is necessary, including regular glycemic control.

Theophylline

In some patients, with simultaneous use of pentoxifylline and theophylline, an increase in the concentration of theophylline is observed. This may subsequently lead to an increase or intensification of side effects associated with theophylline.

Ciprofloxacin

In some patients, with simultaneous use of pentoxifylline and ciprofloxacin, an increase in the concentration of pentoxifylline in blood plasma is observed. This may subsequently lead to an increase or intensification of side effects associated with the use of this combination.

Platelet aggregation inhibitors

With simultaneous use of pentoxifylline with platelet aggregation inhibitors (clopidogrel, eptifibatide, tirofiban, epoprostenol, iloprost, abciximab, anagrelide, NSAIDs [except selective COX-2 inhibitors], acetylsalicylic acid, ticlopidine, dipyridamole) a potential additive effect may develop, increasing the risk of bleeding. Therefore, due to the risk of bleeding, Pentoxifylline should be used with caution simultaneously with the above-mentioned platelet aggregation inhibitors (see section “With caution”).

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 4 years. Do not use after the expiration date indicated on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.