Trental^® (Tablets, Concentrate) Instructions for Use

ATC Code

C04AD03 (Pentoxifylline)

Active Substance

Pentoxifylline (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Vasodilator drug

Pharmacotherapeutic Group

Vasodilating agent

Pharmacological Action

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

The active substance of Trental^® – Pentoxifylline – is a xanthine derivative. Its mechanism of action is associated with the inhibition of phosphodiesterase and the 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.

It improves microcirculation in areas of impaired blood flow.

Treatment with Trental^® leads to an improvement in the symptoms of cerebrovascular disorders.

In occlusive peripheral arterial diseases, the use of Trental^® leads to an increased walking distance, elimination of nocturnal leg cramps, and disappearance of pain at rest.

Pharmacokinetics

Distribution

Pentoxifylline has a large V_d (168 L after a 30-minute infusion of 200 mg) and a high clearance of approximately 4500-5100 ml/min. Pentoxifylline and its metabolites do not bind to plasma proteins.

Metabolism

Pentoxifylline is intensively metabolized in erythrocytes and the liver. The plasma concentration of the main active metabolite 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (metabolite I) is twice 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. Consequently, the availability of the active substance is significantly greater.

Pentoxifylline is completely metabolized in the body.

Absorption

The T_1/2 of pentoxifylline after IV administration is 1.6 hours. More than 90% is excreted by the kidneys as unconjugated water-soluble metabolites.

Pharmacokinetics in Special Clinical Cases

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

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

Indications

• Occlusive peripheral arterial disease of atherosclerotic or diabetic origin (e.g., intermittent claudication, diabetic angiopathy);
• Trophic disorders (e.g., trophic leg ulcers, gangrene);
• Cerebrovascular disorders (consequences of cerebral atherosclerosis, such as impaired concentration, dizziness, memory deterioration), ischemic and post-stroke conditions;
• Circulatory disorders in the retina and choroid of the eye;
• Otosclerosis, degenerative changes against the background of vascular pathology of the inner ear and hearing loss.

ICD codes

Dosage Regimen

Concentrate

The dose and method of administration are determined by the severity of circulatory disorders, as well as based on the individual tolerance of Trental^®.

The dose is set by the doctor according to the individual characteristics of the patient.

The recommended dose is from 100 mg to 600 mg of Trental^®, diluted in 250 ml or 500 ml of 0.9% sodium chloride solution or Ringer’s solution, 1-2 times/day.

Compatibility with other infusion solutions must be tested separately; only clear solutions should be used.

100 mg of Trental^® should be administered over at least 60 minutes.

Trental^® for oral administration can be additionally prescribed along with infusion therapy. In this case, the total daily dose of Trental^® (IV infusion + oral administration) should not exceed 1200 mg.

Depending on concomitant diseases (e.g., chronic heart failure), it may be necessary to reduce the administered volumes. In such cases, the use of a special infusion pump for controlled infusion is recommended.

In more severe cases, especially in patients with severe pain at rest, with gangrene or trophic ulcers (Fontaine stages III-IV), prolonged IV infusion of Trental^® at a dose of 1200 mg over 24 hours is indicated. This dose can be divided into two infusions of 600 mg each, each of which should last at least 6 hours. In this case, the individual dose can be calculated by the formula: 0.6 mg of pentoxifylline per kg of body weight per hour. The daily dose calculated in this way will be 1000 mg of pentoxifylline for a patient weighing 70 kg and 1150 mg of pentoxifylline for a patient weighing 80 kg.

For maintenance therapy, a switch is made to oral administration of Trental^®.

In patients with renal failure (creatinine clearance less than 30 ml/min), it is necessary to reduce the dose by 30-50%, depending on the individual tolerance of Trental^® by the patient.

A dose reduction considering individual tolerance is necessary in patients with severe hepatic impairment.

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 cerebral vascular stenoses). In these cases, the dose may only be increased gradually.

Tablets

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 according to the individual characteristics of the patient.

The recommended dose of the drug is 100 mg (1 tablet) 3 times/day with a subsequent slow increase in the dose to 200 mg (2 tablets) 2-3 times/day. The maximum single dose is 400 mg. The maximum daily dose is 1200 mg.

In patients with impaired renal function (creatinine clearance less than 30 ml/min), the dose may be reduced to 100-200 mg (1-2 tablets)/day.

A dose reduction considering individual tolerance is necessary in patients with severe hepatic impairment.

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 cerebral vascular stenoses). In these cases, the dose may only be increased gradually.

Adverse Reactions

The following adverse reactions have been reported in clinical studies and during post-marketing use of the drug (frequency unknown).

Nervous system disorders headache, dizziness, aseptic meningitis, seizures.

Psychiatric disorders agitation, sleep disorders, anxiety.

Cardiovascular system disorders tachycardia, arrhythmia, decreased blood pressure, angina pectoris, flushing, bleeding (including bleeding from skin vessels, mucous membranes, stomach, intestines).

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

Hepatobiliary disorders intrahepatic cholestasis, increased activity of liver transaminases, increased activity of alkaline phosphatase.

Blood and lymphatic system disorders leukopenia/neutropenia, thrombocytopenia, pancytopenia, hypofibrinogenemia.

Eye disorders visual impairment, scotoma.

Skin and subcutaneous tissue disorders skin itching, skin rash, erythema (redness of the skin), urticaria, increased nail fragility, edema.

Immune system disorders anaphylactic/anaphylactoid reactions, angioedema, anaphylactic shock, bronchospasm.

Contraindications

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

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, see section “Dosage Regimen”); high risk of blood pressure reduction (including in severe coronary artery disease or hemodynamically significant cerebral vascular stenoses); chronic heart failure; impaired renal function (creatinine clearance less than 30 ml/min) (risk of accumulation and increased risk of adverse effects); severe hepatic impairment (risk of accumulation and increased risk of adverse effects, see section “Dosage Regimen”); after recent surgical interventions; with an increased risk of bleeding (e.g., in disorders of the blood coagulation system (risk of more severe bleeding), see section “Drug Interactions”); with simultaneous use of anticoagulants (including indirect anticoagulants [vitamin K antagonists], see section “Drug Interactions”); simultaneous use with platelet aggregation inhibitors (clopidogrel, eptifibatide, tirofiban, epoprostenol, iloprost, abciximab, anagrelide, NSAIDs [except selective COX-2 inhibitors], acetylsalicylic acid, ticlopidine, dipyridamole) (see section “Drug Interactions”); simultaneous use with oral hypoglycemic agents and insulin (see section “Drug Interactions”); simultaneous use with ciprofloxacin (see section “Drug Interactions”); simultaneous use with theophylline (see section “Drug Interactions”).

Use in Pregnancy and Lactation

The drug is not recommended for use during pregnancy due to insufficient data.

Pentoxifylline passes 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 hepatic impairment (risk of accumulation and increased risk of adverse effects).

Use in Renal Impairment

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

Pediatric Use

Contraindicated under the age of 18 years.

Geriatric Use

In elderly patients, a dose reduction may be required (increased bioavailability and decreased elimination rate).

Special Precautions

Treatment should be carried out under blood pressure control.

In diabetic patients taking hypoglycemic agents, the administration of large doses may cause pronounced hypoglycemia (adjustment of the doses of hypoglycemic agents and glycemic control may be required).

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

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

Patients with low and unstable blood pressure require a reduction in the dose of Trental^®.

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

The compatibility of the pentoxifylline solution with the infusion solution should be checked in each specific case.

During IV infusions, the patient should be in a lying position.

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 and Operate Machinery

Given the possible side effects (e.g., dizziness), caution should be exercised when driving vehicles and engaging in other potentially hazardous activities.

Overdose

Symptoms of overdose: weakness, sweating, nausea, cyanosis, dizziness, decreased blood pressure, tachycardia, fainting, drowsiness or agitation, arrhythmia, hyperthermia, areflexia, loss of consciousness, tonic-clonic convulsions, signs of gastrointestinal bleeding (coffee-ground vomiting).

Treatment is symptomatic: special attention should be paid to maintaining blood pressure and respiratory function. Seizures are controlled by the administration of diazepam.

At the first signs of overdose, administration of the drug should be stopped immediately. Ensure a lower position of the head and upper body.

Drug Interactions

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

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

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

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

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

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

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

When pentoxifylline is used concomitantly with platelet aggregation inhibitors (clopidogrel, eptifibatide, tirofiban, epoprostenol, iloprost, abciximab, anagrelide, NSAIDs [except for selective COX-2 inhibitors], acetylsalicylic acid, ticlopidine, dipyridamole), a potential additive effect may develop, increasing the risk of bleeding. Therefore, Pentoxifylline should be used with caution when administered simultaneously with the aforementioned platelet aggregation inhibitors (see the ” With caution” section).

Storage Conditions

The drug should be stored out of the reach of children, in a place protected from light, at a temperature between 8°C (46.4°F) and 25°C (77°F).

Shelf Life

Shelf life is 4 years. Do not use the drug after the expiration date.

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.