Pentoxifylline (Tablets) Instructions for Use

ATC Code

C04AD03 (Pentoxifylline)

Active Substance

Pentoxifylline (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Drug improving microcirculation. Angioprotector

Pharmacotherapeutic Group

Vasodilating agent

Pharmacological Action

Pentoxifylline is a vasodilating agent. It improves microcirculation and the rheological properties of blood.

The mechanism of action is associated with the inhibition of phosphodiesterase (PDE) and an increase in the content of cyclic AMP in platelets and ATP in erythrocytes with simultaneous saturation of the energy potential, which in turn leads to vasodilation, a decrease in total peripheral vascular resistance, and an increase in stroke and minute blood volume without a significant change in heart rate.

Pentoxifylline reduces blood viscosity, increases the elasticity of the erythrocyte membrane (by acting on pathologically altered erythrocyte deformability), reduces the aggregation of erythrocytes, platelets, and neutrophils, reduces the content of fibrinogen in the blood, reduces the adhesiveness of leukocytes to the vascular endothelium, reduces the stimulation of leukocytes and, as a result, the destruction of the endothelium.

It improves microcirculation in areas of impaired blood circulation. In occlusive diseases of peripheral arteries (intermittent claudication), it leads to an increase in walking distance, elimination of night cramps in the calf muscles and pain at rest.

Pharmacokinetics

Absorption

After oral administration, Pentoxifylline is almost completely absorbed from the gastrointestinal tract.

Distribution and Metabolism

Pentoxifylline undergoes first-pass metabolism in the liver with the formation of 2 main pharmacologically active metabolites: 1-5-hydroxyhexyl-3,7-dimethylxanthine (metabolite I) and 1-3-carboxypropyl-3,7-dimethylxanthine (metabolite V). The plasma concentrations of metabolite I and V are 5 and 8 times higher, respectively, than that of 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.

It is excreted in breast milk.

Elimination

The elimination half-life (T_1/2) is 1.6 hours. Pentoxifylline is excreted mainly by the kidneys – 94% in the form of metabolites (mainly metabolite V), through the intestines – 4%; up to 90% of the dose is excreted within the first 4 hours.

Pharmacokinetics in Special Clinical Cases

In severe renal impairment, the excretion of metabolites is slowed.

In hepatic impairment, an increase in T_1/2 and an increase in bioavailability are noted.

Indications

• Occlusive peripheral arterial disease of atherosclerotic or diabetic origin (e.g., intermittent claudication, diabetic angiopathy);
• Cerebrovascular disorders (consequences of cerebral atherosclerosis, such as impaired concentration, dizziness, memory deterioration), ischemic and post-stroke conditions;
• Trophic tissue disorders due to impaired arterial or venous microcirculation (trophic ulcers, post-thrombophlebitic syndrome, frostbite, gangrene);
• Circulatory disorders in the ocular vessels (acute and chronic circulatory insufficiency in the retina or choroid);
• Impaired function of the middle ear of vascular origin, accompanied by hearing loss.

ICD codes

Dosage Regimen

Tablets

The tablets are taken orally, without chewing, regularly, at the same time, preferably during or after meals, with a sufficient amount of water.

The drug is started at 200 mg (2 tablets) 3 times/day during the first week. In case of sharp arterial hypotension and symptoms of irritation from the gastrointestinal tract or central nervous system, the initial dose is reduced to 100 mg (1 tablet) 3 times/day.

For course treatment, 100 mg (1 tablet) 3 times/day is prescribed. The maximum daily dose is 1200 mg/day.

For patients with low blood pressure, as well as persons at risk due to a possible sharp decrease in blood pressure (patients with severe coronary artery disease or with hemodynamically significant stenoses of cerebral vessels), treatment with Pentoxifylline Zentiva should be started with low doses with a subsequent gradual increase in the daily dose.

Stage II occlusive peripheral arterial disease (intermittent claudication): the daily dose for this category of patients is 1200 mg/day, preferably in the form of sustained-release tablets of 400 mg 3 times/day or 600 mg 2 times/day.

Patients with hepatic impairment

When using Pentoxifylline Sanofi in patients with severe hepatic impairment, caution should be exercised; a possible dose reduction should be carried out taking into account individual tolerance of the drug.

Patients with renal impairment

When using Pentoxifylline Sanofi in patients with a CrCl below 30 ml/min, caution should be exercised. The dose of Pentoxifylline Sanofi may be reduced by 50-70%.

Children and adolescents

The use of Pentoxifylline Sanofi in patients under 18 years of age is contraindicated. The safety and efficacy of Pentoxifylline Sanofi in this age group have not been established.

Adverse Reactions

When using Pentoxifylline Sanofi, the adverse effects listed below may occur, which are divided by system-organ classes in accordance with the MedDRA classification. The WHO classification was used to indicate the frequency of adverse effects: very common (≥10%); common (≥1% and <10%); uncommon (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%); frequency unknown (it is not possible to determine the frequency of the adverse effect from the available data).

Nervous system disorders: frequency unknown – headache, dizziness, seizures, aseptic meningitis.

Psychiatric disorders: frequency unknown – agitation, sleep disorders, anxiety.

Cardiac disorders: frequency unknown – tachycardia, arrhythmia, angina pectoris, decreased blood pressure.

Vascular disorders: frequency unknown – flushing, bleeding (including bleeding from skin vessels, mucous membranes, gastrointestinal bleeding, nosebleeds).

Skin and subcutaneous tissue disorders: frequency unknown – itching, erythema (redness of the skin), urticaria, edema, increased nail brittleness.

Gastrointestinal disorders: frequency unknown – anorexia, intestinal atony, epigastric discomfort, abdominal bloating (feeling of stomach fullness), vomiting, diarrhea, dry mouth, constipation, hypersalivation (increased salivation).

Hepatobiliary disorders: frequency unknown – intrahepatic cholestasis, increased ALT and AST activity, alkaline phosphatase.

Eye disorders: frequency unknown – visual impairment, scotoma.

Blood and lymphatic system disorders: frequency unknown – thrombocytopenia, leukopenia/neutropenia, pancytopenia, hypofibrinogenemia.

Immune system disorders: frequency unknown – anaphylactic/anaphylactoid reactions, angioedema, anaphylactic shock, bronchospasm.

Contraindications

• Hypersensitivity to pentoxifylline, other methylxanthine derivatives or other components of the drug;
• Acute myocardial infarction;
• Massive bleeding (risk of increased bleeding);
• Retinal hemorrhage (risk of increased bleeding);
• Acute hemorrhagic stroke;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established);
• Fructose intolerance, lactose intolerance, lactase deficiency, sucrase/isomaltase deficiency, glucose-galactose malabsorption syndrome (the drug contains lactose and sucrose).

Caution should be exercised when using the drug in patients with a pronounced decrease in blood pressure (risk of further decrease in blood pressure) and hemodynamically significant cardiac arrhythmias; chronic heart failure (CHF); severe hepatic impairment (risk of accumulation and increased risk of adverse effects); renal impairment with CrCl less than 30 ml/min (risk of accumulation and increased risk of adverse effects); peptic ulcer of the stomach and duodenum; with an increased tendency to bleeding, for example, as a result of the use of indirect anticoagulants (vitamin K antagonists) or disorders of the blood coagulation system (risk of developing more severe bleeding); after recent surgery (risk of bleeding); with proliferative diabetic retinopathy; simultaneously with hypoglycemic agents (insulin and oral hypoglycemic agents), ciprofloxacin and theophylline.

Use in Pregnancy and Lactation

The use of Pentoxifylline Sanofi during pregnancy is contraindicated.

The use of Pentoxifylline Sanofi during breastfeeding is contraindicated, since the active substance is excreted in breast milk. If it is necessary to take the drug, breastfeeding should be avoided.

Use in Hepatic Impairment

When using Pentoxifylline Sanofi in patients with severe hepatic impairment, caution should be exercised; a possible dose reduction should be carried out taking into account individual tolerance of the drug.

Use in Renal Impairment

When using Pentoxifylline Sanofi in patients with a CrCl below 30 ml/min, caution should be exercised. The dose of Pentoxifylline Sanofi may be reduced by 50-70%.

Pediatric Use

The use of Pentoxifylline Sanofi in patients under 18 years of age is contraindicated. The safety and efficacy of Pentoxifylline Sanofi in this age group have not been established.

Geriatric Use

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

Special Precautions

Treatment should be carried out under blood pressure control.

In diabetic patients taking hypoglycemic agents, taking Pentoxifylline Sanofi in high doses may cause hypoglycemia (dose adjustment required).

When prescribing Pentoxifylline Sanofi simultaneously with anticoagulants, it is necessary to carefully monitor the parameters of the blood coagulation system.

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

For patients with low and unstable blood pressure, the dose of Pentoxifylline Sanofi should be selected individually.

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

When using Pentoxifylline Sanofi in patients with severe hepatic impairment, caution should be exercised. Given the risk of drug accumulation and an increased risk of adverse effects, dose reduction should be carried out taking into account individual tolerance.

Patients with severe renal impairment (CrCl below 30 ml/min) taking Pentoxifylline Sanofi require careful medical supervision.

If retinal hemorrhages occur in patients during the use of the drug, the drug should be discontinued immediately.

Smoking may reduce the therapeutic efficacy of Pentoxifylline Sanofi.

Pentoxifylline Sanofi contains lactose and sucrose, therefore, it is contraindicated in patients with fructose intolerance, lactose intolerance, lactase deficiency, sucrase/isomaltase deficiency, glucose-galactose malabsorption.

Use in pediatrics

The use of Pentoxifylline Sanofi in children and adolescents under 18 years of age is contraindicated. The safety and efficacy of Pentoxifylline Sanofi in this age group have not been established.

Overdose

Symptoms: dizziness, nausea, coffee-ground vomit, pronounced decrease in blood pressure, tachycardia, arrhythmia, redness of the skin, loss of consciousness, chills, areflexia, tonic-clonic convulsions.

If the above disorders occur, it is necessary to consult a doctor urgently.

Treatment: treatment is symptomatic. 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 removing it (gastric lavage) or slowing absorption (e.g., 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

Pentoxifylline Sanofi may enhance the decrease in blood pressure when used concomitantly with antihypertensive agents (e.g., ACE inhibitors) or other drugs with a potential hypotensive effect (e.g., nitrates).

Pentoxifylline Sanofi may enhance the effect of drugs affecting the blood coagulation system (direct and indirect anticoagulants, thrombolytics, antibiotics such as cephalosporins). In post-marketing studies, cases of enhanced anticoagulant effect (risk of bleeding) have been reported with the combined use of pentoxifylline and indirect anticoagulants (vitamin K antagonists). Therefore, at the start of pentoxifylline or when changing its dose, it is recommended to monitor the degree of anticoagulant effect in patients taking this combination of drugs (e.g., perform regular INR monitoring).

Cimetidine may increase the plasma concentration of pentoxifylline (risk of adverse reactions).

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 simultaneous use of Pentoxifylline Sanofi (increased risk of hypoglycemia). The condition of such patients should be strictly monitored, including regular glycemic control.

In some patients, with simultaneous use of Pentoxifylline Sanofi and theophylline, an increase in the plasma concentration of theophylline is observed. This may subsequently lead to an increase in the frequency of adverse reactions associated with theophylline.

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

When used concomitantly, Pentoxifylline Sanofi may enhance the effect of valproic acid.

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 Sanofi should be used with caution simultaneously with the above-mentioned platelet aggregation inhibitors.

Storage Conditions

The drug should be stored in a place inaccessible to children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 5 years.

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.