Pentilin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PENTILIN (PENTILIN®)

Composition:

Active substance: pentoxifylline;

1 ml of solution contains 20 mg of pentoxifylline;

Excipients: disodium edetate, sodium chloride, sodium dihydrogen phosphate dihydrate, sodium hydrogen phosphate dihydrate, water for injections.

Medicinal form. Solution for injection.

Main physicochemical properties: clear, colorless solution, practically free of visible particles.

Pharmacotherapeutic group. Peripheral vasodilators. ATC code C04AD03.

Pharmacological properties.

Pharmacodynamics.

Pentoxifylline is a derivative of methylxanthine. The mechanism of action of pentoxifylline is associated with inhibition of phosphodiesterase and accumulation of cAMP in vascular smooth muscle cells, blood cells, as well as in other tissues and organs. Pentoxifylline inhibits platelet and erythrocyte aggregation, increases their flexibility, reduces elevated plasma fibrinogen concentration, and enhances fibrinolysis, thereby decreasing blood viscosity and improving its rheological properties. In addition, pentoxifylline exerts a weak myotropic vasodilatory effect, slightly reduces total peripheral vascular resistance, and demonstrates a positive inotropic effect. As a result of pentoxifylline administration, microcirculation and tissue oxygen supply are improved, most notably in the extremities and central nervous system (CNS), and to a moderate extent in the kidneys. The drug slightly dilates coronary vessels.

Pharmacokinetics.

The main pharmacologically active metabolite, 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (metabolite I), is detected in blood plasma at concentrations exceeding those of the unchanged substance by two-fold and exists in reversible biochemical equilibrium with it. Therefore, pentoxifylline and its metabolite should be considered as an active entity. The elimination half-life of pentoxifylline is 1.6 hours.

Pentoxifylline is completely metabolized; over 90% is excreted by the kidneys as non-conjugated, water-soluble, polar metabolites. Less than 4% of the administered dose is excreted in feces. In patients with severe renal impairment, metabolite excretion is delayed. In patients with hepatic dysfunction, prolonged elimination half-life of pentoxifylline has been observed.

Clinical characteristics.

Indications.

Atherosclerotic encephalopathy; ischemic cerebral stroke; dyscirculatory encephalopathy; peripheral circulation disorders due to atherosclerosis, diabetes mellitus (including diabetic angiopathy), inflammation; tissue trophic disorders associated with venous damage or microcirculation impairment (post-thrombophlebitic syndrome, trophic ulcers, gangrene, frostbite); obliterating endarteritis; angioneuropathies (Raynaud's disease); ocular circulation disorders (acute, subacute, chronic insufficiency of retinal and choroidal blood flow); vascular-origin inner ear function disorders accompanied by hearing loss.

Contraindications.

• Hypersensitivity to pentoxifylline, other components of the medicinal product, or to other methylxanthine group agents such as theophylline, caffeine, choline theophyllinate, aminophylline, or theobromine;
• Massive bleeding (risk of bleeding exacerbation);
• Hemorrhages into the retina or brain (risk of bleeding exacerbation); if retinal or cerebral hemorrhage occurs during pentoxifylline treatment, the drug must be discontinued immediately;
• Acute phase of myocardial infarction;
• Gastric and/or intestinal ulcer;
• Hemorrhagic diathesis;
• Pregnancy, breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Pentyl (pentoxifylline) may enhance the hypotensive effect of antihypertensive agents and other drugs capable of reducing arterial pressure.

Oral hypoglycemic agents, insulin

The blood glucose-lowering effect of insulin or oral antidiabetic agents may be enhanced. Therefore, patients receiving medication for diabetes mellitus should be under close monitoring.

Anticoagulants, antiplatelet agents

Concomitant administration of pentoxifylline with anticoagulants or antiplatelet agents may increase the risk of hemorrhage; therefore, prothrombin time should be measured more frequently when initiating or adjusting pentoxifylline dosage.

Potential additive effect with anticoagulants, platelet aggregation inhibitors

An additive effect with anticoagulants and platelet aggregation inhibitors may occur. Due to the increased risk of bleeding, concomitant use of pentoxifylline with platelet aggregation inhibitors (e.g., clopidogrel, eptifibatide, tirofiban, epoprostenol, iloprost, abciximab, anagrelide, nonsteroidal anti-inflammatory drugs (NSAIDs), except selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylates [acetylsalicylic acid], ticlopidine, dipyridamole) should be performed with caution.

Theophylline

Concomitant use of pentoxifylline and theophylline in some patients may lead to increased serum theophylline levels. Therefore, an increased frequency and severity of theophylline-related adverse reactions may occur.

Ketorolac, meloxicam

Concomitant use of pentoxifylline and ketorolac may prolong prothrombin time and increase the risk of bleeding. The risk of bleeding may also increase with concomitant use of pentoxifylline and meloxicam. Therefore, simultaneous treatment with these drugs is not recommended.

Ciprofloxacin

Ciprofloxacin inhibits hepatic metabolism of pentoxifylline; thus, concomitant administration of pentoxifylline and ciprofloxacin may result in increased serum pentoxifylline concentration. If concomitant therapy with pentoxifylline and ciprofloxacin is necessary, a 50% reduction in pentoxifylline dose is recommended.

Cimetidine

Concomitant use with cimetidine may significantly increase serum pentoxifylline concentration. Patients should be monitored for signs of pentoxifylline overdose. Other H2-receptor antagonists (famotidine, ranitidine, nizatidine) have considerably less effect on pentoxifylline metabolism.

Special precautions for use

At the first signs of an anaphylactic or anaphylactoid reaction, infusion of Pentilin must be stopped immediately and medical assistance should be sought.

When using Pentilin in patients with chronic heart failure, hemodynamic compensation should be achieved prior to treatment.

In patients with diabetes mellitus who are receiving insulin or oral antidiabetic agents, high doses of Pentilin may enhance the blood glucose-lowering effect of these medications (see section "Interaction with other medicinal products and other forms of interaction"). In such cases, the dose of insulin or oral antidiabetic agents should be reduced, and particularly careful monitoring of the patient is required.

Pentoxifylline may be administered to patients with systemic lupus erythematosus (SLE) or other connective tissue diseases only after a thorough assessment of potential risks and benefits.

Since there is a risk of developing aplastic anemia during pentoxifylline therapy, regular monitoring of complete blood counts is required.

In patients with impaired renal function (creatinine clearance less than 30 mL/min) or severe hepatic dysfunction, elimination of pentoxifylline may be delayed.

Particularly careful monitoring is necessary for:

• patients with severe cardiac arrhythmias;
• patients with myocardial infarction;
• patients with arterial hypotension;
• patients with severe atherosclerosis of cerebral and coronary arteries, especially in the presence of concomitant arterial hypertension and cardiac rhythm disturbances; in these patients, treatment with the drug may provoke angina attacks, arrhythmias, and arterial hypertension;
• patients with impaired renal function (creatinine clearance below 30 mL/min);
• patients with severe hepatic insufficiency;
• patients with a high risk of bleeding, for example, due to anticoagulant therapy or coagulation disorders (for bleeding, see section "Contraindications");
• patients with a history of gastric or duodenal ulcer, or patients who have recently undergone surgery (increased risk of bleeding, thus requiring regular monitoring of hemoglobin and hematocrit levels);
• patients for whom a reduction in arterial pressure poses a high risk (e.g., patients with severe ischemic heart disease or stenosis of vessels supplying blood to the brain);
• patients receiving concomitant treatment with pentoxifylline and vitamin K antagonists or platelet aggregation inhibitors (see section "Interaction with other medicinal products and other forms of interaction");
• patients receiving concomitant treatment with pentoxifylline and antidiabetic agents (see section "Interaction with other medicinal products and other forms of interaction");
• patients receiving concomitant treatment with pentoxifylline and ciprofloxacin (see section "Interaction with other medicinal products and other forms of interaction");
• patients receiving concomitant treatment with pentoxifylline and theophylline (see section "Interaction with other medicinal products and other forms of interaction").

Pentilin must be used under regular medical supervision.

The medicinal product contains sodium — 1.06 mmol (24.4 mg) of sodium per dose, which corresponds to 1.22% of the WHO recommended maximum daily intake of 2 g of sodium for adults. This should be taken into account when prescribing to patients on a sodium-restricted diet.

The product should be used immediately after opening the ampoule to avoid microbiological contamination. If the product is not used immediately, storage duration and conditions must not exceed 24 hours at a temperature of 2 to 8 °C, unless the solution for infusion was prepared under controlled and validated aseptic conditions. The user is responsible for the storage of the product after opening the ampoule.

Use during pregnancy or breastfeeding

There is insufficient experience with the use of Pentilin in pregnant women. Therefore, Pentilin is not recommended during pregnancy.

Pentoxifylline passes into breast milk in small amounts. If treatment with Pentilin is required, breastfeeding should be discontinued.

Effect on the ability to drive and use machines

No effect.

Method of Administration and Dosage

Dosage

Intravenous infusions are the most effective and best-tolerated forms of parenteral administration of the drug. The dosage regimen is determined by the physician and depends on the severity of circulatory disorders, body weight, and treatment tolerance. Infusion should be administered only if the solution is clear.

Recommended treatment regimens for adults:

1. Intravenous infusion of 100–600 mg of pentoxifylline in 100–500 mL of 0.9% sodium chloride solution once or twice daily. The duration of intravenous drip infusion is 60–360 minutes; thus, administration of 100 mg pentoxifylline should last at least 60 minutes. The infusion may be supplemented with oral administration of Pentilin (400 mg), ensuring that the total daily dose (infusion and oral) does not exceed 1200 mg.
2. In severe patient condition (especially persistent pain, gangrene, or trophic ulcers), Pentilin infusion may be administered continuously over 24 hours. In this regimen, the dose should be calculated at 0.6 mg/kg/hour. The calculated daily dose is 1000 mg for a patient weighing 70 kg and 1150 mg for a patient weighing 80 kg. Regardless of body weight, the maximum daily dose is 1200 mg. The volume of infusion solution is individually adjusted based on concomitant diseases and patient status and averages 1–1.5 L per day.
3. In individual cases, the drug may be administered by intravenous injection of 5 mL (100 mg). The injection should be performed slowly over 5 minutes with the patient in a supine position.

Renal Impairment

If creatinine clearance is less than 30 mL/min (0.5 mL/sec), the drug dosage should be individually adjusted by reducing it by approximately 30–50% of the normally recommended dose.

Hepatic Impairment

Dose reduction may be required in cases of severe hepatic dysfunction. The decision on dosage reduction should be made by the physician based on individual drug tolerance.

Elderly Patients

No dosage adjustment is required for elderly patients.

Method of Administration

Intravenous administration.

Duration of Treatment

The duration of parenteral treatment course is determined by the physician. After improvement in the patient's condition, continuation of therapy with the tablet form of the medicinal product is recommended.

Children

Pentoxifylline must not be administered to children.

Overdose

Initial symptoms of acute pentoxifylline overdose include nausea, dizziness, tachycardia, or decreased arterial pressure. Additionally, symptoms such as fever, excitement, hot flushes, loss of consciousness, areflexia, arrhythmia, somnolence, restlessness, tonic-clonic seizures, and coffee-ground emesis indicating gastrointestinal bleeding may develop.

Treatment. To treat acute overdose and prevent complications, pentoxifylline administration must be immediately discontinued. Symptomatic treatment should be initiated as needed, including support or regulation of arterial pressure, respiratory support, and management of seizures.

Adverse reactions.

Adverse reactions that may occur during pentoxifylline treatment are listed in the table below.

The frequency of adverse reactions is defined according to the following categories:

• very common: >1/10;
• common: >1/100, <1/10;
• uncommon: >1/1000, <1/100;
• rare: >1/10000, <1/1000;
• very rare: <1/10000, including single cases;
• unknown (frequency cannot be estimated from available data).

Frequency of adverse reactions by system organ class:

Most adverse reactions are dose-dependent. When the dose is reduced, adverse reactions decrease or disappear completely.

If severe adverse reactions occur, treatment should be discontinued.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Incompatibilities.

The medicinal product must not be mixed with other solutions in the same container except for those specified in the section "Instructions for use and dosage".

Packaging. 5 ml (100 mg) of solution for injection in a vial; 5 vials in a blister pack; 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia / KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.