Pentylone

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

Composition:

Active substance: pentoxifylline;

One prolonged-release tablet contains 400 mg of pentoxifylline;

Excipients: hypromellose, polyethylene glycol 6000, magnesium stearate, colloidal anhydrous silicon dioxide;

Coating: hypromellose, polyethylene glycol 6000, titanium dioxide (E 171), talc.

Dosage form. Prolonged-release tablets.

Main physicochemical properties: oval, white, biconvex tablets coated with a film coating.

Pharmacotherapeutic group. Peripheral vasodilators. ATC code C04AD03.

Pharmacological properties.

Pharmacodynamics.

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 produces a weak myotropic vasodilatory effect, slightly reduces total peripheral vascular resistance, and has 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.

Absorption.

After oral administration, pentoxifylline is rapidly and completely absorbed from the gastrointestinal tract. Peak plasma concentration is reached within 2–4 hours.

Distribution.

After administration, pentoxifylline is slowly released over 10–12 hours, thus maintaining a steady plasma level for approximately 12 hours.

According to various sources, the volume of distribution, through which pentoxifylline is distributed very rapidly after absorption, ranges from 168 ± 82.3 L to 376 ± 135 L. Pentoxifylline binds to erythrocyte membranes and is rapidly metabolized. To date, no significant binding of pentoxifylline to plasma proteins has been reported.

Metabolism.

Pentoxifylline is primarily metabolized in the liver and to a lesser extent in erythrocytes. After complete absorption, pentoxifylline undergoes first-pass metabolism. The absolute bioavailability of pentoxifylline is 20–30%. Through reduction (by α-ketoreductase), pentoxifylline breaks down into pharmacologically active metabolite 1, and via oxidation into several other metabolites, among which pharmacologically active metabolite 5 is particularly important. The concentration of the main active metabolite (1-(5-hydroxyhexyl)-3,7-dimethylxanthine) exceeds that of pentoxifylline by twofold; both substances are mutually biochemically balanced. Therefore, both pentoxifylline and its metabolite are considered active components, and the bioavailability of the metabolite is notably higher than that of pentoxifylline.

Elimination.

The elimination half-life of pentoxifylline is approximately 1.8 hours, and that of its metabolites is 1–1.6 hours.

Pentoxifylline is completely metabolized, and more than 90% of the administered dose is excreted via the kidneys as non-conjugated, water-soluble polar metabolites. Approximately 94% and 4% of pentoxifylline are excreted in the form of metabolites in urine and feces, respectively. About 2% of the administered dose is excreted unchanged as pentoxifylline. Excretion of metabolites is delayed in patients with severe renal impairment.

The elimination half-life and absolute bioavailability of pentoxifylline may increase in patients with impaired liver function.

Clinical characteristics.

Indications.

Improvement of the pain-free walking distance in patients with chronic occlusive disease of peripheral arteries at Fontaine stage IIb (intermittent claudication), when other measures such as exercise training, angioplasty, and/or revascularization procedures cannot be performed or are not indicated.

Contraindications.

Pentilin is contraindicated in the following cases:

• Hypersensitivity to pentoxifylline or any other component of the medicinal product;
• Hypersensitivity to similar agents, compounds of the xanthine derivatives group (theophylline, caffeine, choline theophyllinate, aminophylline, or theobromine);
• Acute myocardial infarction;
• Porphyria;
• Conditions associated with an increased risk of bleeding;
• Hemorrhagic stroke;
• Pregnancy or breastfeeding period;
• Severe arrhythmia;
• Gastric and/or intestinal ulcers;
• Hemorrhagic diathesis;
• Significant hemorrhage;
• Retinal hemorrhage (if retinal hemorrhage occurs during treatment with pentoxifylline, the treatment should be discontinued immediately).

Interaction with other medicinal products and other forms of interaction.

Food intake does not affect the efficacy of the tablets; on the contrary, it may reduce the frequency of adverse reactions during treatment.

Concomitant use of pentoxifylline and antihypertensive agents enhances the effect of the latter, thus requiring appropriate adjustment of antihypertensive doses.

Concomitant use with adrenergic agents and ganglion blockers may result in a significant decrease in arterial pressure. Simultaneous use of adrenergic substances or xanthines may lead to central nervous system stimulation.

Anticoagulants, antiplatelet agents.

Pentoxifylline increases the frequency of hemorrhagic complications in patients concurrently treated with anticoagulants, antiplatelet, and thrombolytic agents. In patients receiving anticoagulants concomitantly, prothrombin time should be measured more frequently.

During the post-marketing period, cases of increased anticoagulant activity have been reported in patients who received pentoxifylline and vitamin K antagonists simultaneously. When initiating or changing the dosage of pentoxifylline, monitoring of anticoagulant activity in this patient group is recommended.

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 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) with pentoxifylline should be performed with caution.

Cimetidine.

Concomitant administration of cimetidine results in a significant increase in pentoxifylline serum concentration. Careful monitoring for possible signs of pentoxifylline overdose is required. Other H2-receptor antagonists (famotidine, ranitidine, and nizatidine) have considerably less effect on pentoxifylline metabolism.

Theophylline.

Concomitant administration of pentoxifylline and theophylline may lead to an increased serum concentration of theophylline. Therefore, serum theophylline levels should be monitored, and the dose reduced if necessary.

Ketorolac, meloxicam.

Concomitant use of pentoxifylline and ketorolac may lead to an increase in prothrombin time and increase the risk of bleeding. The risk of bleeding may also be increased when pentoxifylline is used concomitantly with meloxicam. Therefore, concomitant treatment with these agents is not recommended.

Ciprofloxacin.

Ciprofloxacin inhibits the hepatic metabolism of pentoxifylline; thus, concomitant use of pentoxifylline and ciprofloxacin may lead to increased serum concentrations of pentoxifylline. When concomitant treatment with pentoxifylline and ciprofloxacin is necessary, it is recommended to reduce the dose of pentoxifylline by half.

Oral antidiabetic agents, insulin.

Pentilin may affect the hypoglycemic effects of insulin and oral antidiabetic agents. Enhanced reduction of blood glucose levels is possible; therefore, patients with diabetes mellitus should be monitored by checking blood glucose levels at intervals individually determined for each patient.

Special precautions for use.

The drug must be used under continuous medical supervision.

If the first signs of an anaphylactic/anaphylactoid reaction occur, treatment with pentoxifylline should be discontinued immediately and medical help should be sought.

Particular caution and careful medical monitoring are required for patients with cardiac arrhythmias, arterial hypotension, coronary sclerosis, or those who have experienced myocardial infarction or undergone surgical procedures.

When prescribing pentoxifylline to patients with chronic heart failure, a compensated phase of circulation should be achieved prior to treatment initiation.

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

Due to the risk of bleeding when pentoxifylline is used concomitantly with oral anticoagulants, careful monitoring and frequent control of blood coagulation parameters (International Normalized Ratio, INR) are required.

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

In diabetic patients receiving insulin or oral antidiabetic agents, high doses of pentoxifylline may potentiate the effect of these drugs on blood glucose levels (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.

In patients with renal impairment (creatinine clearance less than 30 mL/min) or severe hepatic dysfunction, elimination of pentoxifylline may be delayed. Patients with renal impairment. In patients with renal impairment (creatinine clearance less than 30 mL/min), dose titration to 50–70% of the standard dose should be performed based on individual tolerability; for example, pentoxifylline 400 mg twice daily instead of 400 mg three times daily.

Patients with severe hepatic dysfunction. In patients with severe hepatic dysfunction, the decision to reduce the dose should be made by the physician, taking into account the severity of the disease and individual patient tolerability.

Particularly careful monitoring is required for:

• patients with severe cardiac arrhythmias;
• patients with myocardial infarction;
• patients with arterial hypotension;
• patients with significant atherosclerosis of cerebral and coronary vessels, especially when associated with arterial hypertension and cardiac rhythm disturbances. In these patients, treatment with the drug may provoke angina attacks, arrhythmias, and arterial hypertension;
• patients with renal impairment (creatinine clearance below 30 mL/min);
• patients with severe hepatic impairment;
• patients with a high predisposition to bleeding, for example, due to anticoagulant therapy or coagulation disorders. For information on bleeding, see section "Contraindications";
• patients with a history of peptic ulcer of the stomach or duodenum, and patients who have recently undergone surgery (increased risk of bleeding, thus requiring regular monitoring of hemoglobin and hematocrit levels);
• 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").

Use during pregnancy or breastfeeding.

Since there is insufficient experience with the use of pentoxifylline in pregnant women, it should not be administered during pregnancy.

During lactation, pentoxifylline passes into breast milk. However, the infant receives only negligible amounts. Therefore, it is unlikely that the use of pentoxifylline during breastfeeding will have any effect on the infant.

Effect on ability to drive and use machines.

Pentilin has negligible or no influence on the ability to drive a car or operate other machinery. However, in individual patients, it may cause dizziness and thus indirectly reduce psychomotor performance required for driving a car or operating machinery. Until patients determine how they react to the treatment, they should refrain from driving a car or operating machinery.

Dosage and Administration

Dosage

The dosage of the medicinal product should be determined by a physician according to individual patient characteristics and severity of the disease.

If not otherwise prescribed, the recommended dose is 1 prolonged-release tablet of Pentilin three times daily (equivalent to 1200 mg of pentoxifylline per day). Daily doses exceeding 1200 mg do not provide additional therapeutic benefits. After improvement of the clinical condition, the daily dose may be reduced to 1 tablet of 400 mg twice daily. For mild forms of the disease, initial treatment with 1 tablet of 400 mg twice daily is sufficient.

Dosage adjustment is required for patients with low or unstable arterial blood pressure.

Renal Impairment

In patients with creatinine clearance less than 30 mL/min, doses should be titrated to 50–70% of the standard dose, based on individual tolerability. For example, pentoxifylline 400 mg twice daily instead of 400 mg three times daily. For patients undergoing hemodialysis, treatment should be initiated at a daily dose of 400 mg, with gradual dose escalation at intervals of at least 4 days up to the usual recommended dose.

Hepatic Impairment

Dose reduction may be necessary in patients with severe hepatic dysfunction. The decision to reduce the dose should be made by a physician, taking into account the severity of the disease and individual patient tolerability.

Elderly Patients

Dosage adjustment is not required for elderly patients.

Administration

Oral use. Prolonged-release tablets should be swallowed whole (without chewing) during or after meals, with sufficient water.

Duration of Treatment

Although a positive effect may be expected only after 2–4 weeks, treatment should continue for at least 8 weeks to properly assess efficacy. The duration of treatment should be determined by the physician according to the clinical condition of each individual patient.

Note

In cases of accelerated gastrointestinal transit (e.g., use of laxatives, diarrhea, surgical shortening of the intestine), tablet residues may occasionally be excreted from the body. If premature excretion occurs only sporadically, this does not require special attention.

Children

Pentoxifylline should not be used in children. The safety of pentoxifylline in children and adolescents (under 18 years of age) has not been established.

Overdose

Symptoms

Symptoms of overdose may include dizziness, nausea, hypotension, tachycardia, flushing, loss of consciousness, increased body temperature, restlessness, areflexia, tonic-clonic seizures, arrhythmias, and coffee-ground vomitus.

Treatment Measures

If overdose has occurred recently, gastric lavage or administration of activated charcoal may be performed to prevent further absorption.

Treatment should be symptomatic, as there is no known specific antidote. To prevent complications, monitoring in an intensive care unit may be necessary.

Emergency Measures in Case of Severe Hypersensitivity Reactions (Shock)

At the first signs (e.g., skin reactions (urticaria), flushing, restlessness, headache, sudden sweating, nausea), a venous catheter should be inserted. In addition to standard emergency measures—such as placing the patient in a supine position with elevated legs, ensuring airway patency, and administering oxygen—emergency pharmacological treatment is indicated, including intravenous fluid replacement, intravenous epinephrine (adrenaline), glucocorticoids (e.g., 250–1000 mg methylprednisolone intravenously), and histamine receptor antagonists.

Depending on the severity of clinical symptoms, artificial ventilation may be required, and in case of circulatory arrest, resuscitation should be performed according to standard guidelines.

Adverse reactions

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

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

Frequency of adverse reactions by individual body systems:

Most adverse reactions are dose-dependent. They can be minimized or even avoided by reducing the dose. If severe adverse reactions occur, treatment should be discontinued.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via 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 temperatures not exceeding 25 °C. Keep out of reach and sight of children.

Packaging. 10 tablets in a blister pack; 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Location of manufacturer and address of site of activity.
Šmarješka cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.