Pentoxifylline

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PENTOXIFYLLINE

Composition:

Active substance: pentoxifylline;

1 ml of solution contains pentoxifylline (calculated as 100 % substance) 20 mg;

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Peripheral vasodilators. ATC code C04AD03.

Pharmacological properties.

Pharmacodynamics.

Pentoxifylline is a methylxanthine derivative. 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, and moderately 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 plasma at concentrations exceeding those of the unchanged substance by two-fold and remains in a state of reversible biochemical equilibrium with it. Therefore, pentoxifylline and its metabolite should be considered as an active entity. The half-life (T½) 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, excretion of metabolites is delayed. In patients with impaired liver function, an increased T½ 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), and inflammation; tissue trophic disorders associated with venous damage or impaired microcirculation (post-thrombophlebitic syndrome, trophic ulcers, gangrene, frostbite); obliterating endarteritis; angioneuropathy (Raynaud's disease); ocular circulation disorders (acute, subacute, chronic insufficiency of blood flow in the retina and choroid); vascular-origin inner ear function disorders accompanied by hearing loss.

Contraindications.

The drug is contraindicated:

• in patients with hypersensitivity to pentoxifylline, other methylxanthines, or any of the excipients of the drug;
• in patients with massive bleeding (risk of bleeding enhancement);
• in patients with extensive retinal hemorrhage or intracerebral hemorrhage (risk of bleeding enhancement). If retinal hemorrhage occurs during pentoxifylline treatment, the drug should be discontinued immediately;
• in patients during the acute phase of myocardial infarction;
• in patients with gastric ulcer and/or intestinal ulcers;
• in patients with hemorrhagic diathesis.

Interaction with other medicinal products and other forms of interactions.

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

There are data on cases of increased anticoagulant activity in patients who received pentoxifylline and vitamin K antagonists simultaneously. When using pentoxifylline or changing its dosage, monitoring of anticoagulant activity in this group of patients is recommended.

The drug may enhance the hypotensive effect of antihypertensive agents and other drugs that may cause a reduction in arterial pressure.

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

In some patients, concomitant use with ciprofloxacin may lead to increased serum pentoxifylline concentration. As a result, the frequency and severity of adverse reactions associated with concomitant use of these drugs may increase. A potential additive effect with platelet aggregation inhibitors: due to an increased risk of bleeding, concomitant use of platelet aggregation inhibitors (e.g., clopidogrel, eptifibatide, tirofiban, epoprostenol, iloprost, abciximab, anagrelide, NSAIDs except selective COX-2 inhibitors, acetylsalicylates [ASA/ASA], ticlopidine, dipyridamole) with pentoxifylline should be used with caution.

Concomitant use with cimetidine may increase plasma concentrations of pentoxifylline and its metabolite I.

Special precautions for use

At the first signs of an anaphylactic/anaphylactoid reaction, treatment with the drug must be discontinued immediately and medical assistance should be sought.

When using the drug in patients with chronic heart failure, circulatory compensation should be achieved beforehand.

In patients with diabetes mellitus receiving insulin or oral antidiabetic agents, high doses of pentoxifylline may potentiate the effect of these drugs on blood glucose levels. 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 prescribed to patients with systemic lupus erythematosus or other connective tissue disorders 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 count is necessary.

In patients with renal impairment (creatinine clearance less than 30 mL/min) or severe hepatic dysfunction, elimination of pentoxifylline may be delayed. Appropriate monitoring is required.

Particularly careful monitoring is necessary for:

• patients with severe cardiac arrhythmias;
• patients with arterial hypotension;
• patients with pronounced atherosclerosis of cerebral and coronary vessels, especially in the presence of concomitant arterial hypertension and cardiac rhythm disturbances. In these patients, episodes of angina pectoris, arrhythmias, and arterial hypertension may occur during treatment;
• patients with renal impairment (creatinine clearance less than 30 mL/min);
• patients with severe hepatic insufficiency;
• patients with a high predisposition to bleeding, for example, due to anticoagulant therapy or coagulation disorders. For details on bleeding, see section "Contraindications";
• patients who have recently undergone surgery (increased risk of bleeding, therefore systematic monitoring of hemoglobin and hematocrit levels is required);
• 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;
• patients receiving concomitant treatment with pentoxifylline and antidiabetic agents;
• patients receiving concomitant treatment with pentoxifylline and ciprofloxacin;
• patients receiving concomitant treatment with pentoxifylline and theophylline.

This medicinal product contains 7.12 mmol (or 163.8 mg) of sodium per 1200 mg dose of pentoxifylline. Caution is advised when prescribing to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

Pregnancy. There is insufficient experience with the use of the drug in pregnant women; therefore, the drug is not recommended during pregnancy.

Breastfeeding period. Pentoxifylline passes into breast milk in small amounts. If treatment with the drug is necessary, breastfeeding should be discontinued.

Ability to affect reaction rate when driving or operating machinery. No effect.

Dosage and Administration

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 Ringer's lactate solution, 0.9% sodium chloride solution, or 5% glucose solution, administered 1–2 times daily. The duration of intravenous infusion is 60–360 minutes; thus, administration of 100 mg of pentoxifylline should last at least 60 minutes. The infusion may be supplemented with oral pentoxifylline (400 mg), provided that the maximum daily dose (combined infusion and oral) does not exceed 1200 mg.
2. In severe conditions (particularly persistent pain, gangrene, or trophic ulcers), continuous 24-hour infusion of the drug may be performed. In such cases, 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 the infusion solution is individually adjusted based on concomitant diseases and the patient's condition, averaging 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.

The duration of parenteral treatment is determined by the treating physician. After improvement of the patient's condition, continuation of therapy with oral pentoxifylline tablets is recommended.

Children. Experience with the use of the drug in children is lacking.

Overdose

Initial symptoms of acute pentoxifylline overdose include nausea, dizziness, or hypotension. Additionally, symptoms such as fever, excitation, hot flashes, tachycardia, loss of consciousness, areflexia, arrhythmia, tonic-clonic seizures, and coffee-ground emesis indicating gastrointestinal bleeding may develop.

Treatment of overdose. Management of acute overdose and prevention of complications require general and specific intensive medical monitoring and therapeutic interventions.

Adverse reactions.

The adverse reactions listed below occurred during clinical studies. The frequency of occurrence is unknown.

Reporting of suspected adverse reactions.

Reporting of adverse reactions following marketing authorization of a medicinal product is of significant importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are requested to report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 ºC. Do not freeze. Keep out of reach of children.

Incompatibilities. The medicinal product must not be mixed with other solutions in the same container, except for those solutions specified in the section "Dosage and administration".

Packaging. 5 ml in ampoules, 5 ampoules in a blist er pack, 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Subsidiary enterprise "FARMATREYD", Ukraine.

Manufacturer's address and place of business.

82100, Drohobych, Lviv Oblast, Sambirska Street, 85.

Marketing Authorization Holder.

Subsidiary enterprise "FARMATREYD", Ukraine.

Address of the Marketing Authorization Holder and/or its representative.

82100, Drohobych, Lviv Oblast, Sambirska Street, 85.