Pentoxifylline

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PENTOXIFYLLINE (PENTOXIFYLLINE)

Composition:

Active substance: pentoxifylline;

1 ml of solution contains 20 mg of pentoxifylline;

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution, sterile, free from bacterial endotoxins.

Pharmacotherapeutic group. Peripheral vasodilators. Purine derivatives.

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. Leukocyte properties having hemorheological significance have been modified in animal studies and in vitro studies in humans. Pentoxifylline has been shown to enhance leukocyte deformability and to inhibit neutrophil adhesion and activation. 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, particularly in the extremities and central nervous system, and to a moderate extent in the kidneys. The drug causes slight dilation of coronary vessels.

Pharmacokinetics.

The main pharmacologically active metabolite, 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (metabolite I), is detected in plasma at concentrations twice as high as that of the unchanged compound and is in a state of 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; more than 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, the elimination half-life of pentoxifylline is prolonged.

Clinical characteristics.

Indications.

Atherosclerotic encephalopathy; ischemic cerebral stroke; dyscirculatory encephalopathy; peripheral circulation disorders caused by atherosclerosis, diabetes mellitus (including diabetic angiopathy), inflammation; tissue trophic disorders associated with venous damage or impaired microcirculation (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); inner ear vascular dysfunction accompanied by hearing loss.

Contraindications.

• Hypersensitivity to pentoxifylline, other methylxanthines, or any of the excipients of Pentoxifylline;
• Massive bleeding (risk of bleeding enhancement);
• Extensive retinal hemorrhage, cerebral hemorrhage (risk of bleeding enhancement). If retinal hemorrhage occurs during pentoxifylline treatment, the drug should be discontinued immediately;
• Acute phase of myocardial infarction;
• Severe cardiac arrhythmias;
• Gastric and/or duodenal ulcer;
• Hemorrhagic diathesis.

Interaction with other medicinal products and other types of interactions.

When co-administering the following medications, potential drug interactions should be considered.

Oral antidiabetic agents, insulin.

High doses of pentoxifylline injections rarely demonstrate an insulin-like or oral antidiabetic agent-like effect of reducing blood glucose levels, which may be potentiated and lead to hypoglycemic reactions. Therefore, patients receiving medication for diabetes mellitus should be under close monitoring.

Vitamin K antagonists.

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

Agents that lower blood pressure.

Pentoxifylline may enhance the hypotensive effect of antihypertensive medicinal products (particularly angiotensin-converting enzyme inhibitors), potentially causing a reduction in arterial pressure; therefore, appropriate adjustment of antihypertensive drug dosages is necessary.

Theophylline.

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 effects may occur during treatment of respiratory tract disorders.

Ciprofloxacin.

Ciprofloxacin inhibits the hepatic metabolism of pentoxifylline; therefore, concomitant administration of pentoxifylline and ciprofloxacin may result in elevated serum concentrations of pentoxifylline. As a consequence, the frequency and severity of adverse reactions associated with concomitant use of these drugs may increase.

Potential additive effect of anticoagulants, 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, non-selective NSAIDs except selective COX-2 inhibitors, acetylsalicylates [ASA/ASA], ticlopidine, dipyridamole) with pentoxifylline should be performed with caution.

Anticoagulants.

Pentoxifylline may potentiate the effects of anticoagulants. Patients with increased predisposition to bleeding, for example those receiving concomitant anticoagulant therapy, require careful monitoring (including regular monitoring of the international normalized ratio), as there is a risk of developing more severe hemorrhages.

Ketorolac, meloxicam.

Pentoxifylline should not be used concomitantly with ketorolac due to an increased risk of bleeding and/or prolonged prothrombin time. The risk of bleeding is also increased with concomitant use of pentoxifylline and meloxicam. Therefore, concomitant treatment with these drugs is not recommended.

Cimetidine.

Concomitant use with cimetidine may increase serum concentrations of pentoxifylline and its active metabolite, lisofylline. Close monitoring for signs of pentoxifylline overdose is required. Other H2-receptor antagonists (famotidine, ranitidine, nizatidine) have significantly less effect on pentoxifylline metabolism.

Erythromycin.

There are no data on the interaction between pentoxifylline and erythromycin. However, when pentoxifylline and erythromycin are used concomitantly, an increase in theophylline plasma levels with toxic reactions has been observed.

Nitrates.

Pentoxifylline enhances the effect of nitrates.

Special precautions for use

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

Pentoxifylline should be used with caution in patients with hypotension or severe chronic heart failure, as a transient hypotensive effect may occur, which in some cases may lead to reduced coronary artery perfusion. Prior to administration of Pentoxifylline, circulatory compensation should be achieved. Infusion of large volumes of fluids should be avoided. Under these conditions, the use of an infusion pump is highly advantageous.

In patients with diabetes mellitus receiving treatment with insulin or oral antidiabetic agents, high doses of pentoxifylline may enhance the effect of these agents 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.

Pentoxifylline may be prescribed to patients with systemic lupus erythematosus (SLE) 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 treatment with pentoxifylline, regular blood counts must be performed.

In patients with severe hepatic dysfunction, elimination of pentoxifylline may be delayed. Appropriate monitoring is required.

In patients with renal insufficiency (creatinine clearance less than 30 ml/min) or severe hepatic dysfunction, elimination of pentoxifylline may be delayed; therefore, a reduction in the daily dose may be necessary to avoid accumulation.

Particular caution and close monitoring are required for:

• patients with myocardial infarction;
• patients with arterial hypotension or unstable circulatory function: infusions should be initiated with a low dose of the drug and the dose gradually increased, since administration of any vasodilator may cause transient reduction in arterial pressure with a tendency toward collapse, and in some cases may lead to development of angina symptoms;
• 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 with pronounced atherosclerosis of cerebral and coronary vessels, especially in the presence of concomitant arterial hypertension and cardiac arrhythmias. In these patients, episodes of angina, arrhythmias, and arterial hypertension may occur during treatment;
• patients with renal insufficiency (creatinine clearance below 30 ml/min): the dose of the drug may need to be reduced by approximately 30–50%, depending on individual tolerance to treatment;
• patients with severe hepatic insufficiency: elimination of pentoxifylline may be slowed; therefore, dose reduction and patient monitoring are necessary;
• patients with a high predisposition to bleeding, for example, due to anticoagulant therapy or coagulation disorders: careful monitoring and control of coagulation parameters are required; for information on bleeding, see section "Contraindications";
• patients who have recently undergone surgery (increased risk of bleeding, requiring regular monitoring of hemoglobin and hematocrit levels);
• patients receiving concomitant treatment with pentoxifylline and vitamin K antagonists or platelet aggregation inhibitors: careful monitoring is required (see section "Interaction with other medicinal products and other forms of interaction");
• patients receiving concomitant treatment with pentoxifylline and antidiabetic agents: blood glucose levels may decrease; therefore, careful monitoring of patients receiving antidiabetic drugs is necessary (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");
• patients with systemic lupus erythematosus or mixed connective tissue diseases: pentoxifylline should be prescribed only after careful evaluation of the benefit-risk ratio.

The medicinal product Pentoxifylline contains 0.086 mmol (or 1.967 mg) of sodium per 1 ml and 2.58 mmol (or 59.01 mg) of sodium per 30 ml. Caution is advised when administering to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding

Pregnancy

Clinical experience with the use of this medicinal product in pregnant women is limited, although no adverse effects were observed in animal studies. Pentoxifylline is not recommended during pregnancy.

Breastfeeding

Pentoxifylline passes into breast milk in small amounts. Due to limited clinical experience, the potential risks and benefits should be carefully weighed when prescribing Pentoxifylline to nursing mothers.

Ability to influence reaction rate while driving or operating machinery

No effect.

Dosage and Administration.

The medicinal product should be administered via intravenous infusions and slow intravenous injections.

Intravenous infusions are the most effective and better tolerated forms of parenteral administration. The dosage regimen is determined by the physician and depends on the severity of circulatory disorders, body weight, and treatment tolerance.

Recommended treatment regimens for adults:

1. Intravenous infusion of 100–600 mg pentoxifylline in 100–500 mL of Ringer's lactate solution, 0.9% sodium chloride solution, or 5% glucose solution, 1–2 times 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 pentoxifylline (400 mg), provided that the maximum daily dose (infusion and oral) does not exceed 1200 mg.
2. In patients with severe conditions (especially persistent pain, gangrene, or trophic ulcers), a 24-hour infusion of pentoxifylline may be administered. 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 should be individually adjusted according to concomitant diseases and the patient's condition, averaging 1–1.5 L per day.
3. In individual cases, the drug may be administered via intravenous injection of 5 mL (100 mg). The injection should be performed slowly over 5 minutes, with the patient in a lying position.

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

Children.

There is no experience with the use of pentoxifylline in children.

Overdose.

Initial symptoms of acute pentoxifylline overdose include nausea, dizziness, and increased or decreased arterial pressure. Additional symptoms may include fever, excitement, hot flushes, tachycardia, loss of consciousness, areflexia, arrhythmia, tonic-clonic seizures, and coffee-ground vomiting indicating gastrointestinal bleeding.

Treatment of overdose.

Treatment of acute overdose and prevention of complications require general and specific intensive medical monitoring and therapeutic interventions, particularly concerning the cardiovascular system.

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), hot flushes, restlessness, headache, sudden sweating, nausea), a venous catheter should be inserted. Along with standard emergency measures—such as placing the patient in a supine position with elevated lower limbs, ensuring airway patency, and oxygen administration—emergency pharmacological treatment is indicated, including intravenous fluid volume replacement, intravenous epinephrine (adrenaline), intravenous 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.

The adverse reactions listed below occurred during clinical trials and in the post-marketing period of pentoxifylline use.

Adverse reactions are classified by organ systems and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000), including isolated cases, and frequency not known (cannot be estimated based on available data).

1 Upon the first signs of an anaphylactic reaction, administration of the medicinal product must be stopped immediately and the physician informed.

2 There have been several very rare reports of bleeding (e.g. from the skin, mucous membranes) in patients, both with concomitant use of anticoagulants or platelet aggregation inhibitors and without such use. Serious cases mainly involved gastrointestinal, genitourinary tract bleeding, and multiple surgical wound sites, associated with risk factors for bleeding. A causal relationship between pentoxifylline therapy and bleeding has not been established. Thrombocytopenia has been observed in isolated cases.

3 If retinal hemorrhages occur during treatment with pentoxifylline, the drug should be discontinued immediately.

4 Regular blood count monitoring is required.

5 Reports of aseptic meningitis have been received predominantly from patients with underlying connective tissue disorders.

Reporting of adverse reactions

Reporting of adverse reactions following medicinal product registration is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Incompatibilities.

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

Packaging.

5 ml in a glass ampoule, 5 ampoules in a blister pack, 2 blister packs in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's address and location of its business operations.

108, Kozbirska Street, Cherkasy, Cherkasy region, 18030, Ukraine. Tel.: (044) 281-01-01.