Pentoxin

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

Composition:

Active substance: pentoxifylline;

1 ml of solution contains 0.5 mg of pentoxifylline;

Excipients: sodium chloride, potassium chloride, calcium chloride dihydrate, sodium lactate, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless or slightly yellowish 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 cyclic adenosine monophosphate (cAMP) in vascular smooth muscle cells, blood cells, and 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, particularly in the extremities and central nervous system, 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 times 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, metabolite excretion is delayed. In patients with hepatic dysfunction, prolongation of the elimination half-life of pentoxifylline has been observed.

Clinical characteristics.

Indications.

Atherosclerotic encephalopathy; ischemic cerebral stroke; dyscirculatory encephalopathy; peripheral circulatory 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 blood flow in the retina and choroid); vascular-origin inner ear function disorders accompanied by hearing loss.

Contraindications.

Pentoxifylline is contraindicated:

• in patients with hypersensitivity to pentoxifylline, to other methylxanthines, or to any of the excipients of the medicinal product;
• in patients with massive bleeding (risk of exacerbating hemorrhage);
• in patients with extensive retinal hemorrhage or cerebral hemorrhage (risk of exacerbating hemorrhage); if retinal hemorrhage occurs during treatment with pentoxifylline, the drug should be discontinued immediately;
• in patients during the acute phase of myocardial infarction and in patients with severe cardiac arrhythmia;
• in patients with gastric or intestinal ulcers;
• in patients with hemorrhagic diathesis.

Interaction with other medicinal products and other forms of interactions.

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

During the post-marketing period, cases of increased anticoagulant activity have been reported in patients concurrently receiving pentoxifylline and vitamin K antagonists. When pentoxifylline is initiated or its dosage changed, monitoring of anticoagulant activity in these patients is recommended.

Pentoxifylline may enhance the hypotensive effect of antihypertensive agents and other drugs capable of causing 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 elevated serum concentrations of pentoxifylline. As a result, the frequency and severity of adverse reactions associated with concomitant drug use may increase.

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, non-selective nonsteroidal anti-inflammatory drugs, except selective cyclooxygenase-2 inhibitors, acetylsalicylates [acetylsalicylic acid/lysine acetylsalicylate], ticlopidine, dipyridamole) with pentoxifylline should be performed with caution.

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

Pentoxifylline should not be used concomitantly with ketorolac due to an increased risk of bleeding and/or prolonged prothrombin time.

Special precautions for use

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

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

In patients with diabetes mellitus who are receiving insulin or oral antidiabetic agents, high doses of Pentoxin may enhance the blood glucose-lowering effect of these agents (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 close monitoring of the patient is required.

Pentoxifylline may be administered 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 complete blood counts are required.

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 necessary.

Particular caution and close monitoring are required in the following patients:

• Patients with severe cardiac arrhythmias;
• Patients with arterial hypotension;
• Patients with severe atherosclerosis of cerebral and coronary vessels, especially when associated with concomitant 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 insufficiency;
• Patients with a high predisposition to bleeding, for example, due to anticoagulant therapy or coagulation disorders (for bleeding, see section "Contraindications");
• Patients who have recently undergone surgery (increased risk of bleeding, requiring systematic monitoring of hemoglobin and hematocrit levels);
• Patients for whom a reduction in blood 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").

This medicinal product contains 3.0167 mg/mL of sodium, which should be taken into account in patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding

Pregnancy. Experience with the use of this medicinal product in pregnant women is insufficient. Therefore, Pentoxin is not recommended during pregnancy.

Breastfeeding. Pentoxifylline passes into breast milk in small amounts. If Pentoxin is prescribed, breastfeeding must be discontinued.

Ability to influence the speed of reactions when driving or operating machinery

Since this medicinal product is administered under hospital conditions, data regarding such effects are not available.

Dosage and Administration.

Intravenous infusions are the most effective and better-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 may only be administered if the solution is clear.

Recommended treatment regimens for adults:

1. Intravenous infusion of 100–600 mg pentoxifylline 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 pentoxifylline (400 mg), provided that the maximum daily dose (infusion and oral) does not exceed 1200 mg.
2. In severe conditions (particularly persistent pain, gangrene, or trophic ulcers), continuous 24-hour infusion of Pentoxin may be administered. When using this regimen, the dose should be calculated at 0.6 mg/kg/hour. The daily dose calculated in this way 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 according to concomitant diseases and the patient's condition and averages 1–1.5 L per day.

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

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

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 emesis indicating gastrointestinal bleeding.

Treatment of overdose should be symptomatic, with special attention to cardiovascular support. Specific emergency measures may be required to prevent bleeding.

Adverse Reactions

Listed below are adverse reactions observed during clinical trials and in the post-marketing period. The frequency of occurrence is unknown.

Laboratory findings: increased levels of transaminases, increased alkaline phosphatase levels.

Gastrointestinal disorders: gastrointestinal disturbances, sensation of pressure in the stomach, flatulence, nausea, vomiting, diarrhea, constipation, hypersalivation, anorexia, intestinal atony.

Cardiovascular system disorders: arrhythmia, tachycardia, angina pectoris, cardialgia, decreased blood pressure, increased blood pressure, chest tightness, hot flushes, hemorrhage (e.g., skin, mucous membranes, gastrointestinal tract), peripheral edema.

Blood and lymphatic system disorders: thrombocytopenia with thrombocytopenic purpura and aplastic anemia (partial or complete cessation of all blood cell production, pancytopenia), which may be fatal, leukopenia/neutropenia, hypofibrinogenemia.

Nervous system disorders: dizziness, headache, aseptic meningitis, tremor, paresthesia, convulsions.

Skin and subcutaneous tissue disorders: rash, pruritus, erythema, urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Immune system disorders: anaphylactic reactions, anaphylactoid reactions, angioneurotic edema, anaphylactic shock.

Hepatobiliary disorders: intrahepatic cholestasis, exacerbation of cholecystitis, cholestatic hepatitis.

Psychiatric disorders: excitement and sleep disturbances, insomnia, hallucinations, anxiety.

Eye disorders: visual disturbances, lacrimation, conjunctivitis, retinal hemorrhage, retinal detachment, scotoma.

Respiratory, thoracic and mediastinal disorders: bronchospasm, dyspnea.

General disorders and administration site conditions: hypoglycemia, increased sweating, increased body temperature, chills.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children. Do not freeze.

Incompatibility. The medicinal product should not be mixed with other solutions in the same container.

Packaging. 200 ml or 400 ml of solution in a bottle, 1 bottle per carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Infuziya".

Manufacturer's address and location of its business activities.

84A Nemirovskе Highway, Vinnytski Khuторy Village, Vinnytsia District, Vinnytsia Oblast, 23219, Ukraine.