Pentoxifylline-darnitsa

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

Composition:

Active substance: pentoxifylline;

1 ml of solution contains pentoxifylline 20 mg;

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

Peripheral vasodilators. Purine derivatives. 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 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 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 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, with over 90% 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 circulatory disorders due to atherosclerosis, diabetes mellitus (including diabetic angiopathy), and inflammation; tissue trophic disorders associated with venous damage or microcirculation impairment (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); inner ear functional disorders of vascular origin accompanied by hearing loss.

Contraindications.

• Hypersensitivity to pentoxifylline, other components of the medicinal product, or to other methylxanthine derivatives;
• Massive hemorrhage (risk of exacerbating bleeding);
• Hemorrhage into the retina or brain; if retinal or cerebral hemorrhage occurs during pentoxifylline treatment, the drug must be discontinued immediately;
• Hemorrhagic diathesis;
• Acute myocardial infarction;
• Gastric and/or intestinal ulcer;
• Pregnancy.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of pentoxifylline and antihypertensive agents (including angiotensin-converting enzyme inhibitors) enhances the effect of the latter, potentially causing a decrease in arterial blood pressure; therefore, appropriate dose adjustment of antihypertensive agents is required.

Anticoagulants, medicinal products that reduce blood coagulation. Concurrent administration of pentoxifylline and agents that reduce blood coagulation increases the risk of bleeding; therefore, prothrombin time should be monitored more frequently. During the post-marketing period, cases of increased anticoagulant activity have been reported in patients receiving pentoxifylline concomitantly with vitamin K antagonists. When initiating or adjusting the dosage of pentoxifylline, monitoring of anticoagulant activity is recommended in these patients.

Cimetidine. Concomitant administration with cimetidine results in a significant increase in pentoxifylline serum concentration. Close monitoring for possible signs of pentoxifylline overdose is necessary. 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 increased serum theophylline concentration, potentially increasing the frequency and severity of theophylline-related adverse reactions. Monitoring of serum theophylline concentration is required, and dose reduction may be necessary.

Ketorolac, meloxicam. Concomitant use of pentoxifylline and ketorolac may prolong prothrombin time and increase the risk of bleeding. The risk of bleeding is also 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; therefore, concomitant use of pentoxifylline and ciprofloxacin may increase pentoxifylline serum concentration, potentially increasing the frequency and severity of adverse reactions. If concomitant therapy with pentoxifylline and ciprofloxacin is necessary, it is recommended to reduce the pentoxifylline dose by half.

Insulin and oral antidiabetic medicinal products. High intravenous doses of pentoxifylline may enhance the hypoglycemic effects of insulin and oral antidiabetic agents; therefore, dosage adjustment of insulin or the hypoglycemic agent may be required. Patients receiving antidiabetic medication should be closely monitored.

Nitrates. Pentoxifylline potentiates the effect of nitrates.

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

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, nonsteroidal anti-inflammatory drugs (NSAIDs) except selective COX-2 inhibitors, acetylsalicylates (acetylsalicylic acid (ASA)/lysine acetylsalicylate (LAS)), ticlopidine, dipyridamole) with pentoxifylline should be performed with caution.

Special precautions for use

At the first signs of an anaphylactic/anaphylactoid reaction, treatment with the medicinal product should be discontinued immediately and medical help should be sought.

In patients with chronic heart failure, pentoxifylline should only be administered after achieving circulatory compensation.

In diabetic patients receiving insulin or oral antidiabetic agents, high doses of pentoxifylline may enhance the blood glucose-lowering effect of these drugs (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 careful monitoring of the patient is required.

Particular caution and close monitoring are necessary in patients receiving concomitant treatment with pentoxifylline and ciprofloxacin (see section "Interaction with other medicinal products and other forms of interaction").

Pentoxifylline should 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 pentoxifylline therapy, regular monitoring of complete blood counts is 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 required.

Particular caution and close monitoring are required in patients:

• with severe cardiac arrhythmias;
• with myocardial infarction;
• with arterial hypotension;
• with severe atherosclerosis of cerebral and coronary vessels, especially in the presence of concomitant arterial hypertension and cardiac rhythm disturbances. In such patients, treatment with the medicinal product may provoke angina attacks, arrhythmias, and arterial hypertension;
• with renal impairment (creatinine clearance below 30 mL/min);
• with severe hepatic insufficiency;
• with a high predisposition to bleeding, for example, due to anticoagulant therapy or coagulation disorders. For information on bleeding, see section "Contraindications";
• with a history of gastric or duodenal ulcer, or who have recently undergone surgery (increased risk of bleeding; therefore, systematic monitoring of hemoglobin and hematocrit levels is required);
• in whom a decrease in arterial pressure poses a high risk (e.g., patients with severe ischemic heart disease or stenosis of vessels supplying blood to the brain);
• receiving concomitant treatment with pentoxifylline and vitamin K antagonists (see section "Interaction with other medicinal products and other forms of interaction");
• receiving concomitant treatment with pentoxifylline and antidiabetic agents (see section "Interaction with other medicinal products and other forms of interaction").

Important information about excipients

This medicinal product contains 9 mg/mL of sodium. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

Pregnancy

Experience with the use of this medicinal product in pregnant women is insufficient. Therefore, the drug should not be administered during pregnancy.

Breastfeeding

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

Ability to influence reaction speed while driving or operating machinery

No data are available; however, the possibility of adverse reactions affecting the central nervous system should be taken into account.

Dosage and Administration

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

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, administered 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), ensuring that the maximum daily dose (combined infusion and oral) does not exceed 1200 mg.
2. In patients with severe conditions (especially persistent pain, gangrene, or trophic ulcers), pentoxifylline 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 must not exceed 1200 mg.

The volume of the infusion solution should be individually adjusted based on concomitant diseases and the patient's condition, averaging 1–1.5 L per day.

1. In selected cases, the drug may be administered by intravenous injection of 5 mL (100 mg). The injection should be given slowly over 5 minutes, with the patient in a supine position.

The duration of parenteral therapy is determined by the treating physician. After clinical improvement, continuation of treatment with the tablet form of the drug is recommended.

Children

There is no clinical experience with the use of this drug in children.

Overdose

Symptoms: weakness, nausea, dizziness, decreased/increased arterial blood pressure, stupor, arrhythmia, tachycardia, somnolence or agitation, loss of consciousness, hyperthermia, areflexia, tonic-clonic seizures, signs of gastrointestinal bleeding—vomiting (coffee-ground vomitus), fever, sensation of heat (flushing).

Treatment: at the first signs of overdose (sweating, nausea, cyanosis), discontinue the drug immediately. Position the patient with the head and upper body lowered, ensure airway patency. Provide symptomatic therapy, with special attention to maintaining arterial blood pressure and respiratory function. Administer diazepam to control seizures.

Adverse Reactions

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

Ear and labyrinth disorders: ear pain.

Gastrointestinal disorders: gastrointestinal disturbances, sensation of pressure in the stomach, stomach fullness, diarrhea, nausea, vomiting (including repeated episodes), flatulence, epigastric pain, anorexia, intestinal atony, constipation, dry mouth, thirst.

Hepatobiliary disorders: intrahepatic cholestasis, increased liver enzyme activity, exacerbation of cholecystitis, cholestatic hepatitis.

Metabolism and nutritional disorders: hypoglycemia, hypokalemia.

Nervous system disorders: headache, migraine, dizziness, aseptic meningitis (with high-dose administration), hand tremor, insomnia, excitement, restlessness, fear, loss of consciousness, sleep disturbances, hallucinations, darkening of vision, numbness of extremities, hyperhidrosis, seizures, paresthesia.

Cardiovascular disorders: tachycardia, peripheral edema, facial flushing or sensation of warmth (hot flushes), angina pectoris, atypical chest pain, arterial hypotension, arterial hypertension, dyspnea, sensation of air hunger, arrhythmia, palpitations.

Blood and lymphatic system disorders: thrombocytopenia with thrombocytopenic purpura, leukopenia/neutropenia, pancytopenia (which may be fatal), prolonged prothrombin time, hypofibrinogenemia, anemia, aplastic anemia, hemorrhages (e.g., from skin vessels, mucous membranes, stomach, intestine, nose).

Immune system disorders: allergic reactions (anaphylactic/anaphylactoid reactions up to anaphylactic shock, angioneurotic edema, bronchospasm, skin redness, pruritus, rash, urticaria), toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome.

Skin and subcutaneous tissue disorders: increased sweating, facial and upper chest skin hyperemia, edema, maculopapular rash, dermatitis, increased nail fragility.

General disorders and administration site conditions: taste disturbances, increased salivation, malaise, throat/neck pain, laryngitis, nasal congestion, weight gain/loss, chills, fever, hyperthermic syndrome; pain at injection site, hyperemia, swelling, rash.

Laboratory findings: increased activity of liver transaminases (ALT, AST, LDH) and alkaline phosphatase.

Most adverse reactions are dose-dependent. They can be minimized or avoided altogether 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 an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

The medicinal product should not be mixed with other medicinal products in the same container, except for the solutions specified in the section "Administration and dosage".

Packaging.

5 ml in a vial; 5 vials in a blister pack; 1 or 2 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of operations.

13, Boryspilska Street, Kyiv, 02093, Ukraine.