Vazitren

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VASITREN (VAZITREN)

Composition:

Active substance: pentoxifylline;

1 ml of solution contains pentoxifylline 20 mg;

Excipients: sodium chloride, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: colorless clear solution.

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, 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 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 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; 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 hepatic dysfunction, prolonged elimination half-life of pentoxifylline has been observed.

Clinical characteristics.

Indications.

Atherosclerotic encephalopathy; ischemic cerebral stroke; dyscirculatory encephalopathy; peripheral circulation disorders caused by atherosclerosis, diabetes mellitus (including diabetic angiopathy), inflammation; trophic disorders in tissues 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 functional 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 drug Vazitren;
• with massive bleeding (risk of bleeding enhancement);
• with extensive retinal hemorrhage, intracerebral hemorrhage (risk of bleeding enhancement).

If retinal hemorrhage occurs during pentoxifylline treatment, the drug should be discontinued immediately:

• in the acute phase of myocardial infarction;
• with gastric ulcer and/or intestinal ulcers;
• with hemorrhagic diathesis.

Interaction with other medicinal products and other types 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.

Cases of increased anticoagulant activity have been reported in patients receiving pentoxifylline concomitantly with vitamin K antagonists. When initiating or changing the dosage of pentoxifylline, monitoring of anticoagulant activity in these patients is recommended.

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

Concomitant use of pentoxifylline and theophylline in some patients may lead to increased plasma theophylline 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 concentrations of pentoxifylline. As a result, the frequency and severity of adverse reactions associated with concomitant use of these drugs 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, NSAIDs except selective COX-2 inhibitors, acetylsalicylic acid [ASA/ASA], ticlopidine, dipyridamole) with pentoxifylline should be performed 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, infusion of pentoxifylline must be stopped immediately and medical assistance sought.

In patients with chronic heart failure, circulatory compensation should be achieved prior to initiating pentoxifylline therapy.

In diabetic patients receiving insulin or oral hypoglycemic agents, high doses of pentoxifylline may potentiate 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 diseases only after careful assessment of the potential risks and benefits.

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

Particular caution and close monitoring are necessary in patients:

• with severe cardiac arrhythmias;
• with arterial hypotension;
• with severe atherosclerosis of cerebral and coronary vessels, especially in the presence of concomitant arterial hypertension and cardiac rhythm disturbances (in these patients, treatment with the drug may provoke angina attacks, arrhythmias, and arterial hypotension);
• with renal impairment (creatinine clearance below 30 mL/min);
• with severe hepatic insufficiency;
• with a high predisposition to bleeding, e.g., due to anticoagulant therapy or coagulation disorders (for bleeding, see section "Contraindications");
• who have recently undergone surgery (increased risk of bleeding, requiring systematic monitoring of hemoglobin and hematocrit levels);
• in 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);
• who are concurrently receiving pentoxifylline and vitamin K antagonists or platelet aggregation inhibitors (see section "Interaction with other medicinal products and other forms of interaction");
• who are concurrently receiving pentoxifylline and antidiabetic agents (see section "Interaction with other medicinal products and other forms of interaction");
• who are concurrently receiving pentoxifylline and ciprofloxacin (see section "Interaction with other medicinal products and other forms of interaction");
• who are concurrently receiving pentoxifylline and theophylline (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding

Pregnancy. Due to insufficient experience of use, pentoxifylline should not be administered during pregnancy.

Breastfeeding period. Pentoxifylline passes into breast milk in small amounts. Breastfeeding must be discontinued if pentoxifylline treatment is indicated.

Ability to influence reaction rate while driving or operating machinery. No effect.

Method of Administration and Dosage

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 should be administered 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 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 total daily dose (infusion plus oral) does not exceed 1200 mg.
2. In severe conditions (especially persistent pain, gangrene, or trophic ulcers), pentoxifylline infusion may be administered continuously over 24 hours. In this regimen, the dose is 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 patient status, 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 is recommended.

Instructions for ampoule handling:

1. Detach one ampoule from the pack and shake it gently while holding by the neck (Fig. 1).
2. Squeeze the ampoule with your hand (no drug leakage should occur) and, using a twisting motion, break off the top (Fig. 2).
3. Immediately connect the syringe to the opening formed in the ampoule (Fig. 3).
4. Invert the ampoule and slowly draw the contents into the syringe (Fig. 4).
5. Attach the needle to the syringe.

Fig. 1    Fig. 2    Fig. 3    Fig. 4

Children.

Do not use.

Overdose.

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

Treatment. Management of acute overdose requires immediate general and specific intensive medical monitoring and implementation of therapeutic interventions to prevent complications.

Adverse reactions.

Laboratory findings: increased transaminase levels.

Cardiac disorders: arrhythmia, tachycardia, angina pectoris, decreased blood pressure, increased blood pressure.

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

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

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

Skin and subcutaneous tissue disorders: pruritus, skin redness and urticaria, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, rash.

Vascular disorders: feeling of warmth (flushing), hemorrhage, peripheral edema.

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

Hepatobiliary disorders: intrahepatic cholestasis.

Psychiatric disorders: excitement and sleep disturbances, hallucinations.

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

General disorders: hypoglycemia, increased sweating, increased body temperature.

Reporting suspected adverse reactions

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

Shelf life.

2.5 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 must not be mixed in the same container with other solutions except those specified in the section "Method of administration and dosage".

Packaging.

5 ml in a polyethylene ampoule. 5 or 50 ampoules per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "FARMASEL".

Manufacturer's address and location of its business operations.

3, Prorizna Street, Kvitneve, Brovary District, Kyiv Region, 07408, Ukraine.