Latren

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LATREN® (LATREN)

Composition:

Active ingredient: 1 ml of solution contains 0.5 mg of pentoxifylline;

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

Pharmaceutical form. Infusion solution.

Main physico-chemical properties: colorless or slightly yellowish clear solution.

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 3',5'-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 produces a weak myotropic vasodilatory effect, slightly reduces total peripheral vascular resistance, and exerts 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 (CNS), 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 plasma at concentrations exceeding those of the unchanged substance by 2 times and exists in 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 impaired liver function, the elimination half-life of pentoxifylline is prolonged.

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; 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

Latren® is contraindicated in:

• Patients with hypersensitivity to pentoxifylline, other methylxanthines, or any of the excipients of Latren®;
• Patients with massive bleeding (risk of bleeding enhancement);
• 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;
• Patients during the acute phase of myocardial infarction;
• Patients with gastric or intestinal ulcers;
• Patients with hemorrhagic diathesis.

Interaction with Other Medicinal Products and Other Forms of Interaction

The blood glucose-lowering effect of insulin or oral antidiabetic agents may be enhanced. Therefore, patients receiving antidiabetic medication should be closely monitored.

During the post-marketing period, cases of increased anticoagulant activity have been reported in patients concurrently treated with pentoxifylline and vitamin K antagonists. When initiating or adjusting the dosage of pentoxifylline, monitoring of anticoagulant activity is recommended in these patients.

Latren® 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, acetylsalicylates [ASA/LSA], 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, infusion of Latren® should be stopped immediately and medical assistance should be sought.

In patients with chronic heart failure, circulatory compensation should be achieved prior to administration of Latren®.

In patients with diabetes mellitus receiving insulin or oral antidiabetic agents, high doses of Latren® may enhance the effect of these drugs on blood glucose levels (see section "Interaction with other medicinal products and other types of interactions"). 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 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 necessary.

Particularly careful observation is required in:

• patients with severe cardiac arrhythmias;
• patients with arterial hypotension;
• patients with severe 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 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 information 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 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 types of interactions");
• patients receiving concomitant treatment with pentoxifylline and antidiabetic agents (see section "Interaction with other medicinal products and other types of interactions");
• patients receiving concomitant treatment with pentoxifylline and ciprofloxacin (see section "Interaction with other medicinal products and other types of interactions");
• patients receiving concomitant treatment with pentoxifylline and theophylline (see section "Interaction with other medicinal products and other types of interactions").

Use during pregnancy or breastfeeding

Pregnancy

There is insufficient experience with the use of the drug in pregnant women. Therefore, Latren® is not recommended during pregnancy.

Breastfeeding

Pentoxifylline passes into breast milk in small amounts. Breastfeeding should be discontinued if treatment with Latren® is required.

Ability to affect reaction speed when driving or operating machinery

Since the drug is administered under hospital conditions, data regarding such effects are not available.

Administration and Dosage

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.

The recommended treatment regimens for adults are as follows:

1. Intravenous infusion of 100–600 mg pentoxifylline once or twice daily. The duration of intravenous infusion is 60–360 minutes; thus, administration of 100 mg pentoxifylline should last at least 60 minutes.

2. In patients with severe conditions (especially with 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 for a patient weighing 70 kg is 1000 mg, and for a patient weighing 80 kg – 1150 mg. Regardless of body weight, the maximum daily dose is 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.

The duration of parenteral treatment course is determined by the treating physician.

Children

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

Overdose

Initial symptoms of acute pentoxifylline overdose include nausea, dizziness, or hypotension. Additionally, symptoms such as fever, excitement, hot flushes, tachycardia, loss of consciousness, areflexia, arrhythmia, tonic-clonic seizures, and vomiting of "coffee-ground" material (indicating gastrointestinal bleeding) may develop.

Treatment of overdose

For the management of acute overdose and prevention of complications, general and specific intensive medical monitoring and therapeutic interventions are required.

Adverse reactions.

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

Shelf life. 2 years.

Storage conditions.

Store out of reach of children at a temperature not exceeding 25 °C.

Do not freeze.

Incompatibility.

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

Packaging.

200 ml in glass bottles; 200 ml in polymer bottles.

Prescription status. Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's address and place of business.

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