Pentoxifylline

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

Composition:

• Active substance: pentoxifylline
• 1 tablet contains: pentoxifylline 100 mg
• Excipients: lactose monohydrate, potato starch, magnesium stearate, hypromellose (hydroxypropylmethylcellulose), povidone, methacrylic acid copolymer dispersion, propylene glycol, talc, titanium dioxide (E 171), carmoisine (E 122)

Pharmaceutical form: Enteric-coated tablets

Main physicochemical properties:
Round, enteric-coated tablets of pink color, with convex upper and lower surfaces. When examined under a magnifying glass, the cross-section reveals a core surrounded by a single continuous layer.

Pharmacotherapeutic group: Peripheral vasodilators. Pentoxifylline.
ATC code: C04AD03

Pharmacological properties

Pharmacodynamics:
Pentoxifylline is a derivative of methylxanthine. Its mechanism of action 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.

Additionally, pentoxifylline exerts a mild 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 moderately 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 found in plasma at concentrations twice as high as that of the unchanged substance and exists in reversible biochemical equilibrium with it. Therefore, pentoxifylline and its metabolite should be considered as a single active entity.

The elimination half-life of pentoxifylline is approximately 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, 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 circulatory disorders due to atherosclerosis, diabetes mellitus (including diabetic angiopathy), or 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 circulatory 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, other methylxanthines, or any of the excipients
• Patients with massive bleeding (risk of exacerbating hemorrhage)
• Patients with extensive retinal hemorrhage or intracerebral hemorrhage (risk of exacerbating hemorrhage). If retinal hemorrhage occurs during treatment, pentoxifylline must be discontinued immediately
• Patients during the acute phase of myocardial infarction
• Patients with gastric and/or intestinal ulcers
• Patients with hemorrhagic diathesis

Interaction with other medicinal products and other types of interactions

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

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 dose of pentoxifylline, monitoring of anticoagulant activity in this patient group is recommended.

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

Concomitant use of pentoxifylline and theophylline in some patients may lead to increased serum theophylline levels. Therefore, an increased frequency and severity of theophylline-related adverse reactions may occur.

In some patients, concomitant use with ciprofloxacin may increase pentoxifylline plasma concentration. As a result, the frequency and severity of adverse reactions 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/ASA], ticlopidine, dipyridamole) with pentoxifylline should be used with caution.

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

Special precautions for use

At the first signs of anaphylactic/anaphylactoid reaction, treatment with pentoxifylline must be discontinued immediately and medical help sought.

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

In diabetic patients receiving insulin or oral antidiabetic agents, high doses of pentoxifylline 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 is required.

Pentoxifylline may be prescribed to patients with systemic lupus erythematosus (SLE) or other connective tissue diseases only after thorough assessment of potential risks and benefits.

Due to the risk of developing aplastic anemia during pentoxifylline therapy, regular monitoring of complete blood count is required.

In patients with renal impairment (creatinine clearance <30 mL/min) or severe hepatic dysfunction, elimination of pentoxifylline may be delayed. Appropriate monitoring is necessary.

Particular vigilance is required in:

• Patients with severe cardiac arrhythmias
• Patients with arterial hypotension
• Patients with marked atherosclerosis of cerebral and coronary vessels, especially with concomitant arterial hypertension and cardiac rhythm disturbances. In these patients, angina attacks, arrhythmias, and arterial hypertension may occur during treatment
• Patients with renal impairment (creatinine clearance <30 mL/min)
• Patients with severe hepatic insufficiency
• Patients with high bleeding tendency due to, for example, anticoagulant therapy or coagulation disorders. See section "Contraindications" regarding bleeding
• Patients who have recently undergone surgery (increased risk of bleeding, requiring systematic monitoring of hemoglobin and hematocrit levels)
• Patients for whom a decrease 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")

The product contains lactose; therefore, it should not be used in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding

Pregnancy:
There is insufficient experience with the use of pentoxifylline in pregnant women; therefore, pentoxifylline is not recommended during pregnancy.

Breastfeeding:
Pentoxifylline passes into breast milk in small amounts; therefore, breastfeeding must be discontinued during treatment with pentoxifylline.

Ability to affect reaction speed when driving or operating machinery

There are no data available; however, the possible occurrence of adverse reactions affecting the nervous system and visual organs should be considered.

Method of administration and dosage

Pentoxifylline should be administered at a dose of 2–4 tablets 2–3 times daily. Tablets should be taken after meals, without chewing, with sufficient liquid. The maximum daily dose should not exceed 1.2 g.

For patients with labile or low blood pressure, significant renal impairment (creatinine clearance <30 mL/min), or those at high risk of adverse consequences from blood pressure reduction (e.g., severe coronary vessel disease, marked stenosis of cerebral trunk vessels), treatment should be initiated with low doses, individualized dosing should be applied, and doses should be gradually increased according to treatment tolerance.

Children:
Experience with use in children is lacking.

Overdose

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

Treatment of overdose:
General and specific intensive medical supervision and therapeutic measures are required to treat acute overdose and prevent complications.

Adverse reactions

Adverse reactions may occur in some patients, including:

• Cardiovascular system: arrhythmia, tachycardia, angina pectoris, arterial hypotension/hypertension, hot flushes, peripheral edema
• Blood and lymphatic system: thrombocytopenia with thrombocytopenic purpura, aplastic anemia (partial or complete cessation of all blood cell formation, pancytopenia), which may be fatal, hemorrhages, leukopenia/neutropenia
• Nervous system: dizziness, headache, aseptic meningitis, tremor, paresthesia, seizures, excitement, sleep disturbances, hallucinations
• Gastrointestinal tract: gastrointestinal disorders, epigastric pressure, flatulence, nausea, vomiting, or diarrhea, constipation, hypersalivation
• Skin and subcutaneous tissues: pruritus, skin redness and urticaria, toxic epidermal necrolysis and Stevens-Johnson syndrome, rash
• Immune system: anaphylactic reactions, anaphylactoid reactions, angioedema, bronchospasm, anaphylactic shock
• Liver and biliary system: intrahepatic cholestasis
• Visual organs: visual disturbances, conjunctivitis, retinal hemorrhage, retinal detachment
• Laboratory findings: increased transaminase levels
• Other: hypoglycemia, increased sweating, elevated body temperature

Shelf life

3 years

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging

10 tablets in a blister.
10 tablets in a blister; 5 blisters in a cardboard box.

Prescription category

Prescription only

Manufacturer

JSC "Technolog"
Location and address of manufacturer:
8 Staroproryzna Street, Uman, Cherkasy Oblast, 20300, Ukraine