Pentoxifylline-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

C04AD03 (Pentoxifylline)

Active Substance

Pentoxifylline (Rec.INN registered by WHO)

Dosage Form

Pentoxifylline-SZ

Prolonged-release film-coated tablets 400 mg: 20, 30, or 60 pcs.

Dosage Form, Packaging, and Composition

Prolonged-release film-coated tablets pink in color, round, biconvex; the tablet core on the cross-section is white or almost white.

Excipients: hydroxypropyl methylcellulose (hypromellose) – 66 mg, povidone K30 (medium molecular weight polyvinylpyrrolidone) – 24 mg, lactose monohydrate (lactopress) (milk sugar) – 68 mg, colloidal silicon dioxide (aerosil) – 2 mg, magnesium stearate – 5 mg.
Coating composition: hypromellose, polysorbate-80 (tween-80), talc, titanium dioxide E171, aluminum lake based on dye azorubine (carmoisine) E122.

10 pcs. – contour cell blisters (2) – cardboard packs.
10 pcs. – contour cell blisters (3) – cardboard packs.
10 pcs. – contour cell blisters (6) – cardboard packs.
30 pcs. – jars (1) – cardboard packs.
30 pcs. – bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Vasodilator drug

Pharmacotherapeutic Group

Peripheral vasodilators; purine derivatives

Pharmacological Action

The drug Pentoxifylline-SZ reduces blood viscosity and improves the rheological properties of blood (fluidity) by

• Improving impaired erythrocyte deformability;
• Reducing platelet and erythrocyte aggregation;
• Decreasing fibrinogen concentration;
• Reducing leukocyte activity and decreasing leukocyte adhesion to the vascular endothelium.

The active substance of the drug Pentoxifylline-SZ is a xanthine derivative – Pentoxifylline. Its mechanism of action is associated with the inhibition of phosphodiesterase and the accumulation of cyclic adenosine monophosphate (cAMP) in vascular smooth muscle cells and blood cells.

Exerting a weak myotropic vasorelaxant effect, Pentoxifylline slightly reduces total peripheral vascular resistance and slightly dilates coronary vessels.

Pentoxifylline has a weak positive inotropic effect on the heart.

It improves microcirculation in areas of impaired blood circulation.

Treatment with the drug Pentoxifylline-SZ leads to an improvement in the symptoms of cerebrovascular disorders.

In occlusive diseases of peripheral arteries, the use of the drug Pentoxifylline-SZ leads to an increase in walking distance, elimination of nocturnal cramps in the calf muscles, and disappearance of pain at rest.

Pharmacokinetics

Absorption

After oral administration, Pentoxifylline is almost completely absorbed. Pentoxifylline undergoes a significant first-pass effect through the liver. The absolute bioavailability of the parent substance is 19±13%.

The prolonged release of pentoxifylline allows maintaining its constant (peakless) concentration in the blood, which ensures better tolerability of the drug in the prolonged-release dosage form.

Metabolism and Excretion

The concentration of the main active metabolite 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (metabolite I) in blood plasma is 2 times higher than the concentration of the parent pentoxifylline. Metabolite I is in reversible biochemical redox equilibrium with pentoxifylline. Therefore, Pentoxifylline and metabolite I are considered together as an active unit. Consequently, the availability of the active substance is significantly greater.

The T_1/2 of pentoxifylline after oral administration is 1.6 hours.
Pentoxifylline is completely metabolized and more than 90% is excreted by the kidneys in the form of unconjugated water-soluble metabolites.

Pharmacokinetics in Special Patient Groups

In patients with impaired renal function, the excretion of metabolites is slowed.

In patients with impaired liver function, the T_1/2 of pentoxifylline is prolonged and the absolute bioavailability is increased.

Indications

• Occlusive peripheral arterial disease of atherosclerotic or diabetic origin (e.g., “intermittent” claudication, diabetic angiopathy);
• Trophic disorders (e.g., trophic leg ulcers, gangrene);
• Cerebrovascular disorders (consequences of cerebral atherosclerosis, such as decreased concentration, dizziness, memory impairment), ischemic and post-stroke conditions;
• Circulatory disorders in the retina and choroid of the eye;
• Otosclerosis, degenerative changes against the background of vascular pathology of the inner ear and hearing loss.

ICD codes

Dosage Regimen

Enteric-coated tablets (100 mg)

The drug is taken orally after meals. The tablets are coated with a special enteric-soluble coating, so they should be swallowed whole with a small amount of water.

Take 200 mg (2 tablets) 3 times/day. If necessary, the dose can be gradually increased to 1200 mg/day, divided into 2-3 doses.

The maximum daily dose is 1200 mg. The course of treatment is 1-3 months.

In patients with chronic renal failure (CrCl<10 ml/min), the dose should be reduced by half.

The duration of treatment and dosing regimen with the drug Pentoxifylline-SZ is determined individually by the attending physician, depending on the clinical picture of the disease and the therapeutic effect achieved.

Prolonged-release tablets (400 mg)

The dose is determined by the doctor according to the individual characteristics of the patient.

The drug should be swallowed whole during or immediately after a meal with a sufficient amount of water.

The usual dose is 1 tab. 400 mg 2 or 3 times/day. The maximum daily dose is 1200 mg.

In patients with impaired renal function (CrCl<30 ml/min), the dose may be reduced to 1-2 tablets per day.

A dose reduction, taking into account individual tolerance, is necessary in patients with severe hepatic impairment.

Treatment may be started with low doses in patients with low blood pressure, as well as in persons at risk due to possible blood pressure reduction (patients with severe coronary artery disease or with hemodynamically significant stenoses of cerebral vessels). In these cases, the dose can only be increased gradually.

Adverse Reactions

The following adverse reactions have been reported in clinical studies and post-marketing use of the drug (frequency unknown).

Nervous system disorders headache, dizziness, aseptic meningitis, convulsions.

Psychiatric disorders agitation, sleep disorders, anxiety.

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

Vascular disorders flushing, bleeding (including bleeding from skin vessels, mucous membranes, stomach, intestines).

Gastrointestinal disorders xerostomia (dry mouth), anorexia, intestinal atony, feeling of pressure and fullness in the gastric region, nausea, vomiting, diarrhea, constipation, hypersalivation (increased salivation).

Hepatobiliary disorders intrahepatic cholestasis, increased activity of “liver” transaminases, increased alkaline phosphatase activity.

Blood and lymphatic system disorders: leukopenia/neutropenia, thrombocytopenia, pancytopenia, hypofibrinogenemia.

Eye disorders visual impairment, scotoma.

Skin and subcutaneous tissue disorders skin itching, skin rash, erythema (reddening of the skin), urticaria, brittle nails, edema.

Immune system disorders anaphylactic/anaphylactoid reactions, angioedema, anaphylactic shock, bronchospasm.

Contraindications

• Hypersensitivity to pentoxifylline, other methylxanthines, or any excipient of the drug;
• Massive bleeding (risk of increased bleeding);
• Extensive hemorrhages in the retina (risk of increased bleeding);
• Cerebral hemorrhage;
• Acute myocardial infarction;
• Age under 18 years;
• Pregnancy (insufficient data);
• Breastfeeding period (insufficient data);
• Galactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome.

With caution

• Severe cardiac arrhythmias (risk of worsening arrhythmia);
• Arterial hypotension (risk of further decrease in blood pressure);
• Chronic heart failure;
• Peptic ulcer of the stomach and duodenum;
• Impaired renal function (CrCl below 30 ml/min) (risk of accumulation and increased risk of adverse reactions);
• Severe hepatic impairment (risk of accumulation and increased risk of adverse reactions);
• Recent surgical interventions;
• Increased risk of bleeding (e.g., in coagulation disorders (risk of more severe bleeding);
• Concomitant use with anticoagulants (including indirect anticoagulants [vitamin K antagonists]);
• Concomitant use with platelet aggregation inhibitors (clopidogrel, eptifibatide, tirofiban, epoprostenol, iloprost, abciximab, anagrelide, NSAIDs [except selective COX-2 inhibitors], acetylsalicylic acid, ticlopidine, dipyridamole);
• Concomitant use with hypoglycemic agents (insulin and oral hypoglycemic agents);
• Concomitant use with ciprofloxacin;
• Concomitant use with theophylline.

Use in Pregnancy and Lactation

The drug Pentoxifylline-SZ is contraindicated for use during pregnancy (due to insufficient data).

Pentoxifylline penetrates into breast milk in small amounts. If it is necessary to use the drug, breastfeeding should be discontinued (taking into account the lack of experience with its use).

Use in Hepatic Impairment

With caution: severe hepatic impairment (risk of accumulation and increased risk of adverse reactions).

Use in Renal Impairment

With caution: impaired renal function (CrCl below 30 ml/min) (risk of accumulation and increased risk of adverse reactions).

Geriatric Use

In elderly patients, a reduction in the dose of pentoxifylline may be required (increased bioavailability and reduced elimination rate).

Special Precautions

Treatment should be carried out under blood pressure monitoring.

In patients with diabetes mellitus taking hypoglycemic agents, the administration of large doses of pentoxifylline may cause pronounced hypoglycemia (dose adjustment of hypoglycemic agents and glycemic control may be required).

When prescribing the drug Pentoxifylline-SZ simultaneously with anticoagulants, monitoring of blood coagulation parameters is necessary.

In patients who have recently undergone surgery, regular monitoring of hemoglobin and hematocrit is necessary.

Patients with low and unstable blood pressure require a reduction in the dose of pentoxifylline.

In elderly patients, a reduction in the dose of pentoxifylline may be required (increased bioavailability and reduced elimination rate).

The safety and efficacy of pentoxifylline in children have not been sufficiently studied.

Smoking may reduce the therapeutic effectiveness of the drug.

Effect on ability to drive vehicles and operate machinery

Given the possible side effects (e.g., dizziness), caution should be exercised when driving vehicles and engaging in other potentially hazardous activities.

Overdose

Symptoms dizziness, nausea, coffee-ground vomiting, drop in blood pressure, tachycardia, arrhythmia, reddening of the skin, loss of consciousness, chills, areflexia, tonic-clonic convulsions.

Treatment: in case of the above disorders, it is necessary to urgently consult a doctor.

Treatment is symptomatic. At the first signs of overdose (sweating, nausea, cyanosis), the drug should be discontinued immediately. If the drug was taken recently, measures should be taken to prevent further absorption of the drug by its removal (gastric lavage) or by slowing absorption (e.g., taking activated charcoal).

Special attention should be paid to maintaining blood pressure and respiratory function. For convulsive seizures, diazepam is administered.

A specific antidote is unknown.

Drug Interactions

With antihypertensive agents

Pentoxifylline increases the risk of arterial hypotension when used concomitantly with antihypertensive agents (e.g., ACE inhibitors) or other drugs with potential antihypertensive effects (e.g., nitrates).

With drugs affecting the blood coagulation system

Pentoxifylline may enhance the effect of drugs affecting the blood coagulation system (direct and indirect anticoagulants, thrombolytics, antibiotics such as cephalosporins).

In post-marketing studies, cases of enhanced anticoagulant effect (risk of bleeding) have been reported with the combined use of pentoxifylline and indirect anticoagulants (vitamin K antagonists). Therefore, at the start of pentoxifylline administration or when changing its dose, it is recommended to monitor the degree of anticoagulant effect in patients taking this drug combination, for example, by regular INR monitoring.

With cimetidine

Cimetidine increases the plasma concentration of pentoxifylline and active metabolite I (risk of adverse reactions).

With other xanthines

Concomitant administration with other xanthines may lead to excessive nervous excitement.

With hypoglycemic agents (insulin and oral hypoglycemic agents)

The hypoglycemic effect of insulin or oral hypoglycemic agents may be enhanced with the concomitant use of pentoxifylline (increased risk of hypoglycemia). Strict monitoring of such patients is necessary, including regular glycemic control.

With theophylline

In some patients, concomitant use of pentoxifylline and theophylline leads to an increase in theophylline concentration. This may subsequently lead to an increase or intensification of side effects associated with theophylline.

With ciprofloxacin

In some patients, concomitant use of pentoxifylline and ciprofloxacin leads to an increase in the plasma concentration of pentoxifylline. This may subsequently lead to an increase or intensification of side effects associated with the use of this combination.

With platelet aggregation inhibitors

When pentoxifylline is used concomitantly with platelet aggregation inhibitors (clopidogrel, eptifibatide, tirofiban, epoprostenol, iloprost, abciximab, anagrelide, NSAIDs [except selective COX-2 inhibitors], acetylsalicylic acid, ticlopidine, dipyridamole), a potential additive effect may develop, increasing the risk of bleeding. Therefore, due to the risk of bleeding, Pentoxifylline should be used with caution simultaneously with the above-mentioned platelet aggregation inhibitors.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.