INSTRUCTIONS FOR MEDICAL USE
PENTOFIRAL
Trade name of the drug: Pentofiral
Active substance (INN): Pentoxifylline
Dosage form: solution for injection.
Contents:
5 ml of solution (1 ampoule) contains:
Active ingredient: Pentoxifylline – 100 mg.
Excipients: sodium chloride, water for injections.
Description: clear, colorless or slightly yellowish liquid.
Pharmacotherapeutic group: agents for treatment of peripheral circulation disorders.
ATX code: C04AD03.
Pharmacological properties
Pentoxifylline is a derivative of methylxanthine. Mechanism of action of pentoxifylline is associated with inhibition of phosphodiesterase and accumulation of CAMF in cells of vascular smooth muscle, in blood cells and other tissues and organs. Pentoxifylline inhibits platelet and erythrocyte aggregation, increases their flexibility, reduces the increased concentration of fibrinogen in the blood plasma and enhances fibrinolysis, which reduces blood viscosity and improves its rheological properties. In addition, pentoxifylline causes a weak myotropic vasodilator effect, slightly reduces total peripheral vascular resistance and has a positive inotropic effect. As a result of pentoxifylline improves microcirculation and tissue oxygen supply, to the greatest extent in the limbs, CNS, moderately – in the kidneys. The drug slightly dilates coronary vessels.
Pharmacokinetics
Main pharmacologically active metabolite 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (metabolite I) is determined in blood plasma concentration exceeding by 2 times the concentration of unchanged substance and is in reversible biochemical equilibrium with them. Therefore, pentoxifylline and its metabolite should be considered as an active unit. The half-life (T1/2) of pentoxifylline is 1.6 hours.
Pentoxifylline is completely metabolized, more than 90% is excreted by the kidneys as unconjugated water-soluble polar metabolites. Less than 4% of the dose is excreted with the feces. Excretion of metabolites is delayed in patients with severe renal dysfunction. Prolongation of T1/2 of pentoxifylline was noted in patients with impaired liver function.
Indications for use
Atherosclerotic encephalopathy, ischemic cerebral stroke; discirculatory encephalopathy, peripheral circulatory disorders, caused by atherosclerosis, diabetes (including diabetic angiopathy), inflammation; trophic disorders in tissues, associated with vein damage or microcirculatory disorders (postthrombophlebitic syndrome, trophic ulcers, gangrene, frostbite); obliterating endarteritis, angioneuropathy (Raynaud’s disease), ocular circulation disorders (acute, subacute, chronic circulatory failure in the retina and choroid), inner ear malfunction of vascular genesis, accompanied by hearing loss.
Dosage and administration
Intravenous (IV) infusions are the most effective forms of parenteral administration of the drug, which are better tolerated. Dosing regimen is determined by the physician and depends on the severity of circulatory disorders, body weight and tolerability of treatment.
Infusion may be carried out only if the solution is clear.
The following treatment regimens are recommended for adults:
- IV infusion of 100-600 mg of pentoxifylline in 100-500 ml of Ringer’s lactate solution, 0.9% sodium chloride solution or 5% glucose solution 1-2 times a day. The duration of the intravenous drip infusion is 60-360 minutes, that is – the injection of 100 mg of pentoxifylline should last at least 60 minutes. The infusion can be supplemented with oral administration of pentoxifylline (400 mg) at the rate that the maximum daily dose (infusion and oral) is 1200 mg.
- If the patient’s condition is severe (especially in persistent pain, gangrene, or trophic ulcers), a 24-hour infusion of the drug is possible. With such a scheme of administration, the dose is determined at the rate of 0.6 mg/kg/h. Thus calculated daily dose for a patient with body weight of 70 kg is 1000 mg, for a patient with body weight of 80 kg -1150 mg.
Regardless of the patient’s body weight, the maximum daily dose is 1200 mg.
The volume of infusion solution is calculated individually, taking into account concomitant diseases and patient’s state, and averages 1-1.5 liters per day.
- In some cases, the drug is used by intravenous injection of 5 ml (100 mg). The injection is carried out slowly, for 5 minutes, the patient’s position is lying down.
Elderly patients. No dosage adjustment is necessary for elderly patients.
The duration of the parenteral course of treatment is determined by the treating physician.
After the patient’s condition improves, it is recommended to continue treatment using the tablet form of the drug.
Side effects
The incidence of adverse reactions on individual body systems:
Cardiovascular system: rare-tachycardia; not frequent-peripheral edema, facial redness and feeling of heat (flushes), very rare- atypical chest pain, arterial hypotension, angina progression, arterial hypertension, dyspnea, arrhythmia, palpitation.
Blood and lymphatic system disorders: single cases – thrombocytopenia and thrombocytopenic purpura, leukopenia, pancytopenia (which may be fatal), prolongation of prothrombin time, hypofibrinogenemia, anemia, aplastic anemia, bleeding (eg, from vessels of skin, mucous membranes, stomach, intestines, nose).
Nervous system: rarely – headache, dizziness, aseptic meningitis (in high doses); single cases – tremor of hands, insomnia, agitation, anxiety, fear, loss of consciousness, sleep disorders, hallucinations, darkened eyes, numbness of extremities, hyperhidrosis, seizures, paresthesias.
Senses: visual disturbances, scotoma, lacrimation, conjunctivitis, ear pain, migraine, retinal hemorrhages, retinal detachment.
Gastrointestinal tract: often – gastrointestinal disorders, feeling of pressure in the stomach, its overflow, diarrhea; not often – nausea, vomiting (including repeated), flatulence, epigastric pain, anorexia, bowel atony, constipation, dry throat, thirst.
Metabolism: very rare – hypoglycemia, hypokalemia.
Immune system: single cases – allergic reactions (anaphylactic/anaphylactoid reactions up to shock, angioedema, bronchospasm, skin redness, itching, rash, urticaria), toxic epidermal necrolysis (Lyell syndrome), Stevens-Johnson syndrome.
Hepatobiliary system: very rarely – intrahepatic cholestasis, increased liver enzyme activity, exacerbation of cholecystitis, cholestatic hepatitis.
Skin and subcutaneous tissue: very rarely – increased sweating, hyperemia of the face and upper chest, edema, maculopapular rash, increased nail fragility.
Changes at the injection site: pain at the injection site, hyperemia, swelling, rash.
Others: taste disorders, increased salivation, malaise, sore throat/neck, laryngitis, nasal congestion, weight gain/loss, chills, fever, hyperthermia.
Laboratory parameters: increased activity of liver transaminases (ALT, ACT, LDH) and alkaline phosphatase.
Most adverse reactions are dose-related. They can be minimized or avoided altogether by reducing the dose.
If severe adverse reactions occur, treatment should be discontinued.
Contraindications
- Hypersensitivity to pentoxifylline, to other ingredients of the drug or to other preparations of the methylxanthine group such as theophylline, caffeine, choline theophylline, aminophylline or theobromine;
- Massive bleeding (risk of increased bleeding);
- Retinal hemorrhages, cerebral hemorrhages; if retinal hemorrhages occur during treatment with pentoxifylline, the drug should be discontinued immediately;
- hemorrhagic diathesis;
- acute myocardial infarction;
- hepatic or renal insufficiency;
- peptic ulcer and/or intestinal ulcers;
- porphyria;
- Pregnancy and lactation;
- Childhood under 18 years of age.
Drug interactions
Concomitant use of pentoxifylline and antihypertensive drugs (particularly angiotensin converting enzyme inhibitors) increases the effect of the latter, so appropriate adjustment of doses of hypotensive drugs is required.
Anticoagulants, drugs that reduce blood coagulation. Simultaneous use of pentoxifylline and drugs that reduce blood coagulation increases the possibility of bleeding, so prothrombin time should be monitored more often. When pentoxifylline dosing is prescribed or changed, it is recommended that anticoagulant activity be monitored in these patients.
Cimetidine. Simultaneous administration of cimetidine results in a significant increase in serum pentoxifylline concentrations. Possible signs of pentoxifylline overdose should be closely monitored.
Other H2 – receptor antagonists (famotidine, ranitidine and nizatidine) have significantly less effect on pentoxifylline metabolism.
Theophylline. Simultaneous administration of pentoxifylline and theophylline may lead to increased serum concentration of theophylline. Therefore, it is necessary to monitor the concentration of theophylline in blood serum, if necessary – to reduce its dose.
Ketorolac, meloxicam. Concomitant use of pentoxifylline and ketorolac may lead to increased prothrombin time and increase the risk of bleeding. The risk of bleeding may also increase with concomitant use of pentoxifylline and meloxicam. Therefore, concomitant treatment with these drugs is not recommended.
Ciprofloxacin. Ciprofloxacin inhibits the metabolism of pentoxifylline in the liver, so the simultaneous use of pentoxifylline and ciprofloxacin may lead to an increase in serum pentoxifylline concentrations. If concomitant treatment with pentoxifylline and ciprofloxacin is necessary, it is recommended that the dose of pentoxifylline be halved.
Insulin and oral antidiabetic drugs. Large intravenous doses of pentoxifylline may exacerbate the hypoglycemic effects of insulin and oral antidiabetic drugs so dosages of insulin or hypoglycemic drug should be adjusted accordingly.
Nitrates. Pentoxifylline enhances the effects of nitrates.
Erythromycin. There are no data on possible interaction between pentoxifylline and erythromycin. However, when pentoxifylline and erythromycin are used together, an increase in plasma levels of erythromycin with signs of toxic reactions is observed.
Special indications
Pentoxifylline should not be used during pregnancy or lactation.
There is no experience of using the drug in children under 18 years of age.
At the first signs of anaphylactic/anaphylactoid reaction, treatment with the drug should be discontinued and the patient should seek medical attention. When using the drug in patients with chronic heart failure, the circulatory compensation phase should be reached beforehand. In diabetic patients treated with insulin or oral antidiabetic agents, when using high doses of the drug, the effect of these drugs on blood sugar levels may increase. In such cases, the dose of insulin or oral antidiabetic agents should be reduced and the patient should be monitored particularly closely. Patients with systemic lupus erythematosus (SLE) or other connective tissue diseases should be prescribed pentoxifylline only after a detailed analysis of possible risks and benefits. Since there is a risk of aplastic anemia during treatment with pentoxifylline, regular monitoring of general blood counts is necessary.
In patients with renal insufficiency (creatinine clearance less than 30 ml/min) or severe hepatic dysfunction, excretion of pentoxifylline may be delayed. Proper monitoring is necessary.
In elderly patients, it may be necessary to reduce the average therapeutic dose due to increased bioavailability and reduced excretion rate of the active substance.
Smoking may reduce the therapeutic efficacy of the drug. Particularly close monitoring is necessary for:
- patients with severe cardiac arrhythmias;
- patients with myocardial infarction;
- Patients with arterial hypotension;
- patients with severe atherosclerosis of cerebral and coronary vessels, especially with concomitant arterial hypertension and heart rhythm disturbances. In these patients, when taking the drug, angina pectoris, arrhythmias and arterial hypertension may occur;
- patients with renal insufficiency (creatinine clearance (CK) below 30 ml/min);
- patients with severe hepatic impairment;
- patients with a high propensity for bleeding, e.g., due to treatment with anticoagulants or clotting disorders. Regarding bleeding – see section “Contraindications”;
- Patients with a history of gastric or duodenal ulcers;
- Patients who have recently undergone surgical treatment (increased risk of bleeding, and therefore requires systematic monitoring of hemoglobin and hematocrit levels);
- patients for whom decreased blood pressure is a high risk (e.g., patients with severe coronary heart disease or stenosis of vessels that deliver blood to the brain);
- patients concomitantly treated with pentoxifylline and antivitamins K (coumarins);
- patients simultaneously treated with pentoxifylline and antidiabetic agents.
The possibility of adverse reactions from the central nervous system should also be considered.
The drug should not be mixed with other drugs in the same container, except for solutions specified in section “Dosage and administration”.
Form of production
Solution for injection 100 mg/5 ml in 5 ml ampoules #5 (1×5), #10 (2×5)
Storage conditions
Store in a dry, dark place at a temperature not exceeding 25°C. Keep out of the reach of children!
Shelf life
2 years. Do not use after the expiration date.
Conditions of dispensing from pharmacies
Released by a doctor’s prescription.