Pentoxifylline-zdorovya
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE | consumption | of the medicinal product PENTOXIFYLLINE-ZDOROV’YA (PENTOXIFYLLINE-ZDOROVYE)
Composition:
Active substance: pentoxifylline;
One tablet contains 100 mg of pentoxifylline;
Excipients: lactose monohydrate; corn starch; calcium stearate.
Pharmaceutical form. Tablets.
Main physicochemical characteristics: white or almost white tablets, flat cylindrical shape, with bevel.
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 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 CNS, and to a moderate extent in the kidneys. The drug slightly dilates coronary vessels.
Pharmacokinetics
After oral administration of 100 mg pentoxifylline, the drug is almost completely absorbed from the gastrointestinal tract. Cmax of pentoxifylline and its main metabolite (metabolite I) is reached within 1 hour after administration. The drug undergoes a pronounced "first-pass" effect in the liver. The bioavailability of the unchanged substance averages 19% (ranging from 6% to 32%). The primary pharmacologically active metabolite, 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (metabolite I), is present in plasma at concentrations exceeding those of the parent compound by two-fold and exists in a state of reversible biochemical equilibrium with it. Therefore, pentoxifylline and its metabolite should be considered as a single active entity, implying that the bioavailability of the active moiety is considerably higher.
The elimination half-life (T½) of pentoxifylline is 1.6 hours.
Pentoxifylline is completely metabolized, with over 90% of the dose 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, elimination of metabolites is delayed. In patients with impaired hepatic function, prolonged T½ of pentoxifylline and increased bioavailability are observed.
Clinical characteristics.
Indications. Atherosclerotic encephalopathy; ischemic cerebral stroke; dyscirculatory encephalopathy; peripheral circulation disorders due to atherosclerosis, diabetes mellitus (including diabetic angiopathy), inflammation; tissue trophic disorders associated with venous damage or microcirculation impairment (post-thrombophlebitic syndrome, trophic ulcers, gangrene, frostbite); obliterating endarteritis; angiopathies (Raynaud's disease); ocular circulation disorders (acute, subacute, chronic insufficiency of retinal and choroidal blood flow); vascular-origin inner ear function disorders accompanied by hearing loss.
Contraindications.
The medicinal product is contraindicated:
- in patients with hypersensitivity to pentoxifylline, to other methylxanthines, or to any of the excipients of the drug;
- in patients with massive bleeding (risk of bleeding exacerbation);
- in patients with extensive retinal hemorrhage or cerebral hemorrhage (risk of bleeding exacerbation). If retinal hemorrhage occurs during pentoxifylline treatment, the drug should be discontinued immediately;
- in patients with cerebral hemorrhage;
- in patients during the acute phase of myocardial infarction;
- in patients with gastric or intestinal ulcers;
- in patients 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 concurrently receiving pentoxifylline and vitamin K antagonists. When initiating or changing the dosage of pentoxifylline, monitoring of anticoagulant activity in these patients is recommended.
The drug may enhance the hypotensive effect of antihypertensive agents and other drugs that may cause arterial pressure reduction.
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 is possible.
Concomitant use of pentoxifylline and ketorolac may lead to prolonged prothrombin time and increase the risk of bleeding.
In some patients, concomitant use with ciprofloxacin may increase pentoxifylline plasma concentration. As a result, the frequency and severity of adverse reactions associated with concomitant administration 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.
If the first signs of an anaphylactic/anaphylactoid reaction occur, treatment with the drug should be discontinued immediately and medical advice should be sought.
In patients with chronic heart failure, circulation should first be stabilized into a compensated phase before initiating treatment.
In patients with diabetes mellitus receiving insulin or oral antidiabetic agents, high doses of pentoxifylline may enhance the blood glucose-lowering effect of these drugs (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 careful monitoring of the patient is required.
Pentoxifylline may be administered to patients with systemic lupus erythematosus 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 complete blood counts are necessary.
In patients with renal impairment (creatinine clearance < 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 the following patients:
- patients with severe cardiac arrhythmias;
- patients with myocardial infarction;
- 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 < 30 ml/min);
- patients with severe hepatic impairment;
- patients with a high predisposition to bleeding, e.g., due to anticoagulant therapy or coagulation disorders. For details on bleeding, see section "Contraindications";
- patients who have recently undergone surgery (increased risk of bleeding, requiring systematic monitoring of hemoglobin and hematocrit levels);
- patients receiving pentoxifylline concomitantly with vitamin K antagonists or platelet aggregation inhibitors (see section "Interaction with other medicinal products and other forms of interaction");
- patients receiving pentoxifylline concomitantly with antidiabetic agents (see section "Interaction with other medicinal products and other forms of interaction");
- patients receiving pentoxifylline concomitantly with ciprofloxacin (see section "Interaction with other medicinal products and other forms of interaction");
- patients receiving pentoxifylline concomitantly with theophylline (see section "Interaction with other medicinal products and other forms of interaction").
If a patient has known intolerance to certain sugars, medical advice should be sought before taking this medicinal product.
Use during pregnancy or breastfeeding.
Pregnancy. Experience with the use of pentoxifylline in pregnant women is insufficient. Therefore, the use of this drug during pregnancy is not recommended.
Breastfeeding. Pentoxifylline passes into breast milk in small amounts. If treatment with this drug is prescribed by a physician, breastfeeding should be discontinued.
Ability to influence the speed of reactions while driving or operating machinery.
Has no effect.
Dosage and Administration
The medicinal product should be administered at a dose of 2–4 tablets 2–3 times daily. Tablets should be taken after meals, without chewing, and washed down with sufficient amount of liquid. The maximum daily dose should not exceed 1.2 g.
For patients with labile or reduced arterial pressure or with significantly impaired renal function (creatinine clearance < 30 mL/min), as well as for patients at high risk of complications due to decreased arterial pressure (e.g. severe coronary artery disease, marked stenosis of cerebral main arteries), treatment should be initiated with low doses. Doses should be individually adjusted and gradually increased according to treatment tolerance.
Children. Experience with use of the drug in children is lacking.
Overdose. Initial symptoms of acute pentoxifylline overdose include nausea, dizziness, or hypotension. Additionally, symptoms such as fever, excitation, hot flushes, tachycardia, loss of consciousness, areflexia, arrhythmia, tonic-clonic seizures, and coffee-ground vomitus as a sign of gastrointestinal bleeding may develop.
Treatment of overdose. There is no known specific antidote. If excessive doses have been recently ingested, measures should be taken to prevent further systemic absorption of the active substance by primary elimination (e.g. gastric lavage) or by preventing its absorption (e.g. with activated charcoal).
In cases of acute overdose, general and specific intensive medical monitoring and therapeutic interventions are required 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 and aplastic anemia (partial or complete cessation of formation of all blood cells, pancytopenia), which may be fatal, leukopenia/neutropenia.
Nervous system disorders: dizziness, headache, aseptic meningitis, tremor, paresthesia, seizures.
Gastrointestinal disorders: gastrointestinal disturbances, feeling of pressure in the stomach, flatulence, nausea, vomiting, diarrhea, constipation, hypersalivation.
Skin and subcutaneous tissue disorders: itching, skin redness and urticaria, toxic epidermal necrolysis (Lyell's syndrome) and Stevens–Johnson syndrome, rash.
Vascular disorders: sensation of heat (flushing), bleeding, 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 hemorrhages, retinal detachment.
Other: hypoglycemia, increased sweating, increased body temperature.
Shelf life. 4 years.
Storage conditions. Store in original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging. Tablets, 30 pcs; 10×3 in blisters in a box.
Category of release. Prescription only.
Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".
Manufacturer's address and place of business.
22 Shevchenka Street, Kharkiv, Kharkiv region, 61013, Ukraine.