Pentoxifylline-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PENTOXIFYLLINE-DARNITSA

Composition:

Active substance: pentoxifylline;

1 tablet contains 200 mg of pentoxifylline;

Excipients: lactose monohydrate, potato starch, povidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white-colored, round-shaped tablets with a flat surface, beveled edges, and a score line.

Pharmacotherapeutic group.

Peripheral vasodilators. Purine derivatives. ATC code C04AD03.

Pharmacological Properties

Pharmacodynamics

Pentoxifylline is a derivative of methylxanthine. The mechanism of action of pentoxifylline is related to inhibition of phosphodiesterase and accumulation of cAMP in vascular smooth muscle cells, blood cells, as well as in 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 has a positive inotropic effect. As a result of pentoxifylline administration, microcirculation and tissue oxygenation are improved, most notably in the extremities and central nervous system, and to a moderate extent in the kidneys. The drug slightly dilates coronary vessels.

Pharmacokinetics

After oral administration, the drug is almost completely absorbed from the gastrointestinal tract. Maximum concentrations of pentoxifylline and its main metabolite (metabolite I) are reached within 1 hour after administration. The drug undergoes a pronounced "first-pass" effect through 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 twice those of the parent compound and exists in a state of reversible biochemical equilibrium with it. Pentoxifylline and its metabolite should be considered as a single active entity; therefore, the bioavailability of the active moiety is considered to be substantially higher.

The elimination half-life 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, excretion of metabolites is delayed. In patients with impaired liver function, prolonged elimination half-life and increased bioavailability of pentoxifylline have been 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 impaired microcirculation (post-thrombophlebitic syndrome, trophic ulcers, gangrene, frostbite); obliterating endarteritis; angioneuropathy (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.

• Hypersensitivity to pentoxifylline, to other methylxanthines, or to any of the excipients;
• Massive bleeding (risk of bleeding enhancement);
• Retinal hemorrhage (if retinal hemorrhage occurs during pentoxifylline treatment, the drug should be discontinued immediately);
• Cerebral hemorrhage;
• Hemorrhagic diathesis;
• Acute myocardial infarction;
• Gastric and/or duodenal ulcer.

Interaction with other medicinal products and other forms of interaction.

Pentoxifylline enhances the effect of antihypertensive and other vasodilating agents (ACE inhibitors, nitrates), which may cause severe arterial hypotension. When used concomitantly with adrenergic agents and ganglion blockers, a significant decrease in arterial pressure may occur.

Concomitant use of adrenergic agents or xanthines may lead to central nervous system stimulation.

Higher doses of pentoxifylline potentiate the effect of insulin and oral hypoglycemic agents. Due to the risk of hypoglycemia, more frequent monitoring of blood glucose levels is recommended, and adjustment of antidiabetic therapy may be necessary over time.

Pentoxifylline increases the frequency of hemorrhagic complications in patients concurrently treated with anticoagulants, antiplatelet agents, and thrombolytic agents. Patients receiving anticoagulants should have their prothrombin time measured more frequently.

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 changing the dosage of pentoxifylline, monitoring of anticoagulant activity in this patient group is recommended.

Cimetidine increases the plasma concentration of pentoxifylline, thereby increasing the risk of adverse reactions. Other H2-receptor antagonists (famotidine, ranitidine, and nizatidine) have significantly less effect on pentoxifylline metabolism.

Concomitant administration of pentoxifylline and theophylline may lead to increased serum theophylline concentration. Therefore, monitoring of serum theophylline levels is necessary, and its dose should be reduced if needed.

Concomitant use of pentoxifylline and ketorolac may lead to prolonged prothrombin time and increased risk of bleeding. The risk of bleeding may also be increased when pentoxifylline is used concomitantly with meloxicam. Therefore, concomitant treatment with these drugs is not recommended.

Cyprofl oxacin inhibits the hepatic metabolism of pentoxifylline; thus, concomitant administration of pentoxifylline and ciprofloxacin may lead to increased serum concentration of pentoxifylline. If concomitant treatment with pentoxifylline and ciprofloxacin is necessary, it is recommended to reduce the dose of pentoxifylline by half.

Antacids: for patients experiencing gastrointestinal adverse effects, antacids may be co-administered with pentoxifylline. In a comparative bioavailability study, antacids did not alter the absorption of pentoxifylline.

Platelet aggregation inhibitors: due to the increased risk of bleeding, concomitant use of platelet aggregation inhibitors (e.g., clopidogrel, eptifibatide, tirofiban, epoprostenol, iloprost, abciximab, anagrelide, non-selective non-steroidal anti-inflammatory drugs (NSAIDs) except selective COX-2 inhibitors, acetylsalicylates (acetylsalicylic acid (ASA) / lysine acetylsalicylate (LAS)), ticlopidine, dipyridamole) with pentoxifylline should be performed with caution.

Special precautions for use

At the first signs of an anaphylactic/anaphylactoid reaction, treatment with the drug should be discontinued and medical advice should be sought immediately.

When using pentoxifylline in patients with chronic heart failure, circulatory compensation should be achieved prior to initiating therapy.

In patients with diabetes mellitus 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 forms of interaction"). In such cases, the dose of insulin or oral antidiabetic agents should be reduced, and particularly careful monitoring of the patient is required.

The medicinal product should be used with caution in patients who are concurrently receiving pentoxifylline and ciprofloxacin (see section "Interaction with other medicinal products and other forms of interaction").

Pentoxifylline should 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.

Particular caution and close monitoring are required in patients:

• with severe cardiac arrhythmias;
• with myocardial infarction;
• with arterial hypotension;
• with pronounced atherosclerosis of cerebral and coronary vessels, especially in the presence of concomitant arterial hypertension and cardiac rhythm disturbances. In such patients, treatment with the medicinal product may provoke angina attacks, arrhythmias, and arterial hypertension;
• with renal impairment (creatinine clearance below 30 mL/min);
• with severe hepatic insufficiency;
• with a high predisposition to bleeding, for example, due to anticoagulant therapy or coagulation disorders. For details on bleeding, see section "Contraindications";
• with a history of gastric or duodenal ulcer, or patients who have recently undergone surgery (increased risk of bleeding, therefore systematic monitoring of hemoglobin and hematocrit levels is required);
• who are concurrently treated with pentoxifylline and vitamin K antagonists (see section "Interaction with other medicinal products and other forms of interaction");
• who are concurrently treated with pentoxifylline and antidiabetic agents (see section "Interaction with other medicinal products and other forms of interaction").

Since the medicinal product contains lactose, it should not be administered to patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding

As there is insufficient experience with the use of pentoxifylline in pregnant women, the drug should not be administered during pregnancy.

Pentoxifylline passes into breast milk in small amounts. If treatment with pentoxifylline is necessary, breastfeeding should be discontinued.

Ability to influence the speed of reactions while driving or operating machinery

Given that adverse reactions such as dizziness and blurred vision may occur in sensitive patients during pentoxifylline therapy, patients should refrain from driving vehicles or operating machinery, and from performing other tasks requiring concentration, during treatment with this medicinal product.

Dosage and Administration.

The medicinal product should be administered at a dose of 2–4 tablets 2–3 times daily. The tablets should be taken after meals, without chewing, with sufficient amount of liquid. The maximum daily dose should not exceed 1200 mg (6 tablets).

In case of arterial hypotension or adverse reactions from the gastrointestinal tract or central nervous system, the initial dose may be reduced to 100 mg of pentoxifylline 3 times daily.

In patients with impaired renal function (creatinine clearance < 30 mL/min), the dose should be reduced by 50–70%, according to individual sensitivity.

Patients with severe hepatic dysfunction also require dosage reduction according to individual sensitivity.

In patients with arterial hypotension, as well as in patients at risk of a sharp drop in arterial pressure (e.g., those with coronary artery disease or pronounced cerebral arterial stenosis), treatment should be initiated with low doses, gradually increasing them until a therapeutic effect is achieved.

The medicinal product in tablet form may be prescribed as an addition to parenteral administration or as maintenance therapy following its intravenous administration.

The duration of treatment is determined individually by the physician.

Children.

Due to insufficient clinical experience, the medicinal product is not recommended for use in children.

Overdose.

Symptoms: initial symptoms of acute pentoxifylline overdose may include nausea, dizziness, tachycardia, or decreased arterial pressure. Subsequently, fever, hyperthermia, agitation, flushing, loss of consciousness, arrhythmia, areflexia, tonic-clonic seizures, and vomiting of "coffee-ground" material indicating gastrointestinal bleeding may occur.

Treatment: in case of overdose, further systemic absorption of pentoxifylline should be prevented by immediate removal (e.g., gastric lavage) or delayed absorption (e.g., administration of activated charcoal). A specific antidote is not known.

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

Adverse reactions.

Eye disorders: visual disturbances, blurred vision, scotoma, lacrimation, conjunctivitis, retinal hemorrhage, retinal detachment.

Ear and labyrinth disorders: ear pain.

Gastrointestinal disorders: gastrointestinal disturbances, abdominal pain, gastric pressure sensation, nausea, vomiting, diarrhea, flatulence, anorexia, intestinal atony, constipation, dryness of throat, thirst, taste disturbances, hypersalivation.

Hepatobiliary disorders: intrahepatic cholestasis, exacerbation of cholecystitis, cholestatic hepatitis.

Nervous system disorders: headache, migraine, dizziness, anxiety, restlessness, sleep disturbances, convulsions, aseptic meningitis (with high-dose use), tremor, paresthesia, excitation, hallucinations.

Cardiovascular disorders: tachycardia, arrhythmia, cardialgia, peripheral edema, angina pectoris, decreased blood pressure, increased blood pressure, dyspnea, hemorrhage (e.g., into the skin, mucous membranes, stomach, intestine).

Blood and lymphatic system disorders: thrombocytopenia with thrombocytopenic purpura, leukopenia/neutropenia, pancytopenia which may be fatal, hypofibrinogenemia, anemia, aplastic anemia; bleeding from skin vessels, mucous membranes, stomach, intestine, nose.

Immune system disorders: allergic reactions, including anaphylactic and anaphylactoid reactions, angioneurotic edema, bronchospasm and anaphylactic shock, pruritus, skin hyperemia, urticaria, rash, toxic epidermal necrolysis (Lyell's syndrome), and Stevens-Johnson syndrome.

Skin and subcutaneous tissue disorders: allergic skin reactions, facial hyperemia (flushing) and upper chest, edema, increased nail fragility, skin eruptions (including vesicular).

General disorders: malaise, enlargement and tenderness of glands in the throat and neck, laryngitis, nasal congestion, weight decrease/increase, fever, hyperthermic syndrome, hypoglycemia, increased sweating.

Laboratory findings: increased activity of liver transaminases (ALT, AST, LDH) and alkaline phosphatase.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

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 pack; 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical company "Darnytsia".

Manufacturer's address and location of activity.

13, Boryspilska Street, Kyiv, 02093, Ukraine.