Agapurin - instructions for use, dose, side effects, contraindications

The mechanism of action of pentoxifylin is associated with inhibition of the phosphodiesterase enzyme and an increase in the content of cyclic adenosine monophosphate (cAMP) in cells of the smooth muscles of blood vessels and blood cells, which in turn leads to vasodilation, a decrease in total peripheral vascular resistance, an increase in the shock and minute blood volume without a significant change in frequency heart rate (HR).

Improves microcirculation in areas of impaired blood circulation.

In the occlusive lesion of peripheral arteries ("intermittent" lameness) leads to an elongation of the distance of walking, elimination of night cramps of gastrocnemius muscles and pain at rest.

Pharmacokinetics:

After oral administration pentoxifylline almost completely absorbed from the gastrointestinal tract. Absolute bioavailability of the starting material is 19 ± 13%.The drug undergoes a "primary passage" through the liver with the formation of 2 major pharmacologically active metabolites: 1-5-hydroxyhexyl-3,7-dimethylxanthine (metabolite I) and 1-3-carboxypropyl-3,7-dimethylxanthine (metabolite V). The concentration of metabolite I in blood plasma is 2 times higher than that of the starting substance. Metabolite I is with pentoxifylline in reversible biochemical redox equilibrium. therefore pentoxifylline and the metabolite I are considered together as the active unit. As a consequence, the availability of the active substance is much greater.

Pentoxifylline has a large volume of distribution (168 L after a 30-minute infusion of 200 mg) and a high clearance of approximately 4,500-5100 ml / min. Half-life (T_1/2) is - 1.6 hours. Pentoxifylline is excreted mainly by the kidneys - 94% in the form of unconjugated water-soluble metabolites, the intestine - 4%, in the first 4 hours up to 90% of the dose is excreted.

Patients with impaired renal function

With severe renal dysfunction, excretion of metabolites is slowed down.

Patients with hepatic impairment

If there is a violation of the liver, lengthening T_1/2 and an increase in absolute bioavailability.

Indications:

- Occlusal disease of peripheral arteries of atherosclerotic or diabetic origin (for example, "intermittent" lameness, diabetic angiopathy).

- Trophic disorders (for example, trophic ulcers of the legs, gangrene).

- Disorders of cerebral circulation (the consequences of cerebral atherosclerosis, such as reduced concentration, dizziness, memory impairment), ischemic and post-insult conditions.

- Disturbances of blood circulation in the mesh and choroid of the eye.

- Otosclerosis, degenerative changes on the background of the pathology of the vessels of the inner ear and hearing loss.

Contraindications:

- Hypersensitivity to pentoxifylline, other methylxanthines or to any auxiliary substance of the drug;

- massive bleeding (risk of increased bleeding);

- extensive hemorrhage in the mesh of the eye (risk of increased bleeding);

- hemorrhages in the brain;

- acute myocardial infarction;

- age under 18 years (effectiveness and safety not established);

- pregnancy (insufficient data);

- period of breastfeeding (insufficient data).

Carefully:

Use with caution in patients with a marked decrease in blood pressure (BP) (including patients with severe coronary heart disease or hemodynamically significant stenoses of cerebral vessels), with severe disturbances of the heart rhythm; chronic heart failure (CHF); severe impairment of liver function (risk cumulation and an increased risk of side effects, see section "Method of administration and dose"); impaired renal function (creatinine clearance (CK) less than 30 ml / min) (risk of cumulation and an increased risk of side effects, see section "Method of administration and dose"); with increased tendency to bleeding, for example, as a result of the use of indirect anticoagulants [vitamin K antagonists] or in disorders in the blood coagulation system (risk of developing more severe bleeding) (see section "Interaction with other medicinal products"); after a recent surgery (risk of bleeding).

Caution should be exercised with the simultaneous use of the drug AGAPURIN with platelet aggregation inhibitors (clopidogrel, eptifibatide, tirofiban, epoprostenol, iloprost, abciximab, anagrelide, NSAIDs [other than selective inhibitors cyclooxygenase-2], acetylsalicylic acid, ticlopidine, dipyridamole), hypoglycemic agents (insulin and hypoglycemic agents for oral administration), ciprofloxacin and theophylline (see section "Interaction with other drugs").

Pregnancy and lactation:

The use of the drug AGAPURIN during pregnancy is contraindicated.

The use of the drug Agapurin during breastfeeding is contraindicated, since pentoxifylline excreted in breast milk. If you need to use the drug during lactation, breastfeeding should be canceled.

Dosing and Administration:

The dose and method of application are determined by the severity of circulatory disorders, and also on the basis of the individual tolerability of the drug Agapurin. Dosage is set by the doctor in accordance with the individual characteristics of the patient.

When carrying out infusions, the patient should be lying down.

The usual dose is from 100 mg to 600 mg of the drug AGAPURIN, diluted in 250 ml or 500 ml of a 0.9% solution of sodium chloride or Ringer's solution, once or twice a day.

Compatibility with other infusion solutions should be tested separately; Only transparent solutions can be used.

100 mg of the drug AGAPURIN should be administered for at least 60 minutes.

In addition to infusion therapy, pentoxifylline preparations for oral administration can be prescribed. In this case, the total daily dose of pentoxifylline (intravenous infusion + ingestion) should not exceed 1200 mg.

Depending on the concomitant diseases (for example, chronic heart failure), there may be a need to reduce the amounts administered. In such cases it is recommended to use a special infuser for controlled infusion.

In more severe cases, especially in patients with severe pain at rest, with gangren or trophic ulcers (III-IV stage according to Fontaine's classification) shows a prolonged intravenous infusion of the drug Agapurin at a dose of 1200 mg for 24 hours. This dose can be divided into two infusion injections of 600 mg, each of which must be continued for at least 6 hours. In this case, the individual dose can be calculated by the formula: 0.6 mg pentoxifylline per kg body weight per hour.The daily dose thus calculated will be 1000 mg of pentoxifylline for a patient weighing 70 kg and 1150 mg of pentoxifylline for a patient with a body weight of 80 kg.

With maintenance therapy, the patient is transferred to pentoxifylline preparations for oral administration.

In patients with renal insufficiency (CC less than 30 ml / min), it is necessary to reduce the dosage by 30-50%, which depends on the individual tolerability of the drug AGAPURIN by the patient.

Dose reduction, taking into account individual tolerability, is necessary in patients with severe hepatic impairment.

Treatment can be initiated in small doses in patients with low blood pressure, as well as in patients at risk because of the possible reduction in blood pressure (patients with severe ischemic heart disease or hemodynamically significant stenoses of cerebral vessels). In these cases, the dose can be increased only gradually.

Side effects:

Undesirable reactions are presented according to the systems of organs in accordance with the classification of the Medical Dictionary of Regulatory Activities (MedDRA).

Below are the adverse reactions that were noted in clinical trials and in the post-marketing application of the drug (the frequency is unknown).

Impaired nervous system: headache, dizziness, aseptic meningitis, convulsions.

Disorders of the psyche: agitation, sleep disturbance, anxiety.

Heart Disease: tachycardia, arrhythmia, lowering of arterial pressure, stenocardia.

Vascular disorders: "tides" of blood to the skin, bleeding (including bleeding from the vessels of the skin, mucous membranes, stomach, intestines).

Disorders from the digestive system: xerostomia (dry mouth), anorexia, intestinal atony, feeling of pressure and overflow in the stomach, nausea, vomiting, diarrhea, constipation, hypersalivation (increased salivation).

Disorders from the liver and bile ducts: intrahepatic cholestasis, increased activity of "liver" transaminases, increased activity of alkaline phosphatase.

Violations from the blood and lymphatic system: leukopenia / neutropenia, thrombocytopenia, pancytopenia, hypofibrinogenemia.

Disorders from the side of the organ of vision: impaired vision, scotoma.

Disturbances from the skin and subcutaneous tissues: itching, skin rash, erythema (reddening of the skin), urticaria, increased brittleness of the nails, swelling.

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

Overdose:

When the first signs of an overdose appear, stop the injection immediately. Provide a lower position of the head and upper body.

Symptoms: weakness, dizziness, marked decrease in blood pressure, fainting, tachycardia, arrhythmia, drowsiness, loss of consciousness, tonic-clonic convulsions, increased nervous excitability, hyperthermia, areflexia, signs of gastrointestinal bleeding ("coffee grounds" type vomiting).

Treatment: symptomatic. Particular attention should be directed to maintaining the function of respiration and blood pressure and urgent measures for bleeding. Convulsions stop with the introduction of diazepam.

Interaction:

FROM antihypertensive drugs

Pentoxifylline enhances blood pressure lowering with simultaneous use with antihypertensive agents (eg, angiotensin converting enzyme (ACE) inhibitors or other drugs that have a potential antihypertensive effect (eg, nitrates).

With drugs that affect the blood coagulation system

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

With the combined use of pentoxifylline and indirect anticoagulants (vitamin K antagonists) in post-marketing studies, there have been cases of increased anticoagulant action (risk of bleeding).

Therefore, at the beginning of taking pentoxifylline or changing its dose, it is recommended to monitor the degree of anticoagulant effect in patients taking this combination of drugs, for example, regular monitoring of INR (international normalized ratio).

With cimetidine

Cimetidine increases the concentration of pentoxifylline and active metabolite I in the blood plasma (risk of side effects).

With other xanthines

Co-administration with other xanthines can lead to excessive nervous excitement.

With hypoglycemic agents (insulin and hypoglycemic agents for oral administration)

Hypoglycemic effect of insulin or hypoglycemic agents for receiving inside can be amplified while the use of pentoxifylline (increased risk of hypoglycaemia). Strict monitoring of the condition of such patients is required, including regular glycemic control.

With theophylline

In some patients, while the use of pentoxifylline and theophylline there is an increase in blood concentration of theophylline. This may lead to an increase or increase in side effects associated with theophylline.

With ciprofloxacin

In some patients, while the use of pentoxifylline and ciprofloxacin marked increase in the concentration of pentoxifylline in plasma. This may lead to an increased risk of development or enhancement of side effects associated with the use of this combination.

With platelet aggregation inhibitors

With the simultaneous use of pentoxifylline with inhibitors aggregation of thrombocytes (clopidogrel, eptifibatide, tirofiban, epoprostenol, iloprost, abciximab, anagrelideNSAIDs [besides selective inhibitors of cyclooxygenase-2] acetylsalicylic acid, ticlopidine, dipyridamole) it is possible to develop a potential additive effect that increases the risk of bleeding. Therefore, caution should be applied to the preparation of AGAPURIN concomitantly with the above listed platelet aggregation inhibitors (see the section "With caution").

Special instructions:

Treatment should be carried out under the control of blood pressure.

In patients with diabetes mellitus taking hypoglycemic agents, administration of large doses of the drug AGAPURIN can cause severe hypoglycemia (dose adjustment is required).

When prescribing the drug AGAPURIN concomitantly with anticoagulants, it is necessary to closely monitor the parameters of the blood coagulation system.

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

Patients with low and unstable blood pressure should choose the dose of the drug AGAPURIN individually.

Older patients may need to reduce the dose of the drug AGAPURIN (increased bioavailability and reduced elimination rate).

The safety and effectiveness of the drug AGAPURIN in children are not well understood.

Care should be taken when using the AGAPURIN preparation for patients with severe liver dysfunction. Given the risk of cumulation of the drug and an increased risk of side effects, dose reduction should be carried out taking into account individual tolerability.

Patients with severe impairment of kidney function (QC below 30 ml / min) with the administration of the drug AGAPURIN need careful medical supervision.

In the event that during the period of application of the drug the patients have hemorrhages in the retina of the eye, the drug is immediately canceled.

Smoking can reduce the therapeutic effectiveness of the drug AGAPURIN.

The compatibility of a solution of pentoxifylline with another infusion solution should be checked in each case.

Effect on the ability to drive transp. cf. and fur:

The negative effect of the drug AGAPURIN on the ability to control vehicles and mechanisms was not noted. However, care should be taken when driving and during training, requiring increased concentration and speed of psychomotor reactions,because of the possibility of dizziness and visual impairment when using the drug AGAPURIN.

Form release / dosage:

Concentrate for solution for infusion, 20 mg / ml.

Packaging:

5 ml in ampoules of hydrolytic glass class 1.

5 ampoules are placed in a cardboard box together with instructions for use.

Storage conditions:

At temperatures up to 25 ° С.

Keep out of the reach of children.

Shelf life:

3 years

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N012051 / 02

Date of registration:18.05.2010 / 08.08.2016

Expiration Date:Unlimited

Date of cancellation:2017-04-04

The owner of the registration certificate:Zentiva as.Zentiva as. The Slovak Republic

Manufacturer: & nbsp

ZENTIVA, a.s. Czech Republic

Representation: & nbspZENTIVA ZENTIVA Czech Republic

Information update date: & nbsp04.04.2017

Illustrated instructions

Instructions

Agapurin (Agapurin)