Agapurin (Solution) Instructions for Use

Marketing Authorization Holder

Zentiva, a.s. (Slovakia)

ATC Code

C04AD03 (Pentoxifylline)

Active Substance

Pentoxifylline (Rec.INN registered by WHO)

Dosage Form

Agapurin

Injection solution 20 mg/1 ml: amp. 5 ml 5 pcs.

Dosage Form, Packaging, and Composition

Solution for injection transparent, colorless.

Excipients : sodium chloride, water for injections.

5 ml – ampoules (5) – carton packs.

Clinical-Pharmacological Group

Drug improving microcirculation. Angioprotector

Pharmacotherapeutic Group

Vasodilating agent

Pharmacological Action

Antispasmodic agent from the purine group. It improves microcirculation and the rheological properties of blood. The mechanism of action is associated with the inhibition of phosphodiesterase and an increase in the content of cAMP in platelets and ATP in erythrocytes with simultaneous saturation of the energy potential, which in turn leads to vasodilation, a decrease in total peripheral vascular resistance, and an increase in stroke and minute blood volume without a significant change in heart rate.

By dilating the coronary arteries, it increases oxygen delivery to the myocardium (antianginal effect), and the pulmonary vessels – improves blood oxygenation. It increases the tone of the respiratory muscles (intercostal muscles and diaphragm). When administered intravenously, it leads to enhanced collateral circulation, an increase in the volume of blood flowing per unit cross-section. It leads to an increase in ATP content in the brain and has a beneficial effect on the bioelectrical activity of the CNS. It reduces blood viscosity, increases the elasticity of the erythrocyte membrane (by acting on pathologically altered erythrocyte deformability). It improves microcirculation in areas of impaired blood circulation.

In occlusive lesions of peripheral arteries (intermittent claudication), it leads to an increase in walking distance, elimination of night cramps of the calf muscles and pain at rest.

Pharmacokinetics

The drug is rapidly metabolized in the liver. Several active metabolites are formed during metabolism, the main ones being metabolite 1 and metabolite 5. Their concentrations in blood plasma are 5 and 8 times (respectively) higher than the concentration of the parent substance.

It is excreted as metabolites (94%) and through the intestines (4%), up to 90% of the dose is excreted within the first 4 hours. 2% of the drug is excreted unchanged. Pentoxifylline and its metabolites do not bind to plasma proteins.

In severe renal impairment, the excretion of metabolites is slowed. In case of impaired liver function, an increase in the half-life and an increase in bioavailability are noted.

Indications

• Peripheral circulation disorders against the background of atherosclerotic, diabetic and inflammatory processes (including intermittent claudication caused by atherosclerosis, diabetic angiopathy, obliterating endarteritis);
• Trophic tissue disorders due to impaired arterial or venous microcirculation (varicose ulcers, gangrene, frostbite);
• Angioneuropathies (paresthesias, acrocyanosis, Raynaud’s disease);
• Acute and chronic cerebrovascular accidents of ischemic origin (including in cerebral atherosclerosis);
• Conditions after hemorrhagic or ischemic stroke;
• Circulatory disorders in the eye vessels (acute and chronic insufficiency of circulation of the retina and choroid of the eye);
• Impaired function of the middle ear of vascular origin, accompanied by hearing loss.

ICD codes

Dosage Regimen

The drug can be administered IV, IA, IM. During infusions, the patient should be in a lying position.

Intravenously 100 mg (1 amp.) in 250-500 ml of 0.9% sodium chloride solution or in 5% dextrose (glucose) solution by drip over 1.5-3 hours. With good tolerance, the dose can be increased by 100 mg per day. The maximum daily dose is 300 mg.

Intra-arterially: initially 100 mg of the drug in 20-50 ml of 0.9% sodium chloride solution, on subsequent days – 200-300 mg in 30-50 ml of solvent. Administer at a rate of 100 mg (5 ml of 2% drug solution) over 10 minutes. In severe cerebral vascular atherosclerosis, it should not be administered into the carotid artery.

For patients with chronic renal failure (creatinine clearance less than 10 ml/min), 50-70% of the usual dose is administered.

Intramuscularly: 1-2 times/day, 100 mg (1 amp.) each.

Adverse Reactions

From the CNS: headache, dizziness; anxiety, sleep disorders, convulsions.

From the cardiovascular system: tachycardia, arrhythmia, cardialgia, rarely – progression of angina symptoms, decreased blood pressure.

From the skin: facial skin hyperemia, “flushes” of blood to the skin of the face and upper chest, edema, increased nail brittleness.

From the digestive system: nausea, vomiting, feeling of heaviness in the stomach, decreased appetite, intestinal atony, exacerbation of cholecystitis, cholestatic hepatitis, bleeding from the mucous membranes of the stomach, intestines.

From the sensory organs: visual impairment, scotoma.

From the hemostasis system and hematopoietic organs: thrombocytopenia, leukopenia, pancytopenia, hypofibrinogenemia; bleeding from skin vessels.

Allergic reactions: rarely – itching, skin hyperemia, urticaria, angioedema, anaphylactic shock.

From laboratory parameters: increased activity of liver transaminases: ALT, AST, LDH and ALP.

Contraindications

• Severe coronary or cerebral atherosclerosis;
• Acute myocardial infarction;
• Severe heart rhythm disorders;
• Uncontrolled arterial hypotension;
• Porphyria;
• Massive bleeding;
• Hemorrhage into the retina;
• Acute hemorrhagic stroke;
• Pregnancy, lactation period;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to pentoxifylline and substances from the group of xanthine derivatives.

With caution: patients with labile blood pressure, tendency to arterial hypotension, chronic heart failure, tendency to hemorrhages, condition after recently undergone surgical interventions, hepatic and/or renal insufficiency.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

With caution: hepatic insufficiency.

Use in Renal Impairment

In case of insufficient renal function with a creatinine level above 400 mmol/l, doses are reduced by 30-50%.

Pediatric Use

Contraindication: age under 18 years (efficacy and safety not established).

Geriatric Use

In elderly people, a dose reduction may be required (due to reduced excretion rate).

Special Precautions

Treatment should be carried out under blood pressure control. In patients with chronic heart failure, compensation of circulation should be achieved.

In diabetic patients taking hypoglycemic agents, the use of large doses may cause severe hypoglycemia (dose adjustment is required).

When used simultaneously with anticoagulants, it is necessary to carefully monitor the parameters of the blood coagulation system.

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

The administered dose should be reduced in patients with low and unstable blood pressure.

In elderly people, a dose reduction may be required (due to reduced excretion rate).

Smoking may reduce the therapeutic effectiveness of the drug.

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

Overdose

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

Treatment: symptomatic, aimed at maintaining respiratory function and blood pressure.

Drug Interactions

Pentoxifylline may enhance the effect of drugs affecting the blood coagulation system (indirect and direct anticoagulants, thrombolytics), antibiotics (including cephalosporins: cefamandole, cefoperazone, cefotetan), valproic acid.

It increases the effectiveness of antihypertensive agents, insulin and oral hypoglycemic agents.

Cimetidine increases the concentration of pentoxifylline in blood plasma (risk of side effects).

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

Storage Conditions

Store at a temperature of 10-25°C (50-77°F) in a dry place out of reach of children.

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.