Composition, structure and packing

With modified release capsules are hard gelatin, opaque, with red-brown cap and body ivory.

The composition of the shell capsules: gelatin, titanium dioxide, iron oxide yellow (pigment), iron oxide red (dye).

1 capsule contains: tablets of acetylsalicylic acid, white, round, biconvex, with smooth edges, acetylsalicylic acid 25 mg

Excipients: lactose monohydrate, microcrystalline cellulose, corn starch, desiccated, colloidal silicon dioxide, aluminum stearate, sucrose, acacia gum, titanium dioxide, talc. Pellets dipyridamole yellow. dipyridamole 200 mg.

Excipients: Tartaric acid (spherical), tartaric acid (powder), povidone (Kollidon 25), copolymer of methacrylic acid and methylmethacrylate, gipromellozy phthalate HP 55, gipromelloza, glycerol triacetate (Triacetin), dimethicone 350, stearic acid, talc, gum arabic , purified water (evaporated), isopropanol (evaporates), ethanol 96% (evaporates).

Clinico-pharmacological group: antiagrigant.

Pharmacological action

Antiagrigant. Acetylsalicylic acid inactivates the enzyme cyclooxygenase in platelets and thereby prevents the formation of thromboxane A2 - a potent inducer of platelet aggregation and vasoconstriction. Dipyridamole inhibits the capture of adenosine in erythrocytes, platelets and endothelial cells in vivo and in vitro; inhibition reaches a maximum of 80% and in therapeutic concentrations (0.5-2 mg / ml) was dose-dependent. As a consequence, there is a local increase in the concentration of adenosine, which acts on A2 receptors of platelets, stimulating platelet adenylate cyclase and thus increases the level of c-AMP of platelets. Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. Until then, while the inhibition of c-AMP-PDE is weak, therapeutic concentrations inhibit c-GMP-PDE, and hence contributes to increasing n-GMP under the influence RFVE (relaxing factor released from the endothelium, as identified by NO). Adenosine does not have a vasodilative effect, which is one of the mechanisms by which dipyridamole causes vasodilation. Dipyridamole stimulates prostacyclin biosynthesis and release of endothelium.

Dipyridamole reduces thrombogenicity subendothelial structures by increasing the concentration of protective mediator 13-YEAR (13-gidroksioktadekadienovoy acid). Thus, in response to various stimulants, such as TAF, collagen and ADP, inhibited platelet aggregation. Reduced platelet aggregation leads to the normalization of platelet consumption adenosine. If aspirin inhibits only platelet aggregation, the dipyridamole further inhibits platelet activation and adhesion. Therefore, the combination of these two drugs can expect an additional effect.


Between the pellets with slow release dipyridamole and acetylsalicylic acid, there is no significant pharmacokinetic interaction. Therefore, the pharmacokinetics of the drug pharmacokinetics is characterized by individual components.


Most of the data on the pharmacokinetics obtained in studies in healthy volunteers.

For dipyridamole characteristic linear dependence of pharmacokinetics on the dose.

For long-term dipyridamole treatment were developed with modified release capsule, composed of pellets. Dependence of solubility of dipyridamole on the pH, which prevents the dissolution of dipyridamole in the lower digestive tract (where the drugs with a slow release have yet to release the active ingredient), was overcome by its combination with tartaric acid. Delayed release is achieved through the use of the diffusion membrane, which is a spray applied to the pellet. Various kinetic studies at equilibrium have shown that the pharmacokinetic parameters describing the preparations with modified release capsules with modified release dipyridamole, which take 2 times a day. Or equivalent, or by some measures, superior to dipyridamole tablets, which take 3-4 times a day. Bioavailability is slightly higher maximum concentrations of the same, the concentration between doses significantly higher variability in peak concentrations between doses reduced.


The absolute bioavailability is approximately 70%. Since the "initial pass" is removed about 1 / 3 of the administered dose, we can assume almost complete absorption or dipyridamole after taking the drug. Cmax dipyridamole in plasma after administration of daily doses of 400 mg (200 mg 2 times / day) are observed within 2-3 h after ingestion. Mean Cmax for the equilibrium state is 1.98 mg / ml (range 1.01-3.99 mg / ml) and concentrations between doses are 0.53 mg / ml (range 0.18-1.01 mg / ml). Eating does not affect the pharmacokinetics of dipyridamole.


Due to its high lipophilicity, log P 3.92 (n-oktanol/0.1n, NaOH), dipyridamole is distributed in many organs. Animals dipyridamole mainly distributed in the liver, as well as in the lungs, kidneys, spleen and heart. Fast phase distribution, observed in a / in the introduction, it is impossible to determine the oral. The apparent Vd of the central compartment (Vc) is about 5 liters (similar to plasma volume). The apparent Vd at the equilibrium state is about 100 l, reflecting the distribution in different compartments. The drug does not penetrate the BBB in significant volume. The penetration of the drug through the placental barrier is very low. In one case in breast milk was found the drug in a quantity of 1 / 17 part of its concentration in plasma. Dipyridamole binding to proteins is about 97-99%, mainly binds to α1-acid glycoprotein and albumin. Repeated doses of receiving appreciable accumulation of the medicinal product is not observed.


Metabolism dipyridamole occurs in the liver. Dipyridamole mainly metabolized by conjugation with glucuronic acid to form mainly monoglyukuronida and only small amounts diglyukuronida. In plasma, about 80% of the total number present in the form of the parent compound, and 20% of the total number in the form of monoglyukuronida. Pharmacodynamic activity of the two drugs dipyridamole significantly lower than the activity of dipyridamole.


T1 / 2 of the initial phase of oral, as in the in / in the introduction, is about 40 minutes. Withdrawal of the drug unchanged through the kidneys, small (<0.5%). Urinary excretion of glucuronide metabolite is low (5%), metabolites are mainly (about 95%) are derived through the bile with the feces, while there is enterohepatic recycling. Complete clearance of approximately 250 ml / min, average time spent in the body is about 11 hours, determined on the basis of its own mean residence time in the body about 6.4 h and the average time of 4.6 hours suction As with a / in the introduction, there has been a long T1 / 2 final phase was about 13 h. This phase is relatively unimportant, as it represents a small part of AUC, which is confirmed by the fact that when you receive a modified release capsules 2 times per day equilibrium is reached within 2 days.

Pharmacokinetics in special clinical situations

The concentrations of dipyridamole in plasma (as assessed by AUC) in elderly patients over 65 years were approximately 50% higher in the treatment tablets and approximately 30% higher when taking capsules modified release drug Agrenoks than in younger (under 55 years) subjects. This difference is mainly due to reduced clearance, as it was found that absorption was the same.

Due to the low excretion through the kidneys (5%) can assume the absence of changes of the pharmacokinetics in the case of kidney failure. The study ESPS2 patients with CC of 15 ml / min and up to> 100 ml / min changes of pharmacokinetics dipyridamole or its metabolite - glucuronide dipyridamole - not observed if the correction data for differences in age. Patients with hepatic insufficiency changes in plasma concentrations of dipyridamole were observed, but showed an increase in the concentration of two drugs that have low pharmacodynamic activity. Therefore, dipyridamole dosage adjustment is necessary only if clinical evidence of decompensation of liver function.

Acetylsalicylic acid


Acetylsalicylic acid is rapidly and completely absorbed. Cmax in plasma after administration of a daily dose of 50 mg acetylsalicylic acid in the drug (25 mg 2 times / day) is observed after 30 min, and Cmax in the plasma at the equilibrium state is 319 ng / ml (range 175-463 ng / ml). Cmax of salicylic acid in plasma is achieved through a 60-90 min. 30-40% of the dose acetylsalicylic acid undergoes primary metabolism to the splitting up of salicylic acid, which is the main route of metabolism.

Pharmacodynamics of acetylsalicylic acid (consisting of the drug Agrenoks) does not depend on the meal.


Acetylsalicylic acid bad bound to plasma proteins, and its apparent Vd is small (10 liters). Metabolite of acetylsalicylic acid - salicylic acid - is largely bound to plasma proteins, but binding is dependent on the concentration of (nonlinear). At low concentrations (<100 ug / ml), about 90% salicylic acid is associated with albumin. Salicylic acid is well distributed in all tissues and body fluids, including the central nervous system, breast milk and tissues of the fetus.


Acetylsalicylic acid is rapidly metabolized under the action of nonspecific esterases in the liver and to a lesser extent in the stomach to salicylic acid with subsequent formation gidroksigippurovoy acid by reaction with glycine.


T1 / 2 of acetylsalicylic acid is 15-20 minutes; T1 / 2 primary metabolite (salicylic acid) is 2-3 h, can grow up to 5-18 hours at high doses (> 3 g) due to saturation of the enzyme. About 90% acetylsalicylic acid output in the form of metabolites via the kidneys.

Pharmacokinetics in special clinical situations

In severe renal dysfunction (glomerular filtration rate less than 10 ml / min) should not be given acetylsalicylic acid. Reported an increase in the duration of T1 / 2 2-3 times in patients with kidney disease. In severe deficiency of liver function should not be given acetylsalicylic acid.

secondary prevention of ischemic stroke (according to the mechanism of thrombosis) and transient ischemic attacks.

Dosage regimen

The recommended dose - 1 capsule 2 times per day.

Usually take 1 capsule in the morning and 1 capsule in the evening regardless of the meal. The capsules should be swallowed whole without chewing, drinking a glass of water.

Side effect

Reported hypersensitivity reactions (rash, urticaria, severe bronchospasm and angioedema) in respect of dipyridamole and in respect of acetylsalicylic acid. In very rare cases after administration of acetylsalicylic acid may be a reduction in the number of platelets (thrombocytopenia). Also reported some cases of thrombocytopenia, observed in the treatment of dipyridamole.

Hemorrhages on the skin, such as bruising, bruising, ecchymosis, and hematoma can occur when using the drug.

Adverse effects of dipyridamole at therapeutic doses are usually weak and transient. In the treatment of dipyridamole observed vomiting, diarrhea, and symptoms such as dizziness, nausea, headache, migrenepodobnaya headache (especially at the beginning of treatment), and myalgia. These symptoms usually disappear with prolonged use of the drug.

As a consequence of vasodilative effect of dipyridamole may occur hypotension, flushing and tachycardia. Noted worsening symptoms of coronary heart disease. Acetylsalicylic acid increases bleeding time, and after receiving dipyridamole in very rare cases, there was increased bleeding during and after surgery. When receiving acetylsalicylic acid may occur in the epigastric pain, nausea and vomiting, stomach ulcer or duodenal ulcer and erosive gastritis, which can lead to serious gastrointestinal bleeding. As a result of hidden bleeding, especially when taking aspirin for a long period of time may develop iron deficiency anemia.

stomach ulcer or duodenal ulcer in acute or with a tendency to bleeding;
pregnancy (III term);
age 18;
Hypersensitivity to any component of the drug or salicylates.

Along with other properties of dipyridamole has vasodilating effect. The drug should be used with caution in patients with severe coronary heart disease (including those with unstable angina, recent myocardial infarction, as well as a loss of blood ejection from the left ventricle, or hemodynamic instability / for example, decompensated heart failure /).

As one component of the drug is acetylsalicylic acid, the drug should be used with caution in patients with bronchial asthma, allergic rhinitis, nasal polyposis, chronic or recurrent ulcers of the stomach or duodenum, with impaired renal function or liver disease or deficiency of glucose-6-phosphate dehydrogenase, with hypersensitivity to NSAIDs.

Pregnancy and lactation

Data on the safety of dipyridamole and acetylsalicylic acid in low doses during pregnancy in humans is not enough. In preclinical studies, adverse effects were noted. Dipyridamole and salicylates excreted in breast milk. Drug can take in I and II trimesters of pregnancy or during lactation and only if the benefit for the mother outweighs the potential risk for the fetus (baby).

The drug is contraindicated in the III trimester of pregnancy.

The drug should be used with caution in patients with impaired liver function.

The drug should be used with caution in patients with impaired renal function.


Clinical experience suggests that patients receiving dipyridamole inside and which is also required to conduct pharmacological stress test with in / dipyridamole administration should stop taking medicines containing dipyridamole, 24 hours before the test. Otherwise, the sensitivity of the test may be compromised.

In patients with malignant myasthenia after changing the dose of dipyridamole may require correction of the basic therapy.

In a small number of cases have shown that unconjugated dipyridamole in varying degrees, integrated into gallstones (up to 70% of the dry weight of the stone). All the patients were elderly. They observed the rising cholangitis, and they received dipyridamole for many years. There is no evidence that dipyridamole was a triggering factor in the formation of gallstones is not available. Probably, the presence of dipyridamole in the gallstones can be attributed to bacterial deglyukuronizatsiey conjugated dipyridamole in bile.

A dose of acetylsalicylic acid in the preparation Agrenoks (25 mg) was not investigated, as indicated by prevention of myocardial infarction. Contains 106 mg of lactose and 22.5 mg of sucrose in the maximum daily dosage.

Should not be used in patients with hereditary fructose intolerance and / or galactose, such as galactosemia.


Symptoms: due to the ratio of doses of dipyridamole and acetylsalicylic acid in cases of overdose Agrenoks are likely to prevail signs and symptoms of overdose dipyridamole. Experience with the dipyridamole overdose is limited due to the small number of observations. Presumably, should exhibit such symptoms as hot flashes, hot flushes, increased sweating, excited state, weakness, dizziness, and symptoms of angina. Maybe a sharp decline in BP and tachycardia.

Symptoms of low acute overdose acetylsalicylic acid are hyperventilation, ringing in the ears, nausea, vomiting, blurred vision and hearing loss, dizziness, and causing a dreamy consciousness.

Dizziness and tinnitus, especially among elderly patients, may be symptoms of overdose.

Treatment: perform symptomatic therapy, gastric lavage.

Introduction of xanthine derivatives (eg aminophylline) may reverse the hemodynamic effects of dipyridamole overdose. Since dipyridamole is widely distributed in tissues and is mainly eliminated by the liver, it does not appear in hemodialysis.

Drug Interactions

In the application of dipyridamole in combination with acetylsalicylic acid or warfarin should be taken into account the precautions for these drugs.

Acetylsalicylic acid may exacerbate the effects of anticoagulants (eg coumarin derivatives and heparin), medications that inhibit platelet aggregation (clopidogrel, ticlopidine), valproic acid and increase the risk of side effects from the gastrointestinal tract, while the use of NSAIDs or corticosteroids, as well as the systematic use of ethanol. Combined application of dipyridamole and acetylsalicylic acid does not increase the frequency of bleeding. Selective serotonin reuptake inhibitors may increase the risk of bleeding.

Dipyridamole increases the concentration of adenosine in plasma and enhances its cardiovascular effects. Keep in mind the need to correct dose of adenosine. When the joint application of dipyridamole and warfarin, the frequency and severity of bleeding were not more than the introduction of only one warfarin. Dipyridamole may enhance the hypotensive effect of drugs that reduce blood pressure, and counteract the anticholinesterase effect, reducing the effect of cholinesterase inhibitors, and, consequently, cause the worsening of the malignant myasthenia. The effect of hypoglycemic agents and the toxicity of methotrexate may be intensified or combined with acetylsalicylic acid. Acetylsalicylic acid may reduce the natriuretic effect of spironolactone and inhibit the effect urikozuricheskih medicines (eg, probenecid, sulfinpirazon). Simultaneous reception of ibuprofen (but not other NSAIDs or paracetamol) in patients with increased risk of cardiovascular disease may limit the beneficial effect of aspirin on the cardiovascular system.

It should appoint a drug with caution to patients who receive treatment drugs that increase the risk of bleeding (platelet aggregation inhibitor / clopidogrel, ticlopidine /) or selective serotonin reuptake inhibitors.

Terms and Conditions of storage

The drug should be stored out of reach of children at or above 25 ° C. Shelf life - 3 years. Do not use the drug after the expiration date stated on the packaging.