Agrenox: instructions for using the medicine, structure, Contraindications
Active material: Acetylsalicylic acid
When ATH: B01AC
CCF: Antiplatelet
ICD-10 codes (testimony): G45, I63
Manufacturer: BOEHRINGER INGELHEIM INTERNATIONAL GmbH (Germany)
Agrenox: dosage form, composition and packaging
Modified release capsule hard gelatin, size 0, opaque, with red-brown cap and body ivory.
The composition of the shell capsules: gelatin, Titanium dioxide, iron oxide yellow (dye), iron oxide red (dye).
1 capsule contains:
A tablet of aspirin white, round, biconvex, coated liner, with smooth edges.
| acetylsalicylic acid | 25 mg |
Excipients: lactose monohydrate, microcrystalline cellulose, dried corn starch, colloidal silicon dioxide, aluminum stearate, sucrose, acacia gum, Titanium dioxide, talc.
Pellets dipiridamola yellow color.
| dipiridamol | 200 mg |
Excipients: tartaric acid (spherical), tartaric acid (powder), povidone (Kollidon 25), a copolymer of methacrylic acid and methylmethacrylate, gipromellozы phthalate HP 55, gipromelloza, glycerol triacetate (Triacetine), Dimethicone 350, stearic acid, talc, acacia, Purified water (disappears), isopropanol (disappears), ethanol 96% (disappears).
30 PC. – polypropylene tubes (1) – packs cardboard.
60 PC. – polypropylene tubes (1) – packs cardboard.
Agrenox: pharmachologic effect
Antiplatelet. Atsetilsalitsilovaya Chisloth inaktiviruet platelet ferment COG, and thus 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 80% and in therapeutic concentrations (0.5-2 ug / ml) It is dose-dependent. Consequently, there is a local increase in the concentration of adenosine, which acts on A2-platelet receptors, stimulating platelet adenylate cyclase, and, thus, increases the level of c-AMP platelets.
Dipyridamole inhibits PDE in various tissues. Until, while the inhibition of c-AMP-PDE weak, therapeutic concentrations inhibit c-GMP-PDE, and, Consequently, contribute to an increase in c-GMP by the action RFVE (relaxing factor, released from the endothelium, identified as NO).
Adenosine has a vasodilatory effect, which is one of the mechanisms, by which dipyridamole causes vasodilation.
Dipyridamole stimulates the biosynthesis and release of prostacyclin by the endothelium.
Dipyridamole reduces the thrombogenicity subendothelial structures, increasing the concentration of the protective mediator 13-YEAR (13-gidroksioktadekadienovoy acid).
Thus, in response to various stimulants, eg, TAF, Collagen and ADF, inhibited platelet aggregation. Reduction of platelet aggregation leads to normalization of platelet consumption adenosine.
If acetylsalicylic acid inhibits only platelet aggregation, the dipyridamole in addition inhibits platelet activation and adhesion. Therefore, the combination of these two drugs can be expected additive effect.
Agrenox: pharmacokinetics
Between dipyridamole pellets with a slow release of acetylsalicylic acid and there is no significant pharmacokinetic interactions. Therefore pharmacokinetics characterized pharmacokinetics of the individual components.
Dipiridamol
Most pharmacokinetic data obtained in studies in healthy volunteers.
For dipyridamole characteristic linear dependence on the applied dose pharmacokinetics.
For long-term treatment with dipyridamole been developed with modified release capsules, composed of pellets. Dependence on the pH solubility of dipyridamole, preventing dissolution of dipyridamole in the lower GI (wherein the sustained-release preparations have yet to release the active substance), It was overcome by its combination with tartaric acid. Sustained release is achieved through the use of a diffusion membrane, in which a spray is applied to the pellets.
Various kinetic studies at equilibrium shown, that pharmacokinetic parameters, characterizing the modified release formulations, Capsules dipyridamole modified release, which take 2 times / day, or equivalent, or for some indicators, surpass pills dipyridamole, which take 3-4 times / day. Bioavailability slightly higher, the maximum concentration of the same, concentrations between doses significantly higher, fluctuations in peak concentrations between doses reduced.
Agrenox: Absorption
The absolute bioavailability of approximately 70%. Since “primary passage” removed about 1/3 of the administered dose, It can assume almost complete absorption of dipyridamole or after ingestion.
Cmax dipyridamole in plasma after administration of a daily dose of 400 mg (by 200 mg 2 times / day) observed through 2-3 h after dosing. Middle Cmax at steady state is 1.98 ug / ml (range 1.01-3.99 ug / ml) and concentration between meals up 0.53 ug / ml (range 0.18-1.01 ug / ml).
Food intake has no effect on the pharmacokinetics of dipyridamole.
Agrenox: Distribution
Due to its high lipophilicity, log R 3.92 (n-octanol/0.1n, NaOH), dipyridamole is distributed in many organs.
Animals dipyridamole mainly distributed in liver, and lung, kidney, spleen and heart.
Rapid distribution phase, observed at / introduction, impossible to determine when administered orally.
In Кажущийсяd in the central compartment (Vc) is about 5 l (similar to plasma volume). In Кажущийсяd at steady state is approximately 100 l, reflecting the distribution in different compartments.
The drug does not cross the blood-brain barrier to a significant extent.
The penetration of the drug through the placenta is very low.
In one case human milk has been detected in an amount of drug, constituting 1/17 part of its concentration in plasma.
Dipyridamole binding to proteins is about 97-99%, basically it binds to α1-acid glycoprotein and albumin.
Repeated administration of a dose appreciable accumulation of the drug is observed.
Agrenox: Metabolism
Dipyridamole metabolism occurs in the liver. Dipyridamole mainly metabolized by conjugation with glucuronic acid to form, mainly, monoglyukuronida and only small amounts of diglucuronide. In plasma about 80% the total amount present in the form of starting compound, and 20% of the total in the form monoglyukuronida. Pharmacodynamic activity of dipyridamole glucuronides is considerably lower, than the activity of dipyridamole.
Agrenox: Deduction
T1/2 the initial phase of an orally, as in the on / in, is about 40 m.
Withdrawal in unchanged form via the kidneys slightly (<0.5%). Urinary excretion of the glucuronide metabolite is low (5%), metabolites mainly (about 95%) output via the bile in the faeces, while there is enterohepatic recycling. Complete clearance is about 250 ml / min, the average residence time in the body is about 11 no, determined on the basis of their own mean residence time in the body about 6.4 h and the average time of absorption 4.6 no.
As with the on / in, there is a long T1/2 the final phase, amounting to about 13 no. This phase has a relatively small value, as it represents a small part of AUC, supported by the fact that, When administered to a modified-release capsules 2 times / day equilibrium state is reached within 2 days.
Agrenox: Pharmacokinetics in special clinical situations
Plasma concentrations of dipyridamole (determined by AUC) in elderly patients over 65 It has been around for years, 50% above tablets for the treatment and about 30% higher when taking capsules modified release formulation Agrenoks®, than in younger (younger 55 years) subjects. This difference is mainly due to reduced clearance, as it turned out, that the absorption was the same.
Due to the low excretion via the kidneys (5%) we can assume no change in pharmacokinetics in case of kidney failure. In a study in patients with ESPS2 by QC 15 ml / min and to >100 ml / minute changes in the pharmacokinetics of dipyridamole or its metabolite – gljukuronida dipiridamola – It was observed under the condition adjustment for differences in age.
Patients with liver failure changes in plasma concentrations of dipyridamole was observed, but noted an increase in the concentration of glucuronide, having lower pharmacodynamic activity. Therefore, dipyridamole dosage adjustment is necessary only in case of clinically confirmed hepatic decompensation.
Acetylsalicylic acid
Absorption
Aspirin rapidly and completely absorbed. Cmax in plasma after administration of a daily dose of 50 mg of acetylsalicylic acid in a preparation (by 25 mg 2 times / day) observed through 30 m, and Cmax in plasma at equilibrium is 319 ng / ml (range 175-463 ng / ml). Cmax salicylic acid in the plasma is achieved by 60-90 m.
30-40% dose acetylsalicylic acid undergoes primary metabolism to the splitting up of salicylic acid, which is the major route of metabolism.
Pharmacodynamics of acetylsalicylic acid (in a preparation Agrenoks®) It is independent of the meal.
Distribution
Aspirin poorly bound to plasma proteins, and its apparent Vd little (10 l). Metabolite atsetilsalitsilovoy kislotы – salicylic acid – 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 widely distributed in all tissues and body fluids, including CNS, breast milk and fetal tissue.
Metabolism
Aspirin is rapidly metabolized by 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.
Deduction
T1/2 acetylsalicylic acid is 15-20 m; T1/2 osnovnogo metabolite (salicylic acid) component 2-3 no, may increase to 5-18 hours at high doses (>3 g) because of the saturation of the enzyme.
About 90% acetylsalicylic acid appears in the form of metabolites through the kidneys.
Pharmacokinetics in special clinical situations
In severe renal impairment (glomerular filtration rate of less than 10 ml / min) should not be given aspirin.
It reported an increase of duration T1/2 in 2-3 fold in patients with kidney disease.
In severe deficiency of liver function should not be given aspirin.
Agrenox: testimony
- Secondary prevention of ischemic stroke (the mechanism of thrombosis) and transient ischemic attacks.
Agrenox: dosing regimen
The recommended dose – by 1 capsule 2 times / day.
Usually it takes 1 capsule in the morning and 1 capsule in the evening with or without food.
The capsules should be swallowed whole, without chewing, with a glass of water.
Agrenox: side effects
Reported hypersensitivity reactions (rash, hives, severe bronchospasm and angioedema) in respect of dipyridamole, and acetylsalicylic acid against.
In very rare cases after taking acetylsalicylic acid may be a reduction in the number of platelets (thrombocytopenia). It was also reported isolated cases of thrombocytopenia, observed in the treatment of dipyridamole.
Haemorrhages on the skin, such as bruising, bruising, ecchymosis and hematoma, may occur when using the drug.
Adverse effects of dipyridamole at therapeutic doses are usually mild 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 the vasodilator effect of dipyridamole may occur hypotension, High tides and tachycardia. It was noted worsening symptoms of coronary artery disease.
Aspirin increases the bleeding time, and after receiving dipyridamole in very rare cases increased bleeding during and after surgery.
When receiving acetylsalicylic acid may occur epigastric pain, nausea and vomiting, a stomach ulcer or duodenal ulcer and erosive gastritis, that can cause serious gastrointestinal bleeding.
As a result of hidden bleeding, especially when taking aspirin for a long period of time, may develop iron-deficiency anemia.
Agrenox: Contraindications
- Gastric ulcer or duodenal ulcer in the acute phase or with a propensity to bleed;
- Pregnancy (III Plus);
- Up to 18 years;
- Hypersensitivity to any component of the formulation or to salicylates.
Among other properties dipyridamole has a vasodilator effect. The drug should be used with caution patients with severe coronary artery disease, (incl. with unstable angina and recent myocardial infarction, and the difficulty in ejection of blood from the left ventricle or hemodynamic instability / e.g., In decompensated heart failure /).
Since one of the components of the drug is acetylsalicylic acid, the drug should be with caution used in patients with bronchial asthma, allergic rhinitis, nasal polyposis, chronic or recurrent ulcers of the stomach or duodenum, with impaired renal function or hepatic insufficiency or glucose-6-phosphate dehydrogenase, with hypersensitivity to NSAIDs.
Agrenox: Pregnancy and lactation
Data on the safety of dipyridamole and acetylsalicylic acid in low doses in pregnancy in humans is not enough. Preclinical studies revealed no negative impact.
Dipyridamole and salicylates are excreted in breast milk.
The drug can be taken in I and II trimesters of pregnancy or during breast-feeding and only if, if the benefit to the mother outweighs the potential risk to the fetus (child). The drug is contraindicated in the III trimester of pregnancy.
Agrenox: Special instructions
Clinical experience suggests, patients, receiving dipyridamole in and that also requires a pharmacological stress test with the / in the introduction of dipyridamole, should stop taking drugs, containing dipyridamole, for 24 h before the test. Otherwise the sensitivity of the assay may be compromised.
In patients with myasthenia gravis after changing the dose of dipyridamole may require correction primary therapy.
In a few cases it was shown, that unconjugated dipyridamole to varying degrees embedded into gallstones (to 70% by dry weight of stone). All patients were elderly. They celebrated ascending cholangitis, and dipyridamole are prepared for many years. Evidence, that dipyridamole was the initiating factor in the formation of gallstones, not available. Probably, the presence of dipyridamole in gallstones can be explained by bacterial deglyukuronizatsiey conjugated dipyridamole in bile.
The dose of acetylsalicylic acid in the preparation Agrenoks® (25 mg) I have not been investigated, as indicated by the prevention of myocardial infarction.
Contains 106 mg of lactose, 22.5 mg sucrose maximum daily dose. It should not be used in patients with hereditary fructose intolerance and / or galactose, eg, galactosemia.
Agrenox: overdose
Symptoms: because of the ratio of doses of dipyridamole and acetylsalicylic acid in cases of drug overdose Agrenoks®, probably, will be dominated by signs and symptoms of an overdose of dipyridamole.
Experience with dipyridamole overdose is limited due to the small number of observations. Presumably, We have observed symptoms, as hot flashes, tides, increased perspiration, excited state, weakness, dizziness and symptoms of angina. There may be a sharp decrease in blood pressure and tachycardia.
Symptoms of mild acute aspirin overdose are hyperventilation, tinnitus, nausea, vomiting, visual and hearing impairment, dizziness and blurred consciousness.
Dizziness and ringing in the ears, especially in elderly patients, may be symptoms of overdose.
Treatment: symptomatic therapy, gastric lavage. Introduction xanthine derivatives (eg, aminofillina) It can neutralize the hemodynamic effects of dipyridamole overdose.
Unnecessarily. dipyridamole is widely distributed in tissues and is mainly eliminated by the liver, it does not appear in hemodialysis.
Agrenox: drug interaction
When using dipyridamole in combination with aspirin or warfarin should be taken into consideration precautions for these drugs.
Aspirin may increase the effects of anticoagulants (eg, coumarin derivatives and heparin), preparations, inhibiting 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 use of dipyridamole and acetylsalicylic acid does not increase the incidence 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 for dose adjustment of adenosine.
When combined dipyridamole and warfarin, the frequency and severity of bleeding was no more, than when administered only one warfarin.
Dipyridamole may increase the hypotensive effect of drugs, lowering blood pressure, and to reverse the effect of anticholinesterase, reducing the effects of cholinesterase inhibitors, and, Consequently, cause a worsening of myasthenia gravis.
The effect of hypoglycaemic agents and the toxicity of methotrexate can be amplified when combined with acetylsalicylic acid.
Aspirin can reduce the natriuretic effect of spironolactone and inhibit the effect of uricosuric drugs (eg, probenecid, sulifinpirazona).
Simultaneous administration of ibuprofen (but not other NPHE or paracetamol) in patients with an increased risk of cardiovascular disease may limit the beneficial effect of aspirin on cardiovascular system.
Caution should be prescribed to patients, receiving treatment with drugs, increase the risk of bleeding (platelet aggregation inhibitors / clopidogrel, ticlopidine /) or selective serotonin reuptake inhibitors.
Agrenox: terms of dispensing from pharmacies
The drug is released under the prescription.
Agrenox: terms and conditions of storage
The drug should be stored out of reach of children at or above 25 ° C. Shelf life – 3 year. Do not use the medication after the expiration date, on the package.
