Instructions for Disgren capsules 300 mg blister No. 30
Composition
active ingredient: triflusal;
1 capsule contains 300 mg of triflusal;
excipient: gelatin.
Dosage form
Capsules.
Main physicochemical properties: colorless hard gelatin capsules, size 1, containing white or almost white powder.
Pharmacotherapeutic group
Antithrombotic agents. Platelet aggregation inhibitors, except heparin.
ATX code B01A C18.
Pharmacological properties
Pharmacodynamics.
Triflusal reduces thromboxane biosynthesis by irreversible inhibition of platelet cyclooxygenase, due to its negligible effect on vascular cyclooxygenase in therapeutic doses it does not affect prostacyclin biosynthesis. Also, the main metabolite of triflusal, 2-hydroxy-4-(trifluoromethyl) benzoic acid (GTB), is a reversible inhibitor of platelet cyclooxygenase and due to its long half-life (approximately 34 hours) contributes to the antithrombotic effect of triflusal. Both triflusal and GTB can increase the concentration of cyclic adenosine 5-monophosphate (c-AMP) in platelets by inhibiting platelet phosphodiesterases. In addition, in vitro and ex vivo, triflusal has been shown to stimulate the release of nitric oxide in human neutrophils, which also contributes to the antithrombotic effect. Triflusal has been shown to inhibit platelet aggregation in both healthy volunteers and patients. In ex vivo studies in healthy volunteers, arachidonic acid-induced platelet aggregation was reduced by 65% after 24 hours of administration of 600 mg of triflusal. Repeated administration of triflusal (600 mg/day for 7 days) resulted in a 50-75% inhibition of platelet aggregation induced by arachidonic acid, ADP (adenosine diphosphate), epinephrine or collagen.
Pharmacokinetics.
After oral administration, triflusal is rapidly absorbed (t½ Ka = 0.44 hours), demonstrating an absolute bioavailability of 83 to 100%. Under the action of esterases, the drug is rapidly hydrolyzed to its main active metabolite, 2-hydroxy-4-(trifluoromethyl) benzoic acid (GTB). A secondary conjugated metabolite, GTB-glycine, is found in the urine. The plasma half-life (t½) is 0.53 ± 0.12 hours for triflusal and 34.3 ± 5.3 hours for GTB. Elimination occurs mainly by the kidneys (renal clearance > 60% in 48 hours). Unmetabolized triflusal, GTB, and the GTB-glycine compound are detected in the urine.
After oral administration of a single dose of 300 or 900 mg of triflusal to healthy volunteers, the mean maximum plasma concentration (Cmax) of triflusal was 3.2 ± 1.9 μg/ml and 11.6 ± 1.7 μg/ml, respectively. The Cmax for GTB is 36.4 ±
6.1 μg/ml and 92.7 ± 17.1 μg/ml. The time required to reach Cmax (tmax) is 0.88 ± 0.26 hours for triflusal and 4.96 ± 1.37 hours for GTB at a dose of 900 mg. Pharmacokinetic parameters of GTB after repeated administration (triflusal, 300 mg 3 times/day or 600 mg 1 time/day for 13 days) showed that Cmax of GTB in blood plasma at steady state (Cmax cc) is 178 ± 42 μg/ml and 153 ± 37 μg/ml, respectively. GTB at therapeutic concentrations has a binding index to blood plasma albumin from 98 to 99%. This binding does not change significantly in the presence of caffeine, theophylline, glisentide, enalapril, cimetidine and warfarin. However, the free fraction of GTB increases significantly in the presence of NSAIDs such as diclofenac, ibuprofen, indomethacin, naproxen, piroxicam or salicylic acid. At high concentrations, GTB displaces NSAIDs, glisentide and warfarin in the binding sites of proteins. These substances have affinity for the same binding sites of proteins, they can substitute for each other depending on their affinity for the protein and the concentration of the substituted substance.
In elderly volunteers, after administration of 300 mg of triflusal 2 times a day, the concentration of triflusal and GTB in the blood plasma reaches a constant equilibrium in 3-5 days. The PFC, Cmax and tmax values in elderly volunteers do not differ significantly from those recorded in young volunteers. The t½ in the blood plasma is 0.92 ± 0.16 hours for triflusal and 64.4 ± 6.6 hours for GTB; both values are higher than in young volunteers. However, this increase is not clinically significant and does not require dose adjustment for elderly patients.
In patients with end-stage chronic renal failure undergoing conventional hemodialysis, plasma GTB concentrations before and after hemodialysis were identical.
Indication
Prevention of recurrent vascular disorders of an ischemic nature, such as:
myocardial infarction;
stable and unstable angina;
cerebrovascular non-hemorrhagic transient or permanent circulatory disorders.
Prevention of shunt occlusion after coronary artery bypass graft surgery.
Contraindication
Hypersensitivity to the active substance or to other salicylates. History of active peptic ulcer and its complications. Acute bleeding.
Interaction with other medicinal products and other types of interactions
In vitro studies have shown an increase in the free fraction of the main metabolite of triflusal, 2-hydroxy-4-(trifluoromethyl)benzoic acid (HBA), in the presence of NSAIDs. On the other hand, increasing the concentration of HBA increases the effect of NSAIDs, glisentide and warfarin. It may be necessary to adjust the dose of these drugs when used together with triflusal.
In patients with acute myocardial infarction, the safety of triflusal in combination with thrombolytic agents (rt-PA and streptokinase) was evaluated. The number of cases of intracerebral hemorrhage was lower than in patients who used acetylsalicylic acid and thrombolytic agents (0.1% compared with 1.1% p=0.04).
Application features
Renal or hepatic impairment: Clinical experience in patients with renal or hepatic impairment is limited. Therefore, caution is recommended when treating patients with these conditions.
In patients with severe renal insufficiency receiving hemodialysis, the plasma concentration of the main metabolite of triflusal, 2-hydroxy-4-(trifluoromethyl) benzoic acid (HTB), does not change significantly, so dose adjustment is not required.
Although triflusal has demonstrated a low rate of bleeding in clinical trials, the drug should be used with caution in patients with an increased risk of bleeding due to trauma or other pathological conditions. During treatment with triflusal, caution should be exercised in the use of drugs that may cause bleeding, such as acetylsalicylic acid and other non-steroidal anti-inflammatory drugs (NSAIDs). In the case of planned surgical interventions, the risk of bleeding should be weighed and, if necessary, treatment with Disgren should be discontinued at least 7 days before the planned surgery.
Use during pregnancy or breastfeeding
There are no data on the effects of triflusal during pregnancy, therefore, it is not recommended to use the drug during this period. Animal studies have not revealed direct or indirect negative effects on pregnancy, fetal development, childbirth and postnatal development. There is no data on the penetration of triflusal into breast milk, therefore, it is necessary to weigh the risk of the expected benefit to the mother and the possible risk to the child. Breastfeeding should be avoided during treatment.
Ability to influence reaction speed when driving vehicles or other mechanisms
Not described, but the possibility of adverse reactions from the nervous system should be taken into account.
Method of administration and doses
For use in adults orally. The recommended dose is 600 mg (2 capsules) per day once or in two divided doses or 900 mg (3 capsules) per day in three divided doses. The drug is recommended to be taken with meals.
Children.
The safety and effectiveness of the drug in children have not been established.
Overdose
Cases of overdose have not been described. In case of taking a very high dose, symptoms of salicylate intoxication may occur (headache, tinnitus, dizziness, nausea, vomiting, rapid breathing). In this case, the drug should be discontinued and symptomatic therapy should be prescribed.
Side effects
Most often, adverse reactions occur in the gastrointestinal tract and usually disappear after a few days, even without discontinuation of the drug.
On the skin:
uncommon: rash, itching.
From the central and peripheral nervous system:
common: headache;
uncommon: confusion, dizziness, vertigo, convulsions.
On the part of the hearing organs:
uncommon: tinnitus, hypoacusis.
From the sensory organs:
uncommon: taste disturbances.
From the digestive tract:
very common: dyspeptic disorders;
often: abdominal pain, nausea, constipation, vomiting, flatulence, anorexia;
uncommon: diarrhea, gastrointestinal bleeding, melena, rectal bleeding.
From the cardiovascular system:
uncommon: arterial hypertension, transient ischemic attack, cerebral hemorrhage.
On the part of the respiratory system:
uncommon: dyspnea, upper respiratory tract infections.
From the hematopoietic system:
uncommon: anemia; coagulation disorders and bleeding: epistaxis, hematoma, purpura, gingival bleeding.
From the genitourinary system:
uncommon: hematuria, urinary tract infections.
General reactions:
uncommon: abdominal bloating, fever, flu-like symptoms.
Isolated cases of photosensitivity have been described.
Expiration date
2 years.
Storage conditions
Store in original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.
Do not use after the expiry date stated on the packaging.
Packaging
10 capsules in a blister; 3 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
J. Uriach y Compania, SA
Address
Av. Cami Reial, 51-57, Polіgon Industrial Riera de Caldes, 08184 Palau-Solita i Plegamans (Barcelona), Spain.
