Grendis. (Triflusal) Platelet aggregation inhibitor. Antithrombotic agent COMPOSITION. Each capsule contains 300 mg of Triflusal MODE OF ACTION

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1 Grendis (Triflusal) Platelet aggregation inhibitor. Antithrombotic agent COMPOSITION Each capsule contains 300 mg of Triflusal MODE OF ACTION PHARMACODYNAMIC PROPERTIES Triflusal is an inhibitor of thromboxane biosynthesis that acts by irreversible inhibition of platelet cyclooxygenase, with the advantage of respecting prostacyclin biosynthesis due to its negligible effect on vascular cyclooxygenase at therapeutic dose. In addition, 2-hydroxy-4-(trifluoromethyl) benzoic acid (HTB), triflusal s main metabolite, is a reversible inhibitor of platelet cyclooxygenase and due to its prolonged half-life (about 34 h) contributes favourably to the antiplatelet activity of triflusal. Both triflusal and HTB are also able to increase cyclic adenosine monophosphate (camp) levels in platelets through inhibition of platelet phosphodiesterases. In vitro and ex vivo studies have further demonstrated that stimulates the release of nitric oxide in human neutrophiles, which also contributes to the antiplatelet effect. Triflusal has demonstrated inhibition of platelet aggregation in healthy volunteers and in patients. In ex vivo studies triflusal produced 65% inhibition of arachidonic acid-induced platelet aggregation in platelet-rich plasma (PRP) of healthy volunteers 24 hours after the administration of a single dose of 600 mg. Repeated administration of triflusal (600 mg daily for 7 days) resulted in 50% to 75% inhibition of platelet aggregation (PRP) induced by arachidonic acid, ADP (adenosine diphosphate), epinephrine or collagen. A randomized, multicentre, placebo-controlled clinical trial was conducted with 122 patients (triflusal = 59, placebo = 63) of both gender between 40 and 75 years old, suffering from chronic obliterant peripheral arteriopathy in grade II Leriche fontaine. Triflusal (600 mg/day) was administered during 6 months. The percentage of success (defined as a 40% increase in total walking distance over the basal control) was 63.6% for triflusal and 22.5% for placebo (p = ). Also the analysis of total pain free walking distance over the basal value showed that triflusal was nearly significantly superior to placebo (p = 0.05). The triflusal group also showed significant favourable differences (p = 0.003) in the improvement of symptoms associated with vasculopathy (paraesthesias, heaviness, cold in lower limbs) in comparison with the placebo group. In double - blind randomized clinical trial (TIM study) that included 2270 patients with acute myocardial infarction treated during 35 days with triflusal (600 mg once a day) or ASA (300 mg once a day) the incidence of gastro-intestinal haemorrhage was 0.9% (triflusal) vs1.5% (ASA), and the incidence of intracranial haemorrhage was 0.3% (triflusal) vs 1% (ASA). Most of these haemorrhages in both groups occurred in patients that received concomitant therapy with thrombolytic agents and heparin. In another double-blind, randomized clinical trial (TACIP study) with 2107 stroke patients who were treated with triflusal (600 mg once a day) or ASA (325 mg once a day) during a mean of 30 months, the incidence of clinically relevant haemorrhages was significantly lower (p = 0.004) in triflusal treated patients (1.9% vs 4.0%).

2 PHARMACOKINETIC PROPERTIES Triflusal is rapidly absorbed (t1/2 Ka = 0.44 h), showing and absolute bioavailability of 83% to 100%. Triflusal is rapidly hydrolysed by esterases to its main metabolite HTB, which is also active. An HTB-glycine conjugate was found in urine. Plasma half life (t1/2) was 0.53 ± 0.12 h for triflusal and 34.3 ± 5.3 h for HTB. Elimination preferably occurred by renal excretion (renal clearance > 60% after 48 hours). Unchanged triflusal, HTB and HTB-glycine conjugate were found in urine. Following a single oral dose of 300 or 900 mg triflusal in healthy volunteers, mean peak plasma concentrations (Cmax) for triflusal were 3.2 ± 1.9 µg/ml and 11.6 ± 1.7 µg/ml, respectively, whereas Cmax for HTB reached 36.4 ± 6.1 µg/ml and 92.7 ± 17.1 µg/ml. The time to max (t max ) was 0.88 ± 0.26 h for triflusal and 4.96 ± 1.37 h for HTB at the dose 900 mg. The pharmacokinetic parameters of HTB after repeated doses (300 mg three times a day or 600 mg once daily of triflusal for 13 days) showed steady-state peak plasma HTB concentrations (C max ) of 178 ± 42 µg/ml and 153 ± 37µg/ml, respectively. HTB, at therapeutic concentrations, has a binding rate to plasma albumin of 98% to 99%. This binding was not significantly altered by the presence of caffeine, theophylline, glisentide, enalapril, cimetidine or warfarin. Nevertheless the free fraction of HTB significantly increased in the presence of non-steroidal anti-inflammatory medicinal products (NSAIDs), such as diclofenac, ibuprofen, indomethacin, naproxen, piroxicam or salicylic acid. At high concentrations, HTB displaced NSAIDs, glisentide and warfarin from their protein binding sites. These compounds have affinity for the same albumin binding sites and they can be mutually displaced depending on their affinity for the protein and the total concentration of the displacing agent. Special populations In elderly volunteers, steady-state plasma HTB concentrations were attained after 3 to 5 days administration of triflusal 300 mg two times a day. The values of AUCmax, Cmax and tmax in elderly volunteers were not significantly different of those obtained in young volunteers. Plasma half-life t1/2 was 0.92 ± 0.16 h for triflusal and 64.6 ± 6.6 for h for HTB, both higher than those observed in young volunteers. Nevertheless, this increase has no clinical relevance that justifies a dose adjustment in elderly patient. In patients with terminal chronic renal failure submitted to conventional haemodialysis, postdialysis plasma levels of HTB were similar to predialysis levels. Preclinical safety data Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction. After long-term administration of triflusal to rats and dogs (10, 25 and 50 mg/kg daily for 12 months) biochemical, morphological or histophatological changes were only found at high dose. The most relevant pathological signs were gastro-intestinal intolerance with gastric ulcers, moderate anaemia, vomiting (dogs), slight changes in organ weights (liver, kidney, heart, spleen) and slight to moderate nephrosclerosis. Most of these effects, except nephrosclerosis, were reversible 13 weeks after treatment withdrawal. INDICATIONS

3 Secondary prevention after a first coronary or cerebrovascular ischemic event of: Myocardial infarction Stable and unstable angina Non haemorrhagic stroke or transient ischemic attack Reduction of vein graft occlusion after coronary by-pass. CONTRAINDICATIONS Grendis is contra-indicated in patients with: hypersensitivity to triflusal or other salicylates active peptic ulcer or antecedents of complicated peptic ulcer; any active bleeding WARNING AND PRECAUTIONS Renal or hepatic impairment : Experience is limited. In patients with severe renal impairment undergoing conventional haemodialysis, pre and post-dialysis plasma levels of the main active metabolite of triflusal, HTB (2-hydroxy-4-(trifluoromethyl)benzoic acid), were found to be similar (see posology and method of administration). Bleeding risk : Although triflusal has shown a low rate of bleeding complications in clinical trials, it must be used with caution in patients who may be at risk of increased bleeding from trauma or other pathological conditions. Active substances that may induce such lesions (acethylsalicylic acid (ASA) or other non-steroidal anti-inflammatory drugs (NSAIDs) must be used with caution in patients taking triflusal (see Drug Interaction). If a patient is to undergo elective surgery, the bleeding risk has to be evaluated and, if considered necessary, triflusal must be discontinued 7 days prior to surgery. Pregnancy and lactations For triflusal no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / foetal development, parturition or postnatal development. Potential benefit / risk must be evaluated when prescribing to pregnant women. It is not know if triflusal is excreted in milk. Potential benefit / risk must be evaluated when prescribing to breast feeding women. Effects on the ability to drive and use machines No effects on the ability to drive or use machines have been observed. Overdose No case of overdose has been reported In case of accidental overdose, which may only occur by ingestion of very high doses, symptoms of salicylate intoxication can be expected. In such case, it is necessary to discontinue the administration of the medicinal product, to treat symptomatically and to institute supportive measures as required. UNDESIRABLE EFFECTS The most commonly reported adverse drug reactions affect the gastro-intestinal system usually disappear within a few days even if treatment is continued. The adverse reactions classified by systems and frequency are the following ones :

4 Skin and appendages : Uncommon : pruritus / rash Central and peripheral nervous system disorders : Common : headache. Uncommon : confusion / vertigo / dizziness / convulsions. Hearing and vestibular : Uncommon : tinnitus / hearing decreased. Special senses other : Uncommon : Taste perversion Gastro intestinal : Very common : dyspepsia. Common : abdominal pain / nausea / constipation / vomiting / fistulance / anorexia. Uncommon : diarrhea / gastrointestinal haemorrhage Cardiovascular general : Uncommon : hypertension Cardiovascular, vascular extracardiac : Uncommon : transient Cerebral haemorrhage. Respiratory system : Uncommon : dyspnoea / upper respiratory infection Read blood cell : Uncommon : anaemia Platelet, bleeding and clotting : Uncommon : epistaxis / haematoma / purpura / gingival bleeding Urinary system : Uncommon : haematuria / urinary infection Body as a whole : Uncommon : abdomen enlarged / fever / influenza like symptoms A few isolated cases of photosensitivity reaction have been reported. DRUG INTERACTION In vitro protein binding studies showed that the free fraction of HTB (main active metabolite of triflusal) increases in presence of NSAIDs. Inversely, high concentrations of HTB increase the free fraction and, therefore possibly the effect of NSAIDs, glisentide or warfarin (see Pharmacokinetic properties). It might be required to adjust the dose of these active substances when co-administered with triflusal. The safety of the concomitant administration of triflusal with thrombolytic agents (rt-pa and streptokinase) was evaluated in patients with acute myocardial infarction. The incidence of intracranial haemorrhage was significantly lower than in patients treated with a combination of ASA and thrombolytic agents (0.1% vs 1.1%, p = 0.04) (see Pharmacodynamic properties). POSOLOGY AND METHOD OF ADMINISTRATION Adults and elderly : The recommended dose is 600 mg/day in a single or split dose, or 900 mg/day in split dose. Triflusal should preferably be administered with meals. Use in children : Safety and efficacy in subjects bellow the age of 18 have not been established. Use in renal or hepatic dysfunction : Clinical experience in patients with renal or hepatic impairment is limited, so caution must be exercised when initiating treatment in these populations. In patients with terminal chronic renal failure undergoing conventional haemodialysis, postdialysis plasma levels of the main active metabolite of triflusal, HTB (2-hydroxy-4- (trifluoromethyl)benzoic acid), were found to be similar to pre-dialysis levels, which indicates that no adjustment of dose is required. SPECIAL PRECAUTIONS FOR STORAGE

5 Do not store above 25 o C Keep the container tightly closed PACKAGING Box, Bottle of 30 Capsules Reg. No KEEP OUT OF THE REACH OF CHILDREN ON MEDICAL PRESCRIPTION ONLY Harus dengan resep dokter Manufactured by : J. Uriach & Cla., S.A., Barcelona, Spain Imported by : PT.COMBIPHAR, Bandung, Indonesia Marketing by : Fournier Pharma, Indonesia