1.3.1 Summary of Product Characteristics 1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 300 mg of triflusal.
3. PHARMACEUTICAL FORM
Hard capsule.
Clear hard gelatin capsules containing a white powder.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Secondary prophylaxis, after a first coronary or cerebrovascular ischaemic event, of: - Myocardial infarction - Stable or unstable angina - Transient or permanent non-haemorrhagic cerebrovascular accident.
4.2 Posology and method of administration
Posology
Adults and elderly The recommended dose is 600 mg/day as single or divided doses
Paediatric population Safety and efficacy in subjects under 18 years of age have not been established.
Use in patients with renal or hepatic impairment Clinical experience in patients with renal or hepatic impairment is limited, and special care is therefore recommended when treatment is started in this type of patients. In patients with end stage renal disease on conventional haemodialysis, pre- and post-dialysis plasma levels of the main triflusal metabolite, HTB (2-hydroxy-4-(trifluoromethyl)benzoic acid), have shown no significant changes, and no dose adjustment is therefore required.
Method of administration
Capsules are swallowed whole with a small amount of water. Triflusal is recommended to be taken preferably with meals.
4.3 Contraindications
Triflusal is contraindicated in patients with: - hypersensitivity to triflusal, to other salicylates or to any of the excipients listed in section 6.1.; - active peptic ulcer or a history of complicated peptic ulcer; - active bleeding.
4.4 Special warnings and precautions for use
Renal or hepatic impairment: Experience is limited. In patients with end stage renal disease on conventional haemodialysis, pre- and post-dialysis plasma levels of the main triflusal metabolite, HTB (2-hydroxy-4-(trifluoromethyl)benzoic acid), are similar (see section 4.2).
Bleeding risk: While triflusal has caused a low incidence of bleeding complications in clinical studies, it should be used with caution in patients at risk of bleeding due to trauma or other pathological conditions. Drugs that may induce bleeding, such as acetylsalicylic acid (ASA) or other non-steroidal anti-inflammatory drugs (NSAIDs), should also be used with caution in patients treated with triflusal (see section 4.5). If elective surgery is planned in a patient, bleeding risk should be assessed and, if considered necessary, triflusal should be discontinued 7 days before surgery.
4.5 Interaction with other medicinal products and other forms of interaction
In vitro protein binding studies showed an increase in the free fraction of HTB (main active metabolite of triflusal) in the presence of NSAIDs. In addition, high HTB concentrations increase free fractions and may therefore increase the effect of NSAIDs, glisentide, and warfarin (see section 5.2). Dose adjustment of these drugs may be required if they are administered concomitantly with triflusal.
Safety of concomitant administration of triflusal with thrombolytic agents (rt-PA and streptokinase) was assessed in patients with acute myocardial infarction. Incidence of intracranial haemorrhage was lower than in patients treated with a combination of ASA and thrombolytic agents (0.1% vs. 1.1%, p= 0.04) (see section 5.1).
Triflusal may potentiate the action of oral anti-diabetics. A dose adjustment of oral anti-diabetics may be required.
4.6 Fertility, pregnancy and lactation
Pregnancy
For triflusal, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development. The benefit/risk should therefore be assessed when it is administered to pregnant women.
Breastfeeding
It is not known whether triflusal is excreted in human milk. The benefit/risk should therefore be assessed when it is administered during the lactation period.
4.7 Effects on ability to drive and use machines
Triflusal has no influence on the ability to drive and use machines.
4.8 Undesirable effects
The most commonly reported adverse reactions affect the gastrointestinal tract and usually resolve in a few days even while treatment is continued.
Adverse reactions ordered by system and frequency were as follows: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1.000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data)
Skin and subcutaneous tissue disorders: Uncommon: pruritus/skin rash.
Nervous system disorders: Common: headache. Uncommon: confusion/vertigo/dizziness/seizures.
Ear and labyrinth disorders: Uncommon: tinnitus/hypoacusis.
Other special sense disorders: Uncommon: Taste disturbance.
Gastrointestinal disorders: Very common: dyspepsia. Common: abdominal pain/nausea/constipation/vomiting/flatulence/anorexia. Uncommon: diarrhoea/gastrointestinal bleeding/melena/rectal bleeding.
Vascular disorders: Uncommon: hypertension, cerebral haemorrhage.
Cardiac disorders,: Uncommon: transient ischaemic attack/
Respiratory, thoracic and mediastinal disorders: Uncommon: dyspnoea/upper respiratory tract infection.
Blood and lymphatic disorders: Uncommon: anaemia, epistaxis/haematoma/purpura/gingival bleeding.
Renal and urinary disorders: Uncommon: haematuria/urinary tract infection.
General disorders and administration site conditions: Uncommon: distended abdomen/fever/influenza symptoms.
Some isolated photosensitivity reactions have been reported.
4.9 Overdose
No case of overdose has been reported.
In the event of an accidental overdose, which may only occur after the intake of very high doses, symptoms of salicylate poisoning may occur. If these occur, administration of the medicinal product should be discontinued and both symptomatic treatment and any required support measures should be started.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Platelet aggregation inhibitors, excluding heparin. Antithrombotic agents, ATC code: B01AC18.
Triflusal reduces thromboxan biosynthesis through irreversible inhibition of platelet cyclooxygenase, sparing prostacyclin biosynthesis because its effect on vascular cyclooxygenase at therapeutic doses is negligible. On the other hand, the main triflusal metabolite, 2-hydroxy-4-(trifluoromethyl)benzoic acid (HTB), is a reversible platelet cyclooxygenase inhibitor and, because of its long elimination half-life (approximately 34 h), contributes to the antiplatelet activity of triflusal. Both triflusal and HTB are able to increase the concentration of cyclic adenosine 5-monophosphate (cAMP) in platelets through inhibition of platelet phosphodiesterases. In addition, triflusal has been shown to stimulate in vitro and ex vivo nitric oxide release in human neutrophils, which also contributes to the antiplatelet effect.
Triflusal has been shown to inhibit platelet aggregation in both healthy volunteers and patients. In ex vivo studies, triflusal inhibited by 65% the platelet aggregation induced by arachidonic acid in platelet- rich plasma (PRP) from healthy volunteers 24 hours after administration of a single 600 mg dose. Repeated triflusal administration (600 mg/day for 7 days) caused a 50%-75% inhibition of platelet aggregation (PRP) induced by arachidonic acid, ADP (adenosine diphosphate), epinephrine, or collagen.
In a randomised, multicentre, double-blind, placebo-controlled clinical trial on 122 patients of both sexes aged 40-75 years with Lériche-Fontaine stage II chronic obliterating peripheral arteriopathy, of whom 59 received triflusal (600 mg/day) and 63 placebo for a period of 6 months, rates of success (defined as a 40% increase in the total distance walked compared to baseline) were 63.6% with triflusal versus 22.5% with placebo (p=0.0001). An analysis of the total distance walked without experiencing pain as compared to baseline showed triflusal to be superior to placebo, but the difference was not statistically significant (p=0.05). On the other hand, significant differences favouring triflusal (p=0.003) were seen in improvement of symptoms related to vascular disease (limb paraesthesia, heaviness, and coldness).
In a randomised, double-blind clinical trial involving 2270 patients with acute myocardial infarction treated for 35 days with triflusal (600 mg once daily) or ASA (300 mg once daily) (TIM Study), incidence rates of gastrointestinal bleeding were 0.9% for triflusal versus 1.5% for ASA, and intracranial haemorrhage rates were 0.3% for triflusal versus 1% for ASA. In both groups, most of those haemorrhages were seen in patients who received concomitant treatment with thrombolytic agents and heparin. In another randomised, double-blind clinical trial involving 2107 patients with stroke treated for a mean of 30 months with triflusal (600 mg once daily) or ASA (325 mg once daily) (TACIP Study), the incidence of clinically relevant bleeding was significantly lower (p=0.004) in patients treated with triflusal (1.9% vs 4.0%).
5.2 Pharmacokinetic properties
Triflusal is rapidly absorbed (t1/2 Ka = 0.44 h), and has an absolute bioavailability of 83%-100%. Triflusal is rapidly metabolised by the action of esterases to its main metabolite, HTB, which is also active. In urine, a secondary metabolite was identified as a HTB-glycine conjugate. Plasma half-life (t1/2) was 0.53 ± 0.12 h for triflusal and 34.3 ± 5.3 h for HTB. Elimination preferentially occurs through renal excretion (renal clearance > 60% at 48 hours). Unchanged triflusal, HTB, and the HTB- glycine conjugate were detected in urine.
Following administration of a single oral dose of triflusal 300 mg or 900 mg to healthy volunteers, mean triflusal peak plasma concentrations (Cmax) were 3.2 ± 1.9 g/mL and 11.6 ± 1.7 g/mL respectively, while the Cmax for HTB reached 36.4 ± 6.1 g/mL and 92.7 ± 17.1 g/mL. Time to Cmax (tmax) was 0.88 ± 0.26 h for triflusal and 4.96 ± 1.37 h for HTB at the 900 mg dose. HTB pharmacokinetic parameters after repeated administration (triflusal 300 mg three times daily or 600 mg once daily for 13 days) showed steady state peak plasma concentrations (Cmax ss) of HTB of 178 ± 42 g/mL and 153 ± 37 g/mL respectively.
At therapeutic concentrations, HTB has a plasma albumin binding rate of 98%-99%. This binding was not significantly altered by the presence of caffeine, theophylline, glisentide, enalapril, cimetidine, or warfarin. However, HTB free fraction significantly increased in the presence of non-steroidal anti- inflammatory drugs (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 agents have affinity for the same albumin binding sites and may displace each other as a function of their affinities for the protein and the total concentration of the displacing agent.
Special populations
In elderly volunteers, steady state plasma concentrations of triflusal and HTB were reached 3 to 5 days after administration of triflusal 300 mg twice daily. Values of AUCss, Cmax, and tmax in elderly volunteers were not significantly different from those reported in young volunteers. Plasma half-lives (t1/2) were 0.92 ± 0.16 h for triflusal and 64.6 ± 6.6 h for HTB. However, this increase has no clinical relevance warranting dose adjustment in elderly subjects.
In patients with end-stage chronic renal disease on conventional haemodialysis, HTB plasma concentrations measured before and after dialysis were similar.
5.3 Preclinical safety data
Preclinical data revealed no special risk for humans, according to the results of conventional safety pharmacology, repeated administration toxicity, genotoxicity, and reproductive toxicity studies.
After long-term administration of triflusal to rats and dogs (10, 25, and 50 mg/kg/day for 12 months), biochemical, morphological, and histopathological changes were only found at the high dose. The most significant pathological signs were gastrointestinal intolerance, including gastric ulcers, moderate anaemia, vomiting (in dogs), slight changes in organ weight (liver, kidneys, heart, and spleen), and mild to moderate nephrosclerosis. Most of these effects, except for nephrosclerosis, were reversible 13 weeks after treatment discontinuation.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Do not store above 25ºC.
6.5 Nature and contents of container
Aluminium/PVC-PVDC blisters.
Carton box with 3 PVC/PVDC with 10 hard capsules.
Carton box with 5 PVC/PVDC with 10 hard capsules.
Carton box with 6 PVC/PVDC with 10 hard capsules.
Carton box with 9 PVC/PVDC with 10 hard capsules.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
Glenmark Pharmaceuticals s.r.o. Hvězdova 1716/2b 140 78 Praha 4, Czech Republic
8. MARKETING AUTHORISATION NUMBER
<[To be completed nationally]>
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
<[To be completed nationally]>
10. DATE OF REVISION OF THE TEXT
<[To be completed nationally]>