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Pharmacotherapeutic Group: Other Cardiac Preparations. ATC code: C01EB15 (C: cardiovascular system).
Pharmacology: Pharmacodynamics: Mechanism of action: By preserving energy metabolism in cells exposed to hypoxia or ischaemia, trimetazidine prevents a decrease in intracellular ATP levels, it thereby ensures the proper function of ion pumps and transmembrane sodium-potassium flow while maintaining cellular homeostasis.
Trimetazidine inhibits β-oxidation of fatty acids by blocking 3-ketoacyl-CoA thiolase, thus stimulating glucose oxidation. The energy generated in the ischaemic glucose oxidation requires less oxygen consumption than β-oxidation. Potentiation of glucose oxidation optimizes cellular energy processes, thereby maintaining an adequate energy metabolism during ischaemia.
Pharmacodynamic effects: In patients with ischaemic heart disease, trimetazidine acts as a metabolic agent, preserving myocardial high-energy phosphate intracellular levels. Anti-ischemic effects are achieved without concomitant haemodynamic effects.
Clinical efficacy and safety: Clinical studies have demonstrated the efficacy and safety of trimetazidine in the treatment of patients with chronic angina, either alone or in combination with other antianginal treatments in poorly controlled patients.
In a 426-patient, randomised, double-blind, placebo-controlled study (TRIMPOL-II), trimetazidine (60 mg/day) added to metoprolol 100 mg daily (50 mg b.i.d) for 12 weeks, statistically, significantly improved exercise tolerance test parameters and clinical symptoms as compared to placebo: total exercise duration +20.1s, p=0.023, total workload +0.54 METs, p=0.001, time to 1-mm ST-segment depression +33.4s, p=0.003, time to onset of angina +33.9s, p<0.001, angina attacks/week -0.73, p=0.014 and short acting nitrates consumption/week, -0.63, p=0.032, without hemodynamic changes.
In a 223-patient, randomised, double-blind, placebo-controlled study (Sellier), one 35 mg trimetazidine modified-release tablet (b.i.d.) added to 50 mg atenolol (o.d.) for 8 weeks produced a significant increase (+34.4s, p=0.03) in the time to 1-mm ST-segment depression in exercise tests, in a sub-group of patients (n=173), when compared to placebo, 12 hours after taking the drug. A significant difference was also evidenced for the time to onset of angina pectoris (p=0.049). No significant difference between groups could be found for the other secondary endpoints (total exercise duration, total workload and clinical endpoints).
In a 1,962-patient, three-month randomised, double-blind study (Vasco study) on top of atenolol 50 mg/d, two dosages of trimetazidine (70 mg/d and 140 mg/d) were tested versus placebo. In the overall population, including both asymptomatic and symptomatic patients, trimetazidine failed to demonstrate a benefit on both ergometric (total exercise duration, time to onset of 1 mm ST and time to onset angina) and clinical endpoints. However, in the subgroup of symptomatic patients (n=1574) defined in a post-hoc analysis, trimetazidine (140 mg) significantly improved total exercise duration (+23.8 s versus +13.1 s placebo; p=0.001) and time to onset of angina (+46.3 s versus +32.5 s placebo; p=0.005).
Pharmacokinetics: After oral administration, maximum concentration is found, on average, 5 hours after taking the tablet. Over 24 hours, the plasma concentration remains at levels above or equal to 75% of the maximum concentration for 11 hours.
Steady state is reached by the 60th hour, at the latest.
The pharmacokinetic characteristics of VASTAREL are not influenced by meals.
The apparent distribution volume is 4.8 L/kg; trimetazidine protein binding is low: in vitro measurements give value of 16%.
Trimetazidine is eliminated primarily in the urine, mainly in the unchanged form.
The elimination half-life of VASTAREL is an average of 7 hours in healthy young volunteers and 12 hours in subjects aged more than 65 years.
Total clearance of trimetazidine is the result of major renal clearance which is directly correlated to creatinine clearance and, to a lesser extent, to liver clearance which is reduced with age.
Special populations: Elderly patients: A specific clinical study performed in an elderly population using a posology of 2 tablets per day taken in 2 doses, analysed by a kinetic population approach, showed an increase in plasma exposure.
Trimetazidine exposure may be increased in elderly patients due to age-related decrease in renal function.
A pharmacokinetic study performed specifically in elderly (75-84 years) and very elderly (≥85 years) participants showed that in the event of moderate renal impairment (creatinine clearance between 30 and 60 mL/min) trimetazidine exposure was increased by a factor of 1.0 and 1.3-fold respectively in comparison with younger participants (30-65 years) with moderate renal impairment.
Renal impairment: On average, trimetazidine exposure is multiplied by 1.7 in patients with moderate renal impairment (creatinine clearance between 30 and 60 mL/min) and by 3.1 in patients with severe renal impairment (creatinine clearance below 30 mL/min) as compared to healthy young volunteers, with normal renal function. No safety problem was observed in this population as compared with the general population.
Paediatric population: The pharmacokinetics of trimetazidine have not been studied in the paediatric population (<18 years).
Toxicology: Preclinical safety data: Chronic oral toxicity studies performed in dogs and rats showed a good safety profile.
Genotoxic potential was assessed in in vitro studies, including evaluation of the mutagenic and clastogenic potential, and one in vivo study. All the tests were negative.
Reproductive toxicity studies performed in mice, rabbits and rats showed no embryotoxicity or teratogenicity. In rats, fertility was not impaired and no effects on postnatal development were observed.
