Source: European Medicines Agency (EU)
Pharmacotherapeutic group: Other cardiac preparation
ATC code: C01EB15 (C01E: Other cardiac preparations)
Trimetazidine inhibits -oxidation of fatty acids by blocking long-chain 3-ketoacyl-CoA thiolase, which enhances glucose oxidation. In an ischaemic cell, energy obtained during glucose oxidation requires less oxygen consumption than in the -oxidation process. Potentiation of glucose oxidation optimizes cellular energy processes, thereby maintaining proper energy metabolism during ischaemia.
In patients with ischaemic heart disease, trimetazidine acts as a metabolic agent, preserving the myocardial high-energy phosphate intracellular levels. Anti-ischemic effects are achieved without concomitant haemodynamic effects.
Clinical studies have demonstrated the efficacy and safety of trimetazidine in the treatment of patients with chronic angina, either alone or when the benefit from other antianginal medicinal products was insufficient.
In a 426-patients randomized, double blind, placebo-controlled study (TRIMPOL-II), trimetazidine (60mg/day) added to metoprolol 100mg daily (50 mg b.i.d) for 12 weeks significantly improved statistically exercise tests 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 patients randomized, 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 1962 patients three-month randomised, double-blinded 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 1mm 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).
Trimetazidine after oral administration and absorption from the digestive tract reaches the maximum concentration in the serum after about 5 hours from administration of the drug. The steady concentration of the drug in the serum is reached after 60 hours and is stable throughout the period of treatment. No interactions with foodstuffs have been found.
The drug binds to plasma proteins at about 16%. The volume of distribution is 4.8 l/kg, which means good penetration of the drug into the tissues.
Trimetazidine is eliminated mainly in the urine, in unchanged form. The average half-life is 7 hours, in patients over age 65 years it increases to 12 hours.
No pharmacokinetic data are available for the use of trimetazidine in hepatically impaired patients.
The acute toxicity of trimetazidine in mice, rats and guinea pigs is low. Repeated-dose toxicity studies with trimetazidine have been performed in rats and in dogs and no toxicological target organ was identified in these studies. Trimetazidine was not genotoxic in a standard battery of in vitro and in vivo tests. Reproductive toxicity studies were performed with trimetazidine in rats, mice and rabbits, and no adverse effects of trimetazidine on reproductive function (especially no teratogenic effects) were observed. In embryotoxicity studies in rats and rabbits, trimetazidine did not show any teratogenic effects. No modifications of reproductive functions were observed in a three generation study performed in rats. No conventional studies on fertility or pre/postnatal development were performed.
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