Trimetazidine dihydrochloride 20.00 mg.
Excipients/Inactive Ingredients: Excipients with known effect: Sunset yellow FCF (E110) and cochineal red A (E124).
Maize starch, mannitol, povidone, magnesium stearate, talc.
Film-coating: Mixture of excipients for red coating 37771 FRG (titanium dioxide (E171), glycerol, sunset yellow FCF aluminium lake (E110), cochineal red A aluminium lake (E124), macrogol 6000, hypromellose, magnesium stearate), macrogol 6000.
Pharmacotherapeutic Group: OTHER CARDIOVASCULAR ANTIANGINAL DRUG. 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, thereby ensuring the proper functioning of ion pumps and transmembrane sodium-potassium flow whilst maintaining cellular homeostasis.
Trimetazidine inhibits β-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 β-oxidation process. Potentiation of glucose oxidation optimises cellular energy processes, thereby maintaining proper energy metabolism during ischaemia.
Pharmacodynamic effects: In patients with ischaemic heart disease, trimetazidine acts as a metabolic agent, preserving the myocardial high-energy phosphate intracellular levels. Anti-ischaemic 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 tests parameters and clinical symptoms as compared to placebo: total exercise duration +20.1 s, p=0.023, total workload +0.54 METs, p=0.001, time to 1-mm ST-segment depression +33.4 s, p=0.003, time to onset of angina +33.9 s, p < 0.001, frequency of angina attacks/week -0.73, p=0.014 and short acting nitrates consumption/week, -0.63, p=0.032, without haemodynamic 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 (+34.4 s, 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-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 depression and time to onset of 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 (+43.6 s versus +32.5 s placebo; p=0.005).
Pharmacokinetics: Absorption: After oral administration, absorption of trimetazidine is rapid and the plasma peak is reached in less than 2 hours.
After a single oral dose of 20 mg of trimetazidine, the peak plasma concentration is approximately 55 ng.ml-1.
During repeated administration, the steady state is reached after 24 to 36 hours and remains very stable throughout treatment.
Distribution: The apparent distribution volume is 4.8 l/kg, which suggests good tissue diffusion. Protein binding is low: in vitro measurements give a value of 16%.
Elimination: Trimetazidine is eliminated primarily in the urine, mainly in the unchanged form.
The mean elimination half-life is 6 hours.
Linearity: Trimetazidine pharmacokinetics is linear following single dose administration up to 100 mg. Repeated doses showed a time-linear pharmacokinetic response.
Special populations: Elderly subjects: Trimetazidine exposure may be increased in elderly patients due to an age-related decrease in renal function. A pharmacokinetics 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, respectively in comparison with younger participants (30-65 years) with moderate renal impairment. No safety concerns were observed in the elderly subjects as compared with the general population.
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) compared with healthy young volunteers with normal renal function. No safety concerns were 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 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 in 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.
Trimetazidine is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies.
Posology: Oral route.
The dose is one tablet of 20 mg of trimetazidine three times a day during meals.
The benefit of the treatment should be assessed after three months and trimetazidine should be discontinued if there is no treatment response.
Special populations: Patients with renal impairment: In patients with moderate renal impairment (creatinine clearance [30-60] ml/min) (see Pharmacology: Pharmacokinetics under Actions and Precautions), the recommended dose is 1 tablet of 20 mg twice daily, i.e. one in the morning and one in the evening, during meals.
The information available concerning trimetazidine overdose is limited. Treatment should be symptomatic.
Hypersensitivity to trimetazidine or to any of the excipients listed in Description.
Parkinson's disease, parkinsonian symptoms, tremors, restless leg syndrome, and other related movement disorders.
Severe renal impairment (creatinine clearance < 30 ml/min).
This drug is not a curative treatment for angina attacks, nor is it indicated as an initial treatment for unstable angina or myocardial infarction. It should not be used in the pre-hospital phase or during the first days of hospitalisation.
In the event of an angina attack, the coronary heart disease should be re-evaluated and an adaptation of the treatment considered (drug treatment and possibly revascularisation).
Trimetazidine can cause or worsen parkinsonian symptoms (tremor, akinesia, hypertonia), which should be regularly investigated, especially in elderly patients. In doubtful cases, patients should be referred to a neurologist for appropriate investigations.
The occurrence of movement disorders such as parkinsonian symptoms, restless leg syndrome, tremors or gait instability should lead to definitive withdrawal of trimetazidine.
These cases have a low incidence and are usually reversible after treatment discontinuation. The majority of patients recover within 4 months after trimetazidine withdrawal. If parkinsonian symptoms persist more than 4 months after drug discontinuation, a neurologist opinion should be sought.
Falls may occur, related to gait instability or hypotension, in particular in patients taking antihypertensive treatment (see Adverse Reactions).
Caution should be exercised when prescribing trimetazidine to patients in whom an increased exposure is expected: Moderate renal impairment (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration), Elderly patients older than 75 years old (see Dosage & Administration).
This medicinal product is generally not recommended during breast-feeding (see Use in Pregnancy & Lactation).
This medicinal product contains sunset yellow FCF (E110) and cochineal red A (E124) and may cause allergic reactions.
Effects on ability to drive and use machines: Trimetazidine did not show any haemodynamic effects in clinical studies, however cases of dizziness and drowsiness have been observed in post-marketing experience (see Adverse Reactions), which may affect the ability to drive and use machines.
Pregnancy: There are no data from the use of trimetazidine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). As a precautionary measure, it is preferable to avoid the use of VASTAREL during pregnancy.
Breast-feeding: It is unknown whether trimetazidine/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. VASTAREL should not be used during breast-feeding.
Fertility: Reproductive toxicity studies have shown no effect on fertility in female and male rats (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Concerning the adverse reactions associated with the use of trimetazidine, see also Precautions.
The table as follows includes the adverse reactions from spontaneous notifications and scientific literature. Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). (See table.)
Click on icon to see table/diagram/image
No drug interactions have been identified.
Special precautions for disposal and other handling: No special requirements.
Incompatibilities: Not applicable.
Store below 30°C.
Shelf-Life: 3 years.
C01EB15 - trimetazidine ; Belongs to the class of other cardiac preparations.