Vastarel MR

Trimetazidine dihydrochloride.

Trimetazidine dihydrochloride 35 mg for one modified release film-coated tablet.
Excipients/Inactive Ingredients: Calcium hydrogen phosphate dihydrate; hypromellose; povidone; anhydrous colloidal silica, magnesium stearate.
Film-coating: titanium dioxide (E 171), glycerol, hypromellose, macrogol 6000, red iron oxide (E 172), magnesium stearate.

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 60^th 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.

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 35 mg of trimetazidine twice daily, i.e. once in the morning and once in the evening, 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 Precautions and Pharmacology: Pharmacokinetics under Actions), the recommended dose is 1 tablet of 35 mg in the morning during breakfast.
Elderly patients: Elderly patients may have increased trimetazidine exposure due to age-related renal impairment (see Pharmacology: Pharmacokinetics under Actions). In patients with moderate renal impairment (creatinine clearance [30-60 mL/min]), the recommended dose is 1 tablet of 35 mg in the morning during breakfast.
Dose titration in elderly patients should be exercised with caution (see Precautions).
Paediatric population: The safety and efficacy of trimetazidine in children aged below 18 years have not been established. No data are available.

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, nor myocardial infarction. It should not be used in the pre-hospital phase nor 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, postural instability should lead to definitive withdrawal of trimetazidine.
These cases have a low incidence and are usually reversible after treatment discontinuation. The majority of the patients recover within 4 months after trimetazidine withdrawal. If parkinsonian symptoms persist more than 4 months after treatment discontinuation, a neurologist opinion should be sought.
Severe cutaneous adverse reactions (SCARs): Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with trimetazidine treatment. At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, trimetazidine should be withdrawn immediately and an alternative treatment considered (as appropriate).
Falls may occur, related to postural 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 Dosage & Administration and Pharmacology: Pharmacokinetics under Actions), patients older than 75 years (see Dosage & Administration).
This medicinal product is generally not recommended during breastfeeding (see Use in Pregnancy & Lactation).
Athletes: This medicinal product contains a drug substance that may give a positive result in anti-doping tests.
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 ability to drive and use machines.

Pregnancy: There is no data on the use of trimetazidine in pregnant women. Studies performed in animals have not revealed direct or indirect harmful effects on reproduction (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 not known whether trimetazidine/metabolites are excreted in breast 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, also see 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 interaction has been identified.

Incompatibilities: Not applicable.

Below 30°C.
Shelf-life: 3 years.

Anti-Anginal Drugs

C01EB15 - trimetazidine ; Belongs to the class of other cardiac preparations.

C