TRIMETAZ 20

Dosage Form: Film coated tablets

Strength: 20 mg

Generic Name: Trimetazidine Dihydrochloride

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 of first-line antianginal therapies.

Posology

Adults

Oral administration.

The dose is one tablet of 20mg of trimetazidine three times a day during meals. Special populations

Patients with renal impairment

In patients with moderate renal impairment (creatinine clearance [30-60] ml/min) (see sections 4.4 and 5.2), the recommended dose is 1 tablet of 20mg twice daily, i.e., one in the morning and one in the evening during meals.

Elderly patients

Elderly patients may have increased trimetazidine exposure due to age-related decrease in renal function (see section 5.2). In patients with moderate renal impairment (creatinine clearance [30-60] ml/min), the recommended dose is 1 tablet of 20mg twice daily, i.e., one in the morning and one in the evening during meals.

Dose titration in elderly patients should be exercised with caution (see section 4.4).

Pediatric population:

The safety and efficacy of trimetazidine in children aged below 18 years have not been established. No data is available.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Parkinson disease, Parkinsonian symptoms, tremors, restless leg syndrome, and other related movement disorders.

Severe renal impairment (creatinine clearance < 30ml/min))

Untreated or inadequately treated depression. Patients who are actively suicidal.

This drug is not a curative treatment for angina attacks, nor is indicated as an initial treatment for unstable angina, or myocardial infarction. It should not be used in the prehospital phase nor during the first days of hospitalization.

In the event of an angina attack, angina pectoris disease should be reevaluated and the adaptation of the treatment considered.

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, gait instability should lead to definitive withdrawal of trimetazidine.

These cases have a low incidence and are usually reversible after treatment discontinuation. Most of the patients recovered 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 patients taking antihypertensive treatment.

Caution should be exercised when prescribing trimetazidine to patients in whom an increased exposure is expected:

moderate renal impairment

Elderly patients older than 75 years old Athletes: This medicine contains an active substance which may give a positive reaction in doping tests.

No drug interactions have been identified.

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. As a precautionary measure, it is preferable to avoid the use of Vastarel during pregnancy.

Breastfeeding

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 rates (see section 5.3)

Fertility

Reproductive toxicity studies have shown no effect on fertility in female and male rates.

Trimetazidine does not have hemodynamic effects in clinical studies, however cases of dizziness and drowsiness have been observed in post-marketing experience, which may affect ability to drive and use machines.

Tabulated List of Adverse Reactions

Trimetazidine may cause the following undesirable effects ranked under the following frequency:

Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000 to <1/100); rare

(>1/10000 to <1/1000); very rare (<1/10000), not known (cannot be estimated from the available

data).

Limited information is available on Trimetazidine overdose. Treatment should be symptomatic

Pharmacodynamics Properties

Pharmacotherapeutic group: Other cardiovascular antianginal drug.

Mechanism of Action

By preserving energy metabolism in cells exposed to hypoxia or ischemia, trimetazidine prevents a

decrease in intracellular ATP levels, thereby ensuring the proper functioning of ionic 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 ischemic cell, energy obtained during glucose oxidation

requires less oxygen consumption than in the β-oxidation process. Potentiation of glucose oxidation

optimizes cellular energy processes, thereby maintaining proper energy metabolism during

ischemia.

In patients with ischemic heart disease, trimetazidine acts as a metabolic agent, preserving the myocardial high-energy phosphate intracellular levels. Anti-ischemic effects are achieved without

concomitant hemodynamics 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 when the benefit from other antianginal medicinal

products were insufficient.

In a 426-patients randomized, double blind, placebo-controlled study (TRIMPOL-II), trimetazidine

(60mg/day) added to metoprolol 100mg daily (50 mg bid) 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 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 1962 patients three-month randomized, 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).

Absorption

After oral administration, trimetazidine is rapidly and completely absorbed and the peak plasma

concentration is reached in less than 2 hours. During repeated administration, steady state is reached

after 24 to 36 hours.

Distribution

The apparent distribution volume is 4.8 l / kg; protein binding is low: in vitro measurements give

value of 16%.

Elimination

Trimetazidine is eliminated primarily in the urine, mainly in the unchanged form. The elimination half-life is about 6 hours.

Linearity

Trimetazidine pharmacokinetics are linear following single dose administration up to 100 mg.

Repeated doses showed a time-linear pharmacokinetic response.

Special populations

Elderly:

The elderly may have increased trimetazidine exposure due to age-related decrease in renal

function. A dedicated pharmacokinetic study performed with trimetazidine MR 35mg in elderly

(75-84 years) or very elderly (≥85years) participants showed that moderate renal impairment

(creatinine clearance between 30 and 60 ml/min) increased respectively by 1.0 and 1.3-fold the

Trimetazidine exposure in comparison to younger participants (30-65 years) with moderate renal

impairment.

A specific clinical study carried out in an elderly population (older than 75 years old) using a

dosage of 2 tablets of trimetazidine MR 35mg per day taken in 2 doses, analyzed by a kinetic

population method, showed on average a 2-fold increase in plasma exposure in patients with severe

renal impairment (creatinine clearance below 30ml/min) as compared to those with a creatinine

clearance above 60 ml/min.

No safety concern was observed in the elderly population as compared to the general population.

Renal impairment

Trimetazidine exposure is increased on average by 1.7-fold in patients with moderate renal

impairment (creatinine clearance between 30 and 60 ml/min), and on average by 3.1-fold in patients

with severe renal impairment (creatinine clearance below 30ml/min) as compared to healthy

volunteers, with normal renal function.

No safety concern was observed in this population as compared to the general population.

Pediatric Population

The pharmacokinetics of trimetazidine have not been studied in the pediatric population (<18 years old).

Chronic toxicity studies conducted by the oral route in dogs (5 to 40 mg.kg-1. d-1) and rats (5 to 200

mg.kg-1. d-1), showed a good safety profile.

Neither embryo-fetotoxic effects nor teratogenicity were detected in mice and in rabbits. The general study on reproduction and embryogenesis in 3 generations of rats showed no anomalies.

The genotoxic potential was thoroughly assessed with three in vitro studies including the evaluation

of the mutagenic and clastogenic potential and one in vivo study. All tests were negative

Do not store above 30°C