Vastarel MR

Trimetazidine diHCl.

Each film-coated tablet also contains the following excipients: Dicalcium phosphate, hypromellose, povidone, anhydrous colloidal silica, magnesium stearate. Film-coating: Titanium dioxide (E171), glycerol, hypromellose, macrogol 6000, red iron oxide (E172), magnesium stearate.

Pharmacotherapeutic Group: Other Cardiovascular Antianginal Drug. ATC Code: C01EB15.
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 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 ischaemic 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 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 when the benefit from other antianginal medicinal products was insufficient.
In a 426 patients randomized, double blind, placebo-controlled study (Trimpol-II), trimetazidine (60 mg/day) added to metoprolol 100mg daily (50 mg twice daily) for 12 weeks significantly improved statistically 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, 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 (twice daily) added to 50 mg atenolol (once daily) 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 subgroup 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 patients 3-month randomised, double-blinded study (Vasco study) on top of atenolol 50 mg/d, 2 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 vs 13.1 s placebo; p=0.001) and time to onset of angina (46.3 s vs 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 ≥75% of the maximum concentration for 11 hours.
Steady state is reached by the 60th hour, at the latest.
The pharmacokinetic characteristics of Vastarel MR are not influenced by meals.
The apparent distribution volume is 4.8 L/kg; 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 MR is an average of 7 hours in healthy young volunteers and 12 hours in subjects aged >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.
A specific clinical study carried out in an elderly population using a dosage of 2 tablets per day taken in 2 doses, analysed by a kinetic population method, showed an increase in plasma exposure which does not justify a dosage alteration.
Toxicology: Preclinical Safety Data: Not applicable.

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.

1 tablet of Vastarel MR twice daily during meals.
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 Vastarel MR in the morning during breakfast.
Elderly: Elderly patients may have increased trimetazidine exposure due to age-related decrease in renal function (see Pharmacology: Pharmacokinetics under Actions). In patients with moderate renal impairment (creatinine clearance 30-60 mL/min), the recommended dose is 1 tablet Vastarel MR in the morning during breakfast.
Dose titration in elderly patients should be exercised with caution (see Precautions).
Children: The safety and efficacy of trimetazidine in children <18 years have not been established. No data are available.

Not applicable.

Hypersensitivity to trimetazidine dihydrochloride or to any of the excipients of Vastarel MR. Parkinson's disease, parkinsonian symptoms, tremors, restless leg syndrome, and other related movement disorders, severe renal impairment (creatinine clearance <30mL/min).

Vastarel MR is generally not recommended during breastfeeding (see Use in lactation as follows).
Vastarel MR is not a curative treatment for angina attacks, nor is it indicated as an initial treatment for unstable angina, nor myocardial infarction, nor in the prehospital phase nor during the first days of hospitalisation.
In the event of an angina attack, the coronaropathy should be reevaluated and an adaptation of the treatment considered (medicinal 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 eg, 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. The majority of the patients recovered within 4 months after trimetazidine withdrawal. If parkinsonian symptoms persist >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 Dosage & Administration and Pharmacology: Pharmacokinetics under Actions), elderly patients >75 years (see Dosage & Administration).
Effects on the Ability to Drive or Operate Machinery: Trimetazidine does not have haemodynamic effects in clinical studies; however, cases of dizziness or drowsiness have been observed in post-marketing experience (see Adverse Reactions), which may affect ability to drive and use machines.
Use in Pregnancy: Studies in animals have not demonstrated a teratogenic effect; however, in the absence of clinical data, the risk of malformation cannot be excluded. Therefore, for safety reasons, it is preferable to avoid prescription during pregnancy.
Use in Lactation: In the absence of excretion in breastmilk, breastfeeding is not recommended during treatment.

Use in Pregnancy: Studies in animals have not demonstrated a teratogenic effect; however, in the absence of clinical data, the risk of malformation cannot be excluded. Therefore, for safety reasons, it is preferable to avoid prescription during pregnancy.
Use in Lactation: In the absence of excretion in breastmilk, breastfeeding is not recommended during treatment.

Adverse reactions are listed below using the following convention: 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):
Nervous System Disorders: Common: Dizziness, headache. Not known: Parkinsonian symptoms (tremor, akinesia, hypertonia), gait instability, restless leg syndrome, other related movement disorders, usually reversible after treatment discontinuation, sleep disorders (insomnia).
Cardiac Disorders: Rare: Palpitations, extrasystoles, tachycardia.
Vascular Disorders: Rare: Arterial hypotension, orthostatic hypotension that may be associated with malaise, dizziness or fall, in particular in patients taking antihypertensive treatment, flushing.
Gastrointestinal Disorders: Common: Abdominal pain, diarrhoea, dyspepsia, nausea and vomiting. Not known: Constipation.
Skin and Subcutaneous Tissue Disorders: Common: Rash, pruritus, urticaria. Not known: Acute generalized exanthematus pustulosis (AGEP), angioedema.
General Disorders and Administration Conditions: Common: Asthenia.
Blood and Lymphatic System Disorders: Not known: Agranulocytosis, thrombocytopenia, thrombocytopenic purpura.
Hepatobiliary Disorders: Not known: Hepatitis.

Not applicable.

Store below 30°C.
Shelf-life: 3 years.

Anti-Anginal Drugs

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

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