1. NAME OF THE MEDICINAL PRODUCT

 

CYTO-PROTECTIN MR

35 mg, modified-release film-coated tablet

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

 

1 tablet contains 35 mg of trimetazidine dihydrochloride (Trimetazidini dihydrochloridum).

For a full list of excipients, see section 6.1.

 

3. PHARMACEUTICAL FORM

 

Modified-release film-coated tablet; pale pink, round, biconvex.

 

4. CLINICAL PARTICULARS

 

4.1 Therapeutic indications

 

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.

 

4.2 Posology and method of administration

 

The dose is one tablet of 35 mg of trimetazidine (in the form of dihydrochloride) twice daily during meals.

This product is intended for adult patients.Tablet should not be split, chewed, or crushed. 

 

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 35mg in the morning during breakfast.

 

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 35mg in the morning during breakfast. Dose titration in elderly patients should be exercised with caution (see section 4.4).

 

Paediatric population:

 

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

 

4.3 Contraindications

 

- 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).

 

4.4 Special warnings and precautions for use

 

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. The majority 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 particular in patients taking antihypertensive treatment (see section 4.8).

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

- moderate renal impairment (see sections 4.2 and 5.2),

- elderly patients older than 75 years old (see section 4.2).

 

4.5 Interaction with other medicinal products and other forms of interaction

 

No interactions with other drugs or foods were found.

 

4.6 Fertility, pregnancy and lactation

 

Pregnancy

In experimental studies in animals no embryotoxicity or teratogenicity were observed. However, well- controlled studies with app9ropriate subject number were performed in humans, thus it is not recommended to use CYTO-PROTECTIN MR in pregnant women.

 

Breastfeeding

 

Since there is a lack of appropriate studies It is not recommended to use the product during breastfeeding.

 

4.7 Effects on ability to drive and use machines

 

Trimetazidine does not have haemodynamic effects in clinical studies, however cases of dizziness and drowsiness have been observed in post-marketing experience (see section 4.8), which may affect ability to drive and use machines.

 

4.8 Undesirable effects

 

System Organ Class Frequency Preferred Term Nervous system disorders Common Dizziness, headache Not known Parkinsonian symptoms (tremor, akinesia, Not known Sleep disorders (insomnia, drowsiness) Cardiac disorders Rare Palpitations, extrasystoles, tachycardia Vascular disorders Rare Arterial Hypotension , Orthostatic, Gastrointestinal disorders Common Abdominal pain, diarrhoea, dyspepsia, Skin and subcutaneous tissue disorders Not known Constipation, Common Rash, pruritus, urticaria. Not known Acute generalized exanthematus pustulosis, General disorders and administration conditions, Blood and lymphatic system disorders, Common Asthenia, Not known Agranulocytosis, Hepatobiliary disorders Not known Hepatitis

 

4.9 Overdose

 

No cases of poisoning due to overdose have been reported.

 

5. PHARMACOLOGICAL PROPERTIES

 

5.1 Pharmacodynamic properties

 

Pharmacotherapeutic group: Cardiovascular system, Cardiac therapy, Other cardiac preparations,

trimetazidine. ATC code: C01EB15.

 

Mechanism of action

 

Trimetazidine in conditions of oxygen deficiency sustains metabolic processes in cells, prevents against depletion of energetic reserve accumulated as ATP, prevents against development of acidosis, regulates action of sodium potassium pump in cell membrane, and maintains cell homeostasis. 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. Cytoprotective effect of trimetazidine was confirmed in a study conducted in vitro and in vivo. Cytoprotective action is expressed by protection of structures and functions of cells belonging to different tissues and organs against consequences of hypoxia and ischaemia. Trimetazidine protects against diminution of intracellular ATP concentration, restores correct function of sodium potassium pump maintaining cellular homeostasis. This action is observed mainly in heart and sense organs. It is not accompanied by any direct hemodynamic effect or effect on blood vessels.

 

Pharmacodynamic effects

 

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).

 

5.2 Pharmacokinetic properties

 

Absorption

 

By oral route, maximum concentration in serum is observed, on average, 5 hours after administration.

Steady state is reached by the 60th hour and remains stable throughout the treatment period.

No interaction with foods has been observed.

 

Distribution

 

The drug binds to plasma proteins in approximately 16%. The apparent volume of distribution is 4.8 l/kg body

mass, which means good penetration of the product into tissues.

 

Elimination

 

Trimetazidine is eliminated primarily in the urine, in the unaltered form. The elimination half-life is, on average, 7 hours, increasing to 12 hours in patients over the age of 65 years old.

 

5.3 Preclinical safety data

 

In experimental studies in animals no embryotoxicity or teratogenicity were observed.

 

6. PHARMACEUTICAL PARTICULARS

 

6.1 List of excipients

 

Tablet core: calcium hydrogen phosphate dihydrate, hypromellose 4000, povidone, magnesium stearate, anhydrous colloidal silica.

 

Tablet coating: macrogol, red iron oxide (E172), hypromellose, titanium dioxide

 

6.2 Incompatibilities

 

Not applicable.

 

6.3 Shelf life

 

3 years

 

6.4 Special precautions for storage

 

Store below 25 °C. Keep out of the reach and sight of children.

 

6.5 Nature and contents of container

 

Polypropylene container in a cardboard box containing 60 tablets with the patient information leaflet attached.

 

6.6 Special precautions for disposal and other handling

 

No special requirements.