Preduktal OD, 80 mg 60 pcs

Trimetazidine prevents decrease in intracellular concentration of adenosine triphosphate (ATP) by preserving energy metabolism of cells under hypoxia. Thus, the drug ensures normal functioning of membrane ion channels, transmembrane transport of potassium and sodium ions and preservation of cellular homeostasis.

Trimetazidine inhibits fatty acid oxidation through selective inhibition of the enzyme 3-ketoacyl-CoA-thiolase (3-CAT) mitochondrial long-chain fatty acid isoform, which leads to increased glucose oxidation and accelerated glycolysis with glucose oxidation, which leads to myocardial protection from ischemia.

The switch of energy metabolism from fatty acid oxidation to glucose oxidation underlies the pharmacological properties of trimetazidine.

Pharmacodynamic properties

– Supports energy metabolism of the heart and neurosensory tissues during ischemia;

– reduces the severity of intracellular acidosis and changes in transmembrane ion flow occurring during ischemia;

– decreases the level of migration and infiltration of polynuclear neutrophils in ischemic and reperfused heart tissues;

– reduces the size of myocardial damage;

– has no direct effect on hemodynamic parameters.

In patients with angina pectoris, trimetazidine increases coronary reserve, thereby delaying the onset of exercise-induced ischemia from day 15 of therapy; it limits exercise-induced BP fluctuations without significant changes in HR; significantly reduces the frequency of angina attacks and the need for short-acting nitroglycerin; improves left ventricular contractile function in patients with ischemic dysfunction.

The results of clinical studies have confirmed efficacy and safety of trimetazidine in patients with stable angina pectoris both in monotherapy and in combination therapy when other antianginal drugs have insufficient effect.

In a study involving 426 patients with stable angina pectoris, the addition of trimetazidine (60 mg/day) to therapy with metoprolol 100 mg/day (50 mg 2 times/day) for 12 weeks statistically significantly improved exercise test results and clinical symptoms compared with placebo: total exercise test duration was +20.1 s, p=0.023, total time to load performance +0.54 METs, p=0.001, time to ST-segment depression of 1 mm +33.4 s, p=0.003, time to angina attack development +33.9 s, p< 0.001, number of angina attacks per week -0.73, p=0.014 and short-acting nitrate consumption per week -0.63, p=0.032, no hemodynamic changes.

In a study involving 223 patients with stable angina pectoris, the addition of trimetazidine at a dose of 35 mg (2 times/day) to therapy with atenolol at 50 mg (once/day) for 8 weeks resulted in a 1-mm increase in time to development of ischemic ST-segment depression (+34.4 s, p=0.03) on loading tests in a subgroup of patients (n=173), compared with placebo, 12 h after drug administration. This difference was also shown for the timing of angina attacks (p=0.049). No significant differences were found between groups for other secondary endpoints (total exercise test duration, total exercise time, and clinical endpoints).

In a study involving 1962 patients with stable angina pectoris, trimetazidine at two doses (70 mg/day and 140 mg/day) was added to therapy with atenolol 50 mg/day compared with placebo.

In the general population, including both asymptomatic and symptomatic patients with angina, trimetazidine showed no advantage in ergometric (total duration of exercise tests, time to onset of ischemic ST-segment depression by 1 mm and time to angina attack) and clinical endpoints. However, in a retrospective analysis in a subgroup of patients with symptomatic angina (n=1574), trimetazidine (140 mg) significantly improved total time to load test (+23.8 s versus +13.1 s for placebo; p=0.001) and time to angina attack development (+46.3 s versus +32.5 for placebo; p=0.005).

Pharmacokinetics

Intake

Trimetazidine has a linear pharmacokinetic profile after oral administration of Preduktal® OD capsule and reaches Cmax in plasma approximately 14 hours after administration. At inter-dose intervals (i.e. within 24 hours), the plasma concentration of trimetazidine is maintained at at least 75% of Cmax for 15 hours after drug administration. The equilibrium state is reached after the 3rd dose (after 3 days). Food intake does not affect the bioavailability of trimetazidine when taking Preduktal® OD 80 mg.

Distribution

The Vd is 4.8 l/kg, which indicates good distribution of trimetazidine in the tissues (the degree of binding to plasma proteins is quite low, about 16% in vitro).

Trimetazidine is mainly excreted by the kidneys, mostly unchanged. The T1/2 in young healthy volunteers is about 7 h, in patients older than 65 years – about 12 h.

The renal clearance of trimetazidine directly correlates with CK, hepatic clearance decreases with patient age.

Pharmacokinetics in Special Patient Groups

In patients over 75 years of age, increased exposure to trimetazidine may be observed due to age-related decline in renal function. A specific study was conducted in a population of patients over 75 years of age when trimetazidine tablets were used at a dose of 35 mg twice daily. A population-based kinetic analysis showed, on average, a twofold increase in plasma exposure in patients with severe renal impairment (CK less than 30 mL/min) compared with patients with CK greater than 60 mL/min.

No differences were found regarding safety in patients older than 75 years compared to the general population.

Trimetazidine exposure was on average 2.4-fold increased in patients with moderate renal impairment (CKR 30-60 ml/min), and on average 4-fold increased in patients with severe renal impairment (CKR less than 30 ml/min) compared to healthy volunteers with normal renal function. No differences in safety were found in this patient population compared to the general population.

The pharmacokinetics of trimetazidine in children and adolescents under 18 years of age have not been studied.

Indications

– Long-term therapy for CHD: prevention of stable angina attacks as part of mono- or combination therapy.

Active ingredient

Composition

1 capsule

trimetazidine dihydrochloride (in pellets) 80 mg.

1 sustained-release hard capsule contains:

Pellets with a layer of trimetazidine dihydrochloride, film-coated: 144.85 mg.

Supplementary substances:

sugar spheres** (710-850 microns) – 36.68 mg,

Hypromellose – 6.4 mg.

Composition of the film coating of pellets:

ethylcellulose – 8 mg,

tributylacetylcitrate – 1.2 mg,

talc – 12 mg.

Composition of the pellet powder mixture:

talc – 0.43 mg,

magnesium stearate – 0.14 mg.

The hard gelatin capsule #2 with a white body and orange-red cap, with the company logo and “80” printed on the cap in white*: 61.000 mg.

Composition of the capsule body:

Titanium dioxide (E171) – 0.732 mg,

gelatin*** – 35.868 mg.

Capsule cap composition:

titanium dioxide (E171) – 0.122 mg,

iron oxide red (E172) – 0.366 mg,

gelatin*** – 23.912 mg.

* The printing of the logo and the inscription on the capsule is applied in white ink which contains shellac, titanium dioxide, simethicone, propylene glycol, ammonium hydroxide. The total amount of ink per capsule is approximately 0.15 mg.

** Composition of sugar spheres: sucrose – not more than 92% (in terms of dry matter), corn starch. May also contain products of starch hydrolysis and coloring agents.

*** Contains an average of 14.5% water (weight loss on drying).

How to take, the dosage

The drug is taken orally, 1 capsule 1 time per day, in the morning with breakfast. Capsules should be taken whole, without chewing, with water.

The evaluation of the benefit of treatment can be done after 3 months of using the drug. If there is no improvement during this time, Preductal® OD should be discontinued.

The duration of treatment is determined by the physician.

In patients with moderate renal impairment (CK 30-60 ml/min) (see sections “Pharmacokinetics” and “Special Precautions”), a dose reduction is recommended, i.e., 1 tablet containing 35 mg of trimetazidine per day.

Caution should be exercised when treating patients with severe hepatic impairment (see section “Special Precautions”) due to the fact that the available data are limited and do not allow to completely rule out the absence of influence of hepatic impairment on trimetazidine metabolism.

In patients over 75 years of age, increased exposure to trimetazidine may be observed due to age-related decreased renal function (see section “Pharmacokinetics”). In patients with moderate renal impairment (CKD 30-60 ml/min), a dose reduction is recommended, i.e., 1 tablet containing 35 mg of trimetazidine per day. Dose selection in patients over 75 years of age should be done with caution (see section “Special Precautions”).

The safety and effectiveness of trimetazidine in patients under 18 years of age has not been established. No data are available.

Interaction

No observations were made. The patient should tell the physician about any medications he or she is taking.

Special Instructions

Preductal® OD is not intended to control angina attacks and is not indicated for initial therapy of unstable angina or myocardial infarction in the pre-hospital phase or in the first days of hospitalization.

In case of an angina attack, treatment (drug therapy or revascularization procedure) should be reviewed and adapted. Preduktal® OD may cause or worsen symptoms of parkinsonism (tremor, akinesia, increased tone), therefore patients, especially elderly patients, should be monitored regularly. In doubtful cases, the patient should be referred to a neurologist for appropriate evaluation.

In case of motor disorders such as parkinsonian symptoms, restless leg syndrome, tremor, wobbly gait, Preduktal® OD should be permanently discontinued. Such cases are rare and symptoms usually disappear after discontinuation of therapy: in most patients, within 4 months after drug withdrawal. If symptoms of parkinsonism persist more than 4 months after discontinuation of the drug, a neurologist should be consulted.

There may be falls associated with unsteadiness in the Romberg pose and a “wobbly” gait, or a marked decrease in BP, especially in patients taking hypotensive medications (see section “Adverse effects”).

Preduptal® OD should be used with caution in patients who may have increased exposure to:

– in moderate renal failure (see sections “Pharmacological effects” and “Dosing regimen”);

– in elderly patients older than 75 years (see section “Dosing regimen”).

The drug contains sucrose; therefore, the drug is not recommended for patients with fructose intolerance, glucose-galactose malabsorption syndrome and sucrose-isomaltase deficiency.

Influence on driving and operating ability

In clinical studies there was no effect of trimetazidine on hemodynamic parameters, but there were cases of dizziness and somnolence during post-registration use (see section “Adverse effects”). These symptoms may affect the ability to drive vehicles and perform work requiring increased speed of physical and mental reactions.

Contraindications

– severe renal impairment (CKR less than 30 ml/min);

Parkinson’s disease, Parkinsonian symptoms, tremor, restless legs syndrome and other related movement disorders;

– fructose/sacrose intolerance, glucose-galactose malabsorption syndrome, sucrose/isomaltase deficiency, and other enzymeopathies associated with sucrose intolerance in the drug;

– age less than 18 years (due to insufficient clinical data);

– hypersensitivity to any of the components of the drug.

Patients with severe hepatic impairment (10 to 15 points by Child-Pugh scale), moderate renal impairment (CK 30-60 ml/min), patients older than 75 years old should use the preparation with caution (see sections “Dosage regimen” and “Special indications”).

Side effects

Unwanted reactions, defined as adverse events at least possibly relevant to trimetazidine treatment, are listed in the following grading: Very common (≥1/10); common (≥1/100, < 1/10); infrequent (≥1/1000, < 1/100); rare (≥1/10 000, < 1/1000); very rare (< 1/10 000), unspecified frequency (frequency cannot be calculated from available data).

CNS disorders: common – dizziness, headache; unspecified frequency – symptoms of parkinsonism (tremor, akinesia, increased tone), “wobbly” gait, restless legs syndrome, other related motor disorders, usually reversible after discontinuation of therapy. Sleep disorders (insomnia, somnolence).

Cardiovascular system disorders: rare – palpitations, extrasystole, tachycardia, marked BP decrease, orthostatic hypotension, which may be accompanied by general weakness, dizziness or loss of balance, especially with simultaneous use of antihypertensive agents, “rushes” of blood to the face.

The digestive system: often – abdominal pain, diarrhea, dyspepsia, nausea, vomiting; unspecified frequency – constipation.

Liver and biliary tract: unspecified frequency – hepatitis.

Hematopoietic system: unspecified frequency – agranulocytosis, thrombocytopenia, thrombocytopenic purpura.

Skin and subcutaneous fat: frequently – skin rash, pruritus, urticaria; unspecified frequency – Quincke’s edema, acute generalized exanthematous pustulosis.

General disorders: often – asthenia.

Overdose

There is very limited information about trimetazidine overdose.

Treatment: In case of overdose symptomatic therapy should be given.

Similarities