Angivent OD

Trimetazidine hydrochloride.

Angina pectoris is a symptomatic manifestation of ischaemic heart disease. Myocardial ischaemia has several metabolic consequences: The production and retention of acid metabolites, leading to intracellular acidosis, a reduction in intracellular content of adenosine triphosphate (ATP) and phosphocreatine, accumulation of free fatty acids and the generation of oxygen free radicals. These may lead to myocyte loss and, ultimately, a poor prognosis. Conventional antianginal agents act haemodynamically to restore the imbalance between myocardial oxygen supply and demand. Trimetazidine (2,3,4 trimethoxybenzyl-piperazine dihydrochloride) is a novel anti-ischaemic compound belonging to the class of cytoprotective drugs. It represents a cellular approach to ischaemia by directly counteracting all the major metabolic abnormalities occurring within the ischaemic cell. Its empirical formula is C₁₄H₂₂N₂O₃·2HCl, with a molecular weight of 339.26.
Each capsule contains trimetazidine hydrochloride BP (as sustained release pellets) 60 mg.
Excipients/Inactive Ingredients: Nonparallel seeds, hypromellose, purified talc, colloidal anhydrous silica, ethyl cellulose, triacetin, titanium dioxide, ferric oxide (red).

Pharmacology: Pharmacodynamics: Mechanism of Action: Findings from in vitro and ex vivo studies of myocardial ischaemia have demonstrated that: Trimetazidine limits intracellular acidosis and sodium and calcium accumulation. It maintains intracellular ATP levels and reduces creatine phosphokinase release; preserves mitochondrial function; reduces myocardial fatty acid metabolism and increases myocardial glucose metabolism. Trimetazidine protects against oxygen free-radical induced membrane damage and inhibits neutrophil infiltration.
By inhibiting fatty acid metabolism and secondarily stimulating glucose metabolism, trimetazidine optimizes cardiac metabolism and thus protects the heart against the harmful effects of ischaemia.
Consistent with a cytoprotective effect, trimetazidine exhibited anti-ischaemic effects in vivo. It limited the extent of necrosis in a rat model of myocardial ischaemia and reduced the extent of nephropathy in a rat model of renal ischaemia. In addition, trimetazidine had a direct anti-ischaemic effect in patients undergoing coronary angioplasty.
Haemodynamic Effects: Data from studies in animals and in patients with coronary artery disease indicate that the anti-ischaemic effects of trimetazidine are not associated with any effects on haemodynamic determinants of myocardial oxygen consumption such as heart rate (HR) or blood pressure.
Sustained-release formulation of trimetazidine ensures adequate 24-hour control of myocardial ischaemia, which may not be adequately ensured by the conventional formulation of trimetazidine due to the problem of patient compliance of dosage. The drug exhibits significant anit-anginal effects and its efficacy is observed both during monotherapy as well as during combination therapy. Studies have also justified the use of trimetazidine to prevent reperfusion injury when used in combination with thrombolytics during the acute phase of myocardial infarction.
In addition, trimetazidine has also been shown to improve the outcome of percutaneous transluminal coronary angioplasty (PTCA) and to reduce reperfusion in patients undergoing coronary artery bypass surgery (CABG).
Pharmacokinetics: Absorption and Distribution: Following oral administration of the sustained-release (SR) preparation, trimetazidine is well absorbed from the intestinal mucosa, blood levels reaching a peak in 5 hours. The bioavailability of orally administered trimetazidine is approximately 90%. Food intake is not known to modify absorption. Trimetazidine is only weakly protein bound in plasma (approximately 16%) and therefore is widely distributed throughout the body.
Metabolism and Elimination: The major route of elimination is urinary (80% of the administered dose), with about 62% of the administered dose being eliminated in the unchanged form. Eight metabolites (including 4 phase II metabolites) have been detected in urine, but little is known of the properties of the metabolites. The blood level data of the sustained-release (SR) 60 mg formulation is reported as follows: See table.

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It is apparent from the previous table that the sustained-release trimetazidine 60 mg preparation maintains the concentrations above the reported Cmax (53.6 mg/mL) of 20 mg single dose for over 18 hours. At the end of 24 hours, the levels attained are around 20 mg/mL; even in the case of trimetazidine 60 mg single dose, the end-24 hour concentration is reported to be 14 mg/mL. Since the latter dose has been conclusively proven to be clinically efficacious, the levels seen with the sustained-release trimetazidine preparation for 24-hours may benefit the patients. (See figure.)

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Ischaemic heart disease (angina pectoris, sequelae of myocardial infarction).

Adults: One capsule once a day (early morning or at bedtime).

Trimetazidine is safe and well tolerated. The toxic dose being very high, the safety margin of this drug is wide. The most commonly encountered adverse effects are gastric discomfort, nausea, headache and vertigo.

Hypersensitivity to trimetazidine.

In Impaired Renal and Hepatic Function: Appropriate dosage reductions may be done in patients with impaired renal and hepatic function.
Use in Pregnancy: There is insufficient evidence to recommend the use of trimetazidine in pregnancy. Animal studies do not reveal any teratogenic effect.
Use in Lactation: There is no information on the secretion of trimetazidine into breast milk. However, breastfeeding should be discounted if the use of trimetazidine is considered essential.
Use in Children: There is no experience with trimetazidine in children.

Use in Pregnancy: There is insufficient evidence to recommend the use of trimetazidine in pregnancy. Animal studies do not reveal any teratogenic effect.
Use in Lactation: There is no information on the secretion of trimetazidine into breast milk. However, breastfeeding should be discounted if the use of trimetazidine is considered essential.

Generally, the drug is well tolerated.
The most commonly encountered adverse effects are gastric discomfort, nausea, headache and vertigo. Usually, the adverse effects are mild and reversible on discontinuation of therapy.

No drug interactions have so far been reported. In particular, no interactions of trimetazidine with beta-blockers, calcium antagonists, nitrates, heparin, hypolipidemic agents or digitalis have been reported.

Store below 25°C. Protect from light and moisture.
Shelf-Life: 24 months

Anti-Anginal Drugs

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

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