Date of approval.
Date of revision.
Trimetazidine Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician.
[Drug Name].
Generic Name: Trimetazidine Hydrochloride Tablets
English name: Trimetazidine Hydrochloride Tablets
Hanyu Pinyin: Yansuan Qumeitaqin Pian
Ingredients
The active ingredient of this product is trimetazidine hydrochloride, its chemical name: 1-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride
Chemical structure formula.
Molecular formula: C14H22N2O3 -2HCl
Molecular weight: 339.26
Properties
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
As an additive drug, it is used for the symptomatic treatment of adult patients with stable angina pectoris who are poorly controlled or intolerant to first-line anti-anginal therapy.
Specification】 20mg
Dosage]
Take 1 tablet orally 3 times daily with 3 meals.
Evaluate the therapeutic effect after three months and discontinue if there is no therapeutic effect.
Special Populations
Patients with renal impairment.
For patients with moderate renal impairment (creatinine clearance [30-60] ml/min) (see [Precautions] and [Pharmacokinetics]), the recommended dose is one 20 mg tablet taken twice a day, i.e., one tablet in the morning and one tablet in the evening during meals.
[Adverse Reactions].
For adverse reactions associated with the use of trimetazidine hydrochloride, see [Precautions].
The adverse reactions in the table below are derived from spontaneous reports and scientific literature. 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); unknown (cannot be estimated from available data). Fibrillation, as a symptom during angina attack
Systemic organ classification frequency preferred term Neurological disorders common dizziness, headache unknown Parkinson’s syndrome (tremor, motor inability, hypertonia), gait instability, restless legs syndrome, other related movement disorders, usually reversible after discontinuation of medication Unknown sleep disorders (insomnia, somnolence) Ear and inner ear vagal disorders Unknown vertigo Heart disorders Rare palpitations, extrasystoles, tachycardia Vascular disorders Rare low arterial pressure, upright hypotension (may be associated with generalized weakness, dizziness, or falls, especially in patients treated with antihypertensive medications), flushing Gastrointestinal disorders
Common abdominal pain, diarrhea, dyspepsia, nausea and vomiting Unknown constipation Skin and subcutaneous tissue disorders Common rash, pruritus, urticaria Unknown acute generalized eruptive pustulosis (AGEP), angioedema Systemic disorders and administration site conditions Common weakness Blood and lymphatic system disorders Unknown granulocyte deficiency, thrombocytopenia, thrombocytopenic purpura Hepatobiliary disorders Unknown hepatitis
Suspected Adverse Reaction Reporting.
It is important to report post-marketing adverse drug reactions so that the benefit/risk balance of the drug can be monitored on an ongoing basis. Medical professionals should follow the requirements of local regulatory authorities to report suspected adverse reactions.
Contraindications
Contraindicated in patients with hypersensitivity to trimetazidine hydrochloride or any of the excipients.
Parkinson’s disease, Parkinson’s syndrome, tremor, restless legs syndrome, and other related movement disorders.
Severe renal impairment (creatinine clearance <30ml/min).
【Caution】.
This drug should not be used as symptomatic treatment for angina pectoris attacks or for the initial treatment of unstable angina pectoris or myocardial infarction. This drug should not be used for treatment before or during the first few days after admission to hospital. During an angina attack, the coronary condition should be re-evaluated and adjustments in therapy (pharmacotherapy and possible revascularization) should be considered.
Trimetazidine can cause or aggravate Parkinson’s symptoms (tremor, motor inability, hypertonia) and should be checked regularly, especially for elderly patients.
In case of suspicion, appropriate tests should be performed by a neurologist. Trimetazidine should be completely discontinued when movement disorders occur, such as Parkinson’s symptoms, restless legs syndrome, tremor, or unstable gait.
These events have a low incidence and are usually reversible after discontinuation. Most patients recover within 4 months after discontinuation of trimetazidine. If Parkinson’s symptoms persist for more than 4 months after discontinuation, a neurologist’s opinion should be sought.
Falls associated with gait instability or hypotension may occur, especially in patients taking antihypertensive drugs (see [Adverse Reactions]).
Caution should be exercised when prescribing trimetazidine in patients with an expected increased exposure of.
– Moderate renal impairment (see [Dosage] and [Pharmacokinetics])
– Elderly patients over 75 years of age (see [DOSAGE AND ADMINISTRATION])
This product is generally not recommended for use in nursing mothers (see [Pregnancy and Nursing Mothers]).
This product contains Sunset Yellow FCF (E110) and Carmine A (E124), which may cause allergic reactions.
Effects on the ability to drive and use machines
Clinical studies have shown no hemodynamic effects of trimetazidine, however, cases of dizziness and drowsiness have been observed after marketing (see [ADVERSE REACTIONS]), which may affect the ability to drive and operate machinery.
Use with caution in athletes.
For Pregnant and Lactating Women
Pregnancy
There are no data on the use of trimetazidine in pregnant women. Animal studies have not shown direct or indirect harmful effects in terms of reproductive toxicity (see [Pharmacological Toxicology]). For safety reasons, it is best to avoid taking this drug during pregnancy.
Lactation
It is not known whether trimetazidine and its metabolites are excreted via breast milk. Risks to the newborn/infant cannot be excluded. Trimetazidine should not be taken during breastfeeding.
Fertility
Reproductive toxicity studies have shown no effect on fertility in female and male rats (see [Pharmacology and Toxicology]).
Pediatric Dosage]
The safety and efficacy of trimetazidine in people under 18 years of age have not been established. No data available.
Geriatric Use
Trimetazidine exposure may be increased in elderly patients due to the presence of age-related decline in renal function (see [Pharmacokinetics]). In patients with moderate renal impairment (creatinine clearance 30-60 ml/min), the recommended dose is one tablet twice daily, i.e., one tablet with each morning and evening meal.
Caution should be exercised when increasing the dose in elderly patients (see [Precautions]).
Drug Interactions]
No drug interactions have been observed.
Drug overdose]
Available information on trimetazidine overdose is limited. Symptomatic treatment should be administered.
[Clinical Trials].
The efficacy and safety of trimetazidine alone or in combination with other anti-anginal drugs in poorly controlled patients with chronic angina pectoris has been confirmed by clinical studies.
In a randomized, double-blind, placebo-controlled study (TRIMPOL-II) with 426 patients, trimetazidine (60 mg/day) combined with metoprolol 100 mg/day (50 mg/dose, 2x/day) for 12 weeks significantly improved exercise test parameters and clinical symptoms compared with placebo: total exercise time: +20.1s, p = 0.023, total workload : +0.54 METs, p = 0.001, time to reach 1-mm ST-segment depression: +33.4s, p = 0.003, time to onset of angina: +33.9s, p < 0.001, number of angina episodes/week: -0.73, p = 0.014, short-acting nitrate consumption/week: -0.63, p = 0.032, no hemodynamic Changes.
In a randomized, double-blind, placebo-controlled study (Sellier) involving 223 patients, 35 mg trimetazidine extended-release tablets (2 times/day) combined with 50 mg atenolol (o.d.) for 8 weeks was associated with a significant increase in time to reach 1-mm ST-segment depression in the exercise test after 12 hours of dosing compared with placebo in a subgroup of patients (n = 173) (+34.4 s, p = 0.03). The study also found a significant difference in the time to the onset of angina pectoris (p = 0.049). No significant differences were found between groups for other secondary endpoints (total exercise time, total workload and clinical endpoints).
In a 3-month randomized, double-blind study (Vasco study) with 1962 patients, two trimetazidine dose (70 mg/day and 140 mg/day) groups were tested versus placebo control on atenolol 50 mg/day. In the total population, including both asymptomatic and symptomatic patients, trimetazidine failed to demonstrate benefit in terms of functional tests (total exercise duration, time to 1 mm ST, time to angina attack) and clinical endpoints. However, post hoc analysis showed that in the subgroup of symptomatic patients (n = 1574), trimetazidine (140 mg) significantly improved total exercise duration (+23.8s vs. placebo +13.1s; p = 0.001) and time to presentation of an angina attack (+46.3s vs. placebo +32.5s; p = 0.005)
[Pharmacological and toxicological].
Pharmacological effects
Trimetazidine maintains a stable intracellular environment by protecting cellular energy metabolism under hypoxic or ischemic conditions and preventing a decrease in intracellular ATP levels, thereby ensuring the normal function of the ion pump and the normal functioning of the permeable sodium-potassium flow. Trimetazidine inhibits b-oxidation of fatty acids by blocking long-chain 3-ketoesteryl CoA thiolase, thereby promoting glucose oxidation. In ischemic cells, a lower amount of oxygen consumption is required to obtain energy through glucose oxidation compared to the b-oxidation process. Enhanced glucose oxidation optimizes cellular energy processes and thus maintains proper energy metabolism during ischemia. In patients with ischemic heart disease, trimetazidine acts as a metabolic agent to maintain high-energy phosphate levels in cardiac myocytes. The anti-myocardial ischemic effect is achieved without affecting the hemodynamics.
Toxicological studies
Genotoxicity.
In vitro and in vivo tests were performed to evaluate potential genotoxicity and all tests were negative.
Reproductive toxicity.
In mouse and rabbit reproductive toxicity tests, no significant embryo-fetal toxicity or offspring organ growth and development toxicity was observed. A perinatal reproductive toxicity test in rats showed no significant abnormalities.
Pharmacokinetics
Absorption
After oral administration, trimetazidine is rapidly absorbed and reaches peak plasma concentration within 2 hours. The peak plasma concentration is about 55 ng/ml after a single oral dose of trimetazidine 20 mg. After repeated dosing, steady-state concentration is reached in 24-36 hours and is very stable throughout the treatment course.
Distribution
Apparent volume of distribution was 4.8 l/kg, indicating good tissue distribution. Low protein binding: in vitro measurements showed a protein binding rate of 16%.
Excretion
Trimetazidine is cleared mostly in the urine mostly as a prototype. The mean clearance half-life is 6 hours.
Linearity
After single dose administration of up to 100 mg, trimetazidine pharmacokinetic parameters are linear with respect to dose. After multiple doses, trimetazidine pharmacokinetic parameters are linear with respect to time.
Special Populations
Geriatric.
Older subjects may have increased trimetazidine exposure due to the occurrence of age-related decline in renal function. A special pharmacokinetic study in elderly or very elderly (≥ 85 years) subjects aged 75-84 years showed that trimetazidine exposure was 1.0 and 1.3 times greater in elderly subjects with moderate renal insufficiency (creatinine clearance of 30 to 60 ml/min) than in younger subjects with moderate renal insufficiency (30-65 years).
Impairment of renal function.
Compared to healthy young volunteers with normal renal function, trimetazidine exposure increased to a mean of 1.7-fold in patients with moderate renal impairment (creatinine clearance between 30 and 60 ml/min) and 3.1-fold in patients with severe renal impairment (creatinine clearance below 30 ml/min). No new safety concerns were observed in this population compared to the general population.
Pediatrics.
Pharmacokinetic studies of trimetazidine have not been conducted in the pediatric population (<18 years of age).
Storage】Store under shade and seal.
Package】Polyvinyl chloride solid pharmaceutical hard tablets and pharmaceutical aluminum foil, coated with polyester/aluminum/polyethylene pharmaceutical composite film 15 tablets/plate 1 plate/box, 2 plates/box, 4 plates/box; 18 tablets/plate 2 plates/box
Expiration date】24 months
【Execution standard
Approval Number】State Drug Administration H20066534
【Manufacturing enterprise】 【Effective date
Company Name: Ruiyang Pharmaceutical Co.
Address: No. 1, Ruiyang Road, Yiyuan County, Shandong Province
Postal Code: 256100
Telephone number: 4006 123458; 15853312365
Fax number: 0533-3248777
Web address: http://www.reyoung.com
Mailbox: [email protected]