Version 2.0, 08/2011
Rev.1, 10/2011
SUMMARY OF PRODUCT CHARACTERISTICS,
LABELLING AND PACKAGE LEAFLET
1
SUMMARY OF PRODUCT CHARACTERISTICS
2
1.
NAME OF THE MEDICINAL PRODUCT
/.../ modified-release tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 35 mg trimetazidine dihydrochloride.
Excipient with known effect:
Each tablet contains 2.39 mmol sodium.
For the full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Modified-release tablet
White to off white, circular biconvex, film-coated tablets plain on both sides with aperture on one face.
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
Method of administration
Oral administration.
Posology
The dose is one tablet of 35mg of trimetazidine twice daily during meals.
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.
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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
/…/ is not indicated for treatment for angina pectoris attacks and it is not indicated as initial treatment of
unstable angina pectoris or myocardial infarction. The medicinal product should not be used in the prehospitalization phase or during the first days of hospitalization.
In case of an angina pectoris attack, the coronaropathy should be reassessed and the treatment should be
readjusted (pharmacotherapy and revascularization if needed).
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)
This medicinal product contains 2.39 mmol sodium per tablet. To be taken into consideration by patients on
a controlled sodium diet.
4.5
Interaction with other medicinal products and other forms of interaction
No interactions with other medicines have been reported. Trimetazidine can be used in combination with
heparin, calciparin, antivitamin K, oral hypolipemiant agents, acetylsalicylic acid, β-blockers, calcium
channel blockers and digitalis.
4.6
Fertility, pregnancy and lactation
Pregnancy
Animal studies have not demonstrated a teratogenic effect. However, in the absence of clinical data, the risk
for malformation can not be excluded. Therefore, for safety reasons, prescription must be avoided during
pregnancy.
Breastfeeding
In the absence of data, breastfeeding is not recommended during treatment with /…/.
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4.7
Effects on ability to drive and use machines
/.../ 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
The following undesirable effects have been observed during treatment with /.../ with the following
frequencies:
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).
System Organ Class3
Nervous system disorders
Frequency
Common
Not known
Preferred Term
Dizziness, headache
Parkinsonian symptoms (tremor, akinesia,
hypertonia), gait instability, restlessleg
syndrome, other related movement
disorders, usually reversible after treatment
discontinuation
Sleep disorders (insomnia, drowsiness)
Not known
Cardiac disorders
Vascular disorders
Rare
Rare
Gastrointestinal disorders
Common
Skin and subcutaneous
tissue disorders
Not known
Common
Not known
General disorders and
administration conditions
Blood and lymphatic
system disorders
Common
Hepatobiliary disorders
Not known
4.9
Palpitations, extrasystoles, tachycardia
Arterial Hypotension , Orthostatic
hypotension that may be associated with
malaise, dizziness or fall, in particular in
patients taking antihypertensive treatment,
flushing
Abdominal pain, diarrhoea, dyspepsia,
nausea and vomiting
Constipation
Rash, pruritus, urticaria.
Acute generalized exanthematus pustulosis
(AGEP), angioedema
Asthenia
Not known
Agranulocytosis
Thrombocytopenia
Thrombocytopenic purpura
Hepatitis
Overdose
No cases of overdose have been reported.
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5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: other cardiac preparations, ATC code: C01EB15
By preserving energy metabolism in cells exposed to hypoxia or ischemia, trimetazidine prevents the
decrease of ATP intracellular concentration, thereby ensuring the correct functioning of ionic pumps and
sodium-potassium transmembranary flow while maintaining cellular homeostasis.
Mechanism of action
The optimization of cardiac energetic metabolism with trimetazidine is a result of the partial inhibition of
fatty acid oxidation. Trimetazidine inhibits β-oxidation of fatty acids by blocking long-chain 3-ketoacylCoA 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-ischemic 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
(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 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 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).
In animals
Trimetazidine:
helps maintaining of the energetic metabolism of the heart and neurosensory organs during the
episodes of ischemia and hypoxia;
reduces intracellular acidosis and transmembrane ion flow alterations caused by ischemia;
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-
decreases the migration and infiltration of polynuclear neutrophils in ischemic and reperfused cardiac
tissue.
Trimetazidine exerts these actions in the absence of any direct haemodynamic effect.
In humans
In cardiology
Controlled studies in patients with angina pectoris have shown that trimetazidine:
Increases coronary flow reserve, thereby delaying the onset of exercise-induced ischemia, starting
from the 15th day of treatment;
Limits rapid swings in blood pressure without any significant variations in heart rate;
Significantly decreases the frequency of angina attacks;
improves left ventricular dysfunction during ischemia
Leads to a significant decrease in the use of nitroglycerin.
In a 2-month study in patients receiving 50 mg atenolol, adding one 35 mg trimetazidine modified-release
tablet produced a significant increase in the time to 1-mm ST-segment depression in exercise tests, when
compared to a placebo, 12 hours after taking the medicinal product.
5.2
Pharmacokinetic properties
Aborption
After oral administration, maximum concentration is found, on average, 5 hours after taking the tablet. Over
24 hours, the plasma concentration remains at levels greater than or equal to 75% of the maximum
concentration for 11 hours. Steady state is reached by the 60th hour, at the latest.
The pharmacokinetic characteristics of /.../ are not influenced by meals.
Distribution
The apparent distribution volume is 4.8 l/kg; protein binding is low: in vitro measurements give value of
16%.
Elimination
Trimetazidine is eliminated primarily in the urine, mainly in the unchanged form.
The elimination half-life of /.../ is an average of 7 hours in healthy young volunteers and 12 hours in subjects
older then 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, analyzed by a kinetic population method, showed an increase in plasma exposure which does not
justify a dosage alteration.
5.3
Preclinical safety data
The acute toxicity of trimetazidine in mice, rats and guinea pigs is low. Repeated-dose toxicity studies with
trimetazidine have been performed in rats and in dogs and no toxicological target organ was identified in
these studies. Trimetazidine was not genotoxic in a standard battery of in vitro and in vivo tests.
Reproductive toxicity studies were performed with trimetazidine in rats, mice and rabbits, and no adverse
effects of trimetazidine on reproductive function (especially no teratogenic effects) were observed. In
embryotoxicity studies in rats and rabbits, trimetazidine did not show any teratogenic effects. No
modifications of reproductive functions were observed in a three generation study performed in rats. No
conventional studies on fertility or pre/postnatal development were performed.
6.
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
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Tablet core:
Sodium Chloride
Povidone (PVP K-30)
Magnesium stearate
Tablet coating:
Cellulose acetate
Hypromellose
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
2 years.
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
Transparent PVC/PVDC/Aluminium blister pack.
Pack sizes: 60 tablets.
6.6
Special precautions for disposal and other handling
No special requirements.
7.
MARKETING AUTHORISATION HOLDER
<[To be completed nationally]>
{Name and address}
<{tel}>
<{fax}>
<{e-mail}>
8.
MARKETING AUTHORISATION NUMBER(S)
<[To be completed nationally]>
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
<{DD/MM/YYYY}> <{DD month YYYY}>
<[To be completed nationally]>
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10.
DATE OF REVISION OF THE TEXT
<{MM/YYYY}>
<[To be completed nationally]>
<Detailed information on this medicinal product is available on the website of {name of MS/Agency}>
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LABELLING
10
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
NAME OF THE MEDICINAL PRODUCT
/…/ 35 mg modified-release tablets
Trimetazidine dihydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 35 mg trimetazidine dihydrochloride.
3.
LIST OF EXCIPIENTS
Contains sodium. See leaflet for further information.
4.
PHARMACEUTICAL FORM AND CONTENTS
60 modified-release tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
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11.
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
<[To be completed nationally]>
12.
MARKETING AUTHORISATION NUMBER(S)
<[To be completed nationally]>
13.
BATCH NUMBER
Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
<[To be completed nationally]>
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
/…/ 35 mg
12
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
NAME OF THE MEDICINAL PRODUCT
/…/ 35 mg modified-release tablets
Trimetazidine dihydrochloride
2.
NAME OF THE MARKETING AUTHORISATION HOLDER
<[To be completed nationally]>
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
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PACKAGE LEAFLET
14
Package leaflet: Information for the patient
/…/ 35 mg modified-release tablets
Trimetazidine dihydrochloride
Read all of this leaflet carefully before you start taking this medicine because it contains important
information for you.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if
their signs of illness are the same as yours.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects
not listed in this leaflet.
What is in this leaflet
1.
What /…/ is and what it is used for
2.
What you need to know before you take /…/
3.
How to take /…/
4.
Possible side effects
5.
How to store /…/
6.
Contents of the pack and other information
1.
What /…/ is and what it is used for
This medicine is intended for use in adult patients, in combination with other medicines to treat angina
pectoris (chest pain caused by coronary disease).
2.
What you need to know before you take /…/
Do not take /…/
if you are allergic to trimetazidine dihydrochloride or any of the other ingredients of this medicine
(listed in section 6),
if you have a Parkinson disease: disease of the brain affecting movement (trembling, rigid posture,
slow movements and a shuffling, unbalanced walk),
if you have severe kidney problems.
Warnings and precautions
Talk to your doctor or pharmacist before taking /.../
/…/ should not be used for treatment of chest pain (angina pectoris) attacks or for initial treatment of
unstable chest pain (unstable angina pectoris) or heart attack. /…/ should not be used in the prehospitalisation phase or during the first days of hospitalisation.
In case of chest pain (angina pectoris) attack during treatment with /…/, you should contact your doctor who
will prescribe other treatment if necessary.
This medicine can cause or worsen symptoms such as trembling, rigid posture, slow movements and a
shuffling, unbalanced walk, especially in elderly patients, which should be investigated and reported to
your doctor who could reassess the treatment.
Children and adolescents
/.../ is not recommended in children aged below 18 years.
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Tell your doctor if you have reduced kidney function.
Other medicines and /.../
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
No interactions with other medicines have been reported.
Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor or pharmacist for advice before taking this medicine.
You should not take /…/ if you are pregnant, think you might be pregnant or plan to become pregnant.
Please contact your doctor if you become pregnant during treatment with /…/.
You should not breast-feed a baby while taking /…/.
Driving and using machines
This medicine may make you feel dizzy and drowsy which may affect your ability to drive or use
machinery.
/…/ contains sodium
/…/ contains 2.39 mmol sodium per tablet. To be taken into consideration by patients on a controlled
sodium diet.
3.
How to take /…/
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or
pharmacist if you are not sure.
The recommended dose of /.../ 35mg is one tablet to be taken two times a day during
meals in the morning and evening.
If you have kidney problems or if you are older than 75 years old, your doctor may adjust the
recommended dose.
Use in children
The safety and efficacy of trimetazidine has not been established in children.
If you take more /…/ than you should
Please contact your doctor or pharmacist immediatly if you take more tablets then you should.
If you forget to take use /…/
If you forget to take /…/ at the usual time, the next dose must be taken as usual. Do not take a double dose to
make up for a forgotten dose.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Common (occur in 1-10 out of 100 patients): dizziness, headache, abdominal pain, diarrhoea, indigestion,
feeling sick, vomiting, rash, itching, hives and feeling of weakness.
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Rare (occur in 1-10 out of 10,000 patients): Fast or irregular heartbeats (also called palpitations), extra
heartbeats, faster heartbeat, fall in blood pressure on standing-up which causes dizziness, light headedness
or fainting, malaise (generally feeling unwell), dizziness, fall, flushing.
Not known (cannot be estimated from the available data): Extrapyramidal symptoms (unusual movements,
including trembling and shaking of the hands and fingers, twisting movements of the body, shuffling walk
and stiffness of the arms and legs), usually reversible after treatment discontinuation.
Sleep disorders (difficulty in sleeping, drowsiness), constipation, serious generalised red skin rash with
blistering, swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing
or breathing.
Severe reduction in number of white blood cells which makes infections more likely, reduction in blood
platelets, which increases risk of bleeding or bruising.
A liver disease (nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of
the skin and eyes, light coloured bowel motions, dark coloured urine).
If you get any side effects, talk to your doctor or pharmacist. This includes any side effects not listed in this
leaflet.
5.
How to store /…/
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry
date refers to the last day of that month.
This medicinal product does not require any special storage conditions
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw
away medicines you no longer use. These measures will help protect the environment.
6.
Contents of the pack and other information
What /…/ contains
-
The active substance is: trimetazidine dihydrochloride. Each tablet contains 35 mg of trimetazidine
dihydrochloride
The other ingredients is are: sodium chloride, povidone (PVP K-30), magnesium stearate, cellulose
acetate, hypromellose.
What /…/ looks like and contents of the pack
Modified-release tablet.
White to off white, circular biconvex, film-coated tablets plain on both sides with aperture on one face.
The tablets are provided in blister packs containing 60 tablets.
Marketing Authorisation Holder and Manufacturer
<[To be completed nationally]>
{Name and address}
<{tel}>
<{fax}>
17
<{e-mail}>
This medicinal product is authorised in the Member States of the EEA under the following names:
<{Name of the Member State}> <{Name of the medicinal product}>
<{Name of the Member State}> <{Name of the medicinal product}>
This leaflet was last revised in {MM/YYYY}.
<[To be completed nationally]>
<Detailed information on this medicine is available on the web site of {MA/Agency}>
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