EMA đánh giá lại tỉ lệ lợi ích/nguy cơ của tất cả các thuốc có chứa hoạt chất trimetazidine

Questions and answers on the review of medicines containing trimetazidine (20 mg tablets, 35 mg modified release tablet and 20 mg/ml oral solution)

Outcome of a procedure under Article 31 of Directive 2001/83/EC as amended

On 21 June 2012,the European Medicines Agency completed a review of thesafetyand effectiveness oftrimetazidine followingconcerns over its effectiveness and reports of movementdisorders such as parkinsoniansymptoms with these medicines. The Agency’sCommittee forMedicinal Products for Human Use (CHMP) concluded that the benefits continue to outweigh the risksin patients with angina pectoris but that treatment should be restricted to add-on to existing treatments in patients who are not adequatelycontrolled by or who are intolerant to other medicines for angina pectoris.For the symptomatic treatmentof tinnitus, vertigo and visualfield disturbances, theCHMP concluded that the benefits no longer outweigh the risks and that theseuses shouldno longer be authorised. In addition, the Committee recommended new contraindications and warnings to reduce and manage the possible risk of movement disorders, associated with the use of this medicine.

Whatistrimetazidine?

Trimetazidineis amedicine used to prevent anginaattacks,which are suddenpains to thechest, jaw and back brought on by physicaleffort,due to reduced blood flowto theheart.Angina is commonly associated with a narrowing of the blood vessels that supply the heart,called the coronaryarteries.

Trimetazidineis a ‘metabolic agent’,amedicine which has an effecton metabolism (the process by which substances are broken down inthe body).It is believed to protect against myocardial ischaemia (reduced blood supply to the heart muscle) by increasing the rate at which glucose is broken down.

Trimetazidineis also used to treat the symptoms ofvertigo (a spinning sensation) and tinnitus (ringing sensation in the ears),and to treat reduced vision and visualfielddisturbances(unclear or disturbed vision) due to problems affecting the blood vessels.

Medicines containing trimetazidine have been available since the1970s and are currentlymarketed in Bulgaria,Cyprus, Czech Republic, Denmark, Estonia, France,Germany,Greece,Hungary, Ireland, Italy, Latvia,Lithuania,Luxembourg,Malta, Poland,Portugal, Romania, Slovakia, Sloveniaand Spain.

They are marketedunder the invented name Vastareland other trade names.

Whywastrimetazidinereviewed?

In April2011,the French medicines regulatory agency concluded that,basedon a reviewof the evidence in France,the risks of medicines containingtrimetazidine were greater than the benefits for allthe authorised indications.A mainconcern was that the effectiveness of trimetazidine had not been convincinglydemonstrated in any ofthe authorised indications, since the studies supporting the authorised uses had severalmethodological weaknessesand onlyshowed a smallbenefit.

In addition, there were concerns regarding the safety of trimetazidine-containing medicines following reports of Parkinson syndrome (a group of symptomsthat include shaking, slow movementand muscle stiffness) and other motor disorders such as tremor(shaking), muscle rigidity and walking disorders, and restless legs syndrome (a disorder where the patient has uncontrollable urges to move the limbs

to stop uncomfortable, painfulor odd sensations in the body, usually at night). These symptoms were seen insome patients withno previous history of Parkinson syndrome,and in manycases their symptomsresolved whenthey stopped taking trimetazidine.

Despite strengthening the warningsin the prescribing information of these medicines,the French agency remained concerned that the benefitsfor trimetazidine did not outweigh its risks. Consequently,on 22 April2011 it asked the CHMP to issue an opinion on thebenefit-risk balance of trimetzidine-containing medicines,andon whether the marketing authorisation for these medicines should be maintained, varied, suspended or withdrawn across the EU.

WhichdatahastheCHMPreviewed?

The CHMP looked at datafromclinical studies, the published literature,spontaneous reports of side effectsand data submitted by the companies that marketmedicines containing trimetazidine.

WhataretheconclusionsoftheCHMP?

Regarding the use of trimetazidinein angina pectoris,the Committee noted that the studies carried out to show its effects had some limitations and were often of shortduration. Although the studies did not show that the benefits outweighed the risksfor trimetazidine when used alone as first-line treatment, the studies supported theuse oftrimetazidine as add-on to existing treatments inpatients who are not adequatelycontrolled by or intolerantto other medicines for angina pectoris.To address the lack of long-termdata on trimetazidine,a study investigating the long-termeffects of trimetazidine willbe carried out.

Regarding the use oftrimetazidinein tinnitus, vertigo and visualfield disturbances, the studies had poor methodology and didnot demonstratea clinical benefit of trimetazidine when comparedwith placebo (a dummy treatment)or alternative medicines. In addition the CHMP noted thattrimetazidine is often used to treat these conditionsin older patients for longer and at higher doses than recommended, increasingthe risk of side effects such as falls which undermines the use of trimetazidine for these conditions.

An analysis ofrelevant safetydata showed that movementdisorders, including Parkinsonism, cannot be excludedwith trimetazidine,although these arenot commonand are reversible after discontinuing trimetazidine.The CHMP thereforerecommended that a warningshould be included in theproduct informationontrimetazidine-induced parkinsonism, its diagnosisand management.It also recommended contraindicating trimetazidine in patients withParkinsondisease or parkinsonian symptoms and in patientswith severely reduced kidney function.

European Medicines Agency recommends restricting use of trimetazidine-containing medicines

Restricted indication for patients with stable angina pectoris and deletion of existing indications for treatment of vertigo, tinnitus and vision disturbance

The European Medicines Agency has recommended restricting the use of trimetazidine–containing medicines in the treatment of patients with angina pectoris to second–line, add–on therapy. For all

other indications the Agency’s Committee for Medicinal Products for Human Use (CHMP) concluded that

the benefits of these medicines were not sufficiently demonstrated and did not outweigh the risks. The

CHMP therefore recommended their deletion from the marketing authorisation.

There is no need for an urgent change in treatment, but doctors should review their patients’

treatment at their next routine appointment.

Doctors should no longer prescribe trimetazidine for the treatment of patients with tinnitus, vertigo or disturbances in vision. Patients who are taking trimetazidine in these indications should discuss alternatives with their doctor.

Doctors can continue to prescribe trimetazidine for the treatment of angina pectoris, but only as an add–on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line anti-anginal therapies.

The review was initiated by France, mainly because of concerns that the efficacy of trimetazidine was not sufficiently demonstrated. It also looked at reports regarding the occurrence of movement disorders such as Parkinsonian symptoms, restless leg syndrome, tremors and gait instability associated with the medicine. Although patients usually recovered fully within four months after treatment with trimetazidine was discontinued, the Committee recommended new contraindications and warnings to reduce and manage the possible risk of movement disorders associated with the use of this medicine.

Doctors are advised not to prescribe the medicine to patients with Parkinson disease, parkinsonian symptoms, tremors, restless leg syndrome orother related movement disorders, nor to patients with severe renal impairment.