Restricted indications and new contraindication for trimetazidine-containing products

HSA would like to inform healthcare professionals about new restrictions on the use of trimetazidine-containing products arising from Servier's amendments to the local package inserts (PI) of Vastarel® and Vastarel MR®. These amendments, which are initiated by the company, are related to a recent scientific assessment carried out by the European Medicines Agency (EMA) involving the efficacy and safety of trimetazidine. HSA has reviewed these information and deemed the amendments necessary to maintain the positive benefit-risk balance of the products. HSA is also working with the product licence holders of all other locally-registered trimetazidine-containing products to update their PIs accordingly.

Background

Trimetazidine is a metabolic agent that potentiates glucose oxidation and maintains energy metabolism during ischaemia. Locally, trimetazidine has been licensed since 1998 for the treatment of episodes of angina pectoris and adjuvant symptomatic treatment of vertigo and tinnitus (Vastarel® and Vastarel MR®, Servier (S) Pte Ltd). It is also available as generic products, Metagard® (Zyfas Medical Co) and Metazin® (Medipharm Pte Ltd).

On 22 June 2012, the EMA's Committee for Medicinal Products for Human Use (CHMP) completed a review on the benefit-risk balance of trimetazidine-containing products.¹ This review was initiated by France, mainly due to concerns that the effectiveness of trimetazidine had not been convincingly demonstrated in any of the authorised indications. The studies supporting the authorised uses had several methodological weaknesses and only showed a small benefit. Additionally, there were reports of movement disorders such as Parkinsonian symptoms, restless leg syndrome, tremors and gait instability associated with the drug. These symptoms were seen in some patients with no previous history of Parkinsonian syndrome, and patients usually recovered fully within four months after discontinuation of treatment with trimetazidine.

The CHMP reviewed data from clinical studies, the published literature, spontaneous reports of adverse effects and data submitted by the companies that market products containing trimetazidine. Regarding the use of trimetazidine in angina pectoris, the Committee noted that the studies carried out to show its effects had some limitations and were often of short duration. Although the studies did not show that the benefits outweighed the risks for trimetazidine when used alone as first-line treatment, the studies supported the use of trimetazidine as add-on to existing treatments in patients who are not adequately controlled by or intolerant to other drugs for angina pectoris. The CHMP therefore recommended restricting the use of trimetazidine-containing products in the treatment of patients with angina pectoris to second-line, add-on therapy. For all other indications, the CHMP concluded that the benefits were not sufficiently demonstrated and therefore recommended their deletion from the marketing authorisation. In addition, the CHMP recommended new contraindications in patients with Parkinson disease, Parkinsonian symptoms, tremors, restless leg syndrome, and other related movement disorders.

The CHMP also contraindicated the use of trimetazidine in patients with severe renal impairment (creatinine clearance <30mL/min). In patients with moderate renal impairment, a reduced dose of 20mg of the immediate-release formulation twice daily or 35mg of the modified-release formulation in the morning was recommended.

Local situation & HSA's advisory

HSA has reviewed the assessment conducted by the CHMP and the amendments proposed by Servier. HSA's assessment and advisory is as follows:

• Trimetazidine-containing products should only be prescribed in adult patients as add-on therapy for the symptomatic treatment of stable angina pectoris inadequately controlled by first-line anti-anginal therapies or to patients intolerant to such therapy.
• Trimetazidine is no longer indicated for the symptomatic treatment of vertigo, tinnitus and visual field disturbances.
• Trimetazidine is contraindicated in patients with Parkinson disease, Parkinsonian symptoms, tremors, restless leg syndrome, and other related movement disorders.
• The occurrence of movement disorders such as Parkinsonian symptoms, restless leg syndrome, tremors, and gait instability should lead to definitive withdrawal of trimetazidine. A neurologist's opinion should be sought if Parkinsonian symptoms persist for more than four months after discontinuation of treatment.
• Trimetazidine is contraindicated in patients with severe renal impairment. For patients with moderate renal impairment and the elderly, the dose should be reduced.

The local PIs for Vastarel® and Vastarel MR® have been updated in June 2013 to reflect the restricted indications and new contraindication, as well as to strengthen the safety information. The PIs of Metagard® and Metazin® will subsequently be aligned to that of Vastarel®.

Although no local cases of movement disorders associated with the use of trimetazidine have been reported, healthcare professionals are advised to monitor their patients for possible movement disorders such as Parkinsonian symptoms and to discontinue trimetazidine permanently in these patients should such disorders develop.

Healthcare professionals are also encouraged to report adverse reactions associated with the use of trimetazidine to the Vigilance Branch of HSA.

Reference

1. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/
   2012/06/WC500129070.pdf

Published: 29 Aug 2013

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