The Coordination Group for Mutual Recognition and Decentralised Procedures – Human ( CMDh ), a medicines regulatory body representing the European Union ( EU ) Member States, has endorsed the recommendation by the European Medicines Agency's ( EMA's ) Pharmacovigilance Risk Assessment Committee ( PRAC ), that permission to market oral medicines containing Almitrine should be withdrawn across the EU.
Almitrine is a stimulant of the part of the brain responsible for the breathing reflex. In the European Union, it is authorised in France, Poland and Portugal, as 50-mg tablets ( Vectarion, Armanor ), to be taken orally for the treatment of chronic respiratory failure ( inability of the lungs to take in oxygen and get rid of carbon dioxide properly ), which is associated with hypoxaemia ( lower-than-normal levels of oxygen in the blood ). These conditions pose a particular problem in patients with lung conditions known as chronic obstructive pulmonary disease ( COPD ), where the airways and air sacs inside the lungs become damaged or blocked.
The safety review of oral Almitrine was requested by the French medicines agency, the National Agency for the Safety of Medicine and Health Products ( ANSM ), because of concerns about side effects and a view that the available evidence did not support the use of the medicine in the current management of COPD.
The PRAC concluded that there is a clear association between oral Almitrine treatment and potentially serious and long-lasting peripheral neuropathy ( damage to the nerves in the hands and feet ) and significant weight loss that further weakens patients.
The PRAC noted that cases continue to be reported even after additional precautions on the use of the medicines were put in place. Furthermore, oral Almitrine is no longer included as a recommended therapy in international treatment guidelines for the management of COPD.
The safety review confirmed a clear association of oral almitrine therapy with significant weight loss and peripheral neuropathy ( which can be long-lasting and possibly irreversible ). The company marketing Almitrine identified 795 spontaneously reported cases of weight loss and 2,304 cases of peripheral neuropathy over the 30-year period that the medicine has been marketed ( representing several million patient-months of treatment ). In 489 cases, neuropathy was indicated to have been irreversible, or to have led to sequelae. Additional results from clinical studies suggested that neuropathy was most common after three months or more of treatment.
The PRAC noted that cases of weight loss and peripheral neuropathy have continued to be reported, despite the introduction of a number of risk minimisation measures, including sequential administration ( two months treatment followed by a one-month break ), dose reduction and appropriate warnings in the product information. Of the spontaneous reports, 7 cases of weight loss and 20 of peripheral neuropathy had been reported since September 2003 when all these measures were in operation. In three of the latter cases, patients were rechallenged with Almitrine and this led to a recurrence of neuropathic symptoms, including sequelae in two.
The understanding of COPD and the therapeutic options for its management have changed considerably since the original authorisation of oral Almitrine. Almitrine is not one of the treatments currently recommended in international guidelines for COPD management ( GOLD ), and the available evidence does not support a clinical benefit for long-term oral treatment with the medicine.In view of the potentially serious adverse effects and the lack of an established role in the current management of hypoxaemic pulmonary disease, the benefit-risk of oral almitrine is no longer considered favourable. ( Xagena )
Source: European Medicines Agency, 2013