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«SCRIP Intelligence - Martindale brands PRAC methadone reformulation demand unfair»

«Alleged misuse of an oral methadone formulation by Norwegian drug addicts has highlighted a new regulatory risk that pharma companies now face. It appears that though pharma companies have to show their drugs have more than a favorable risk:benefit ratio when used properly, they must also be formulated so as to mitigate risk of harm when taken inappropriately.

The European Medicines Agency's Pharmacovigilance Risk Assessment Committee recommended suspension of the marketing authorizations for oral methadone solutions containing high molecular weight polyvinylpyrrolidone (commonly known as povidone) K90 produced by Martindale Pharma. The recommendation was reviewed and has been endorsed by the Co-ordination Group for Mutual Recognition & Decentralised Procedures – Human (CMDh), a medicines regulatory body representing EU member states.

More significantly, Martindale has been told the suspension will only be lifted if its oral methadone that previously contained K90 is reformulated in such a way as to take into account its misuse potential.

"This has been a sobering and expensive experience. We have incurred significant costs in undertaking this process with the regulators to communicate not only that there is no proven causality between use of Martindale methadone oral solution and the cases referred to, and further, that the PRAC procedure lacks proportionality, undermines the principles of evidence-based medicine and is unfair," a spokesperson at Martindale Pharma told Scrip.

While the decision will have some financial implications for Martindale Pharma the situation is worse for Finnish opiate addicts who have been using the medication properly as part of a supervised opiate substitution therapy as there is no alternative once the product is withdrawn in Finland.

The PRAC's recommendation is based on reports from the Norwegian Medicines Agency (NOMA) that up to 15 known injecting drug users had suffered adverse drug reactions and that povidone might be implicated. NOMA pinned the problem on Martindale because its oral methadone 2mg/ml formulation contains 11.7mg/ml of high molecular weight povidone K90.

Ironically, K90, an accepted excipient commonly used in oral pharmaceutical products, was put into the formulation at the request of Norway to increase the oral methadone solution’s viscosity and so reduce the risk of inappropriate injection. Indeed, the product's Patient Information Leaflet has a clear statement that says: "Under no circumstances should you inject this product as injection may cause serious and permanent damage to your body with possibly fatal consequences."

NOMA suspended the Martindale Pharma product in April 2014, barely two months after the company's European market authorization application (MAA) had been renewed. Subsequently, the PRAC review of oral methadone medicines containing povidone was initiated on 10 April under Article 107i of Directive 2001/83/EC, also known as the "Urgent Union Procedure."

Martindale Pharma's pleas to the PRAC that the Norwegian evidence was flawed fell on deaf ears. The company argued that there was no proof that its product was formerly involved and it was being used without incident in other EU states. The company had hoped that it might have been able to convince the CMDh members to take a more pragmatic line that would have allowed it to return to the market with a povidone-free formulation but to no avail. The CMDh agrees with the PRAC that Martindale "should appropriately reformulate the product taking into account its misuse potential."

"We have committed to reformulating our oral methadone solution to remove the povidone which clearly addresses the issue identified by NOMA and have it ready within four months. We do, however, fear it will be rejected because the wording from the regulators appears to require reformulation of a product for oral use which is safe when misused by injection. This sets a very dangerous precedent," noted the Martindale Pharma spokesperson.

Martindale Pharma believes that the PRAC and the CMDh are making unethical and unfair demands arguing that forcing it to create a povidone-free product so that it can still be safely used if injected would provide tacit support for illicit injection of a product that would be non-sterile, would deny vulnerable people access to a medicine that works for them while it remains suspended, and is treating the company differently from others.

"If the issue is povidone then taking that out should be enough. However, unless the CMDh is proposing that all oral methadone products which are on the market are reformulated to ensure that they cannot be inappropriately injected then it appears that we are being held to a different standard from other manufacturers of oral methadone products that can remain on the market whilst not being designed for safe intravenous use. That creates an uneven playing field and flies in the face of equal treatment," he added.

Martindale Pharma's povidone containing oral methadone was originally granted market authorization by Norway in April 2006 and then subsequently approved via Europe's mutual recognition procedure, with Norway as the reference member state, and is also marketed in Sweden and Finland. That marketing authorization was renewed in February this year. The product has also been licenced in Kenya and South Africa.»