Patients with myasthenia gravis, a rare, autoimmune neuromuscular junction disorder presenting with painless, fluctuating, fatigable weakness involving specific muscle groups as well as ocular weakness with asymmetric ptosis and binocular diplopia, are typically treated with a variety of medications, of which Mestinon (pyridostigmine bromide) has been used as a first line of therapy for many years. This relatively inexpensive treatment, which predates the orphan drug regulations of both the USA and Europe, prevents the breakdown of neurotransmitter acetylcholine by allowing it to accumulate. With more acetylcholine, patients have more control of voluntary functions such as eye movements, limited strength, swallowing and breathing.
Mestinon is certainly not new (it originally received approval in the USA in 1955) and is considered inexpensive – especially in comparison to many other products for rare diseases. Yet in Romania the estimated 2000 myasthenia gravis patients have periodically had trouble obtaining Mestinon over the years. The most recent episode lasted over two months. It was the second such crisis in which the medication was unavailable to patients in the last two years; a similar episode in 2007 lasted some seven months. OrphaNews Europe examines the complex factors that contribute to the frequent unavailability of Mestinon in Romania.
Although Mestinon is used as a treatment for a rare disease, it is not protected by an “orphan medicinal product” designation that would allow special jurisdiction in some areas, including the opportunity to be imported by a government agency in Romania. Mestinon received marketing authorisation many years before European orphan drug regulation was adopted in 1999, and thus predates orphan status. In Romania, this means that importation of the drug is negotiated privately. One importer is presently responsible for negotiating prices for Mestinon. According to patient groups, in countries such as Romania importation is occasionally ceased for products in an effort to force prices up. The trouble occurs when there is just one treatment being imported for an illness, as is the present case with Mestinon, and just one importer responsible for furnishing the product. Fluctuations between the Euro and the Romanian new leu currencies mean that price negotiations for Mestinon must be renewed every trimester. Patient group the Romanian Myasthenia Gravis Association has tried to get other importers to also take on Mestinon, but they have been met with a lack of interest due to the inherent unprofitability of importing an inexpensive medication for a small number of patients. The association has filed a complaint with both the Romanian councils of competition and of discrimination, but the situation remains unresolved to date.
The cost of Mestinon is on average the equivalent of 25-30 euros per month, although some patients need a dosage costing up to 90 euros per month. This amount is significant in a country where the average monthly salary is under 400 euros and often much lower in rural areas. When it is available, Mestinon is fully reimbursed by the government for myasthenia gravis; however, price becomes an issue when patients are required to go abroad to purchase the product, as has been the case in past months and in previous crises.
During this latest crisis, patients were informed that the unavailability of Mestinon was caused by a halt in production due to the installation of a new software system. Under Romanian law (95/2006 art 729-2), halts in production of a medicinal product must be announced to pharmacies, hospitals, and patients at least two months prior to the cessation of product availability. The Romanian Myasthenia Gravis Association claims that they were not informed of the production delays. Enquires made by OrphaNews Europe to both the importer and the manufacturer’s production department were not answered at the time of publication.
An ongoing saga
In Romania, obtaining Mestinon has often been a problem – both before and after January 2007 when Romania became a member of the European Union. Early on, Mestinon was produced and imported from Switzerland by Hoffmann La Roche. Then, in the 1990s, ICN Galenika Yugoslavia took over Mestinon. When this switchover occurred, Romanian patients were unable to obtain Mestinon for about a year. During the Serbian war, when the manufacturer moved from the former Yugoslavia, Mestinon was once again missing for several months in Romania.
The manufacturer eventually moved to Hungary but the importer for Romania was still located in the former Yugoslavian republic of Serbia, which still had a representative in Bucharest who was able to import Mestinon in small amounts. The majority of Romanian patients at this time bought their medication from Hungary, Germany or Spain. After 1 January 2007, when Romania became an EU member, all medicinal products needed a new authorisation according to EU standards. It took several months for the importer to obtain this authorisation. Mestinon was absent from the pharmacies from November 2006 through May 2007, at which time the Health Ministry imported a small amount of the medication at the request of the patient organisation. Finally, the authorisation was given to a unique importer, Valeant Polfa Rzeszow Poland, represented in Romania by a small Romanian firm, Fideliofarm Sibiu. However, the drug was not imported and was again unavailable from May through September 2007. From the beginning of 2008 it was once again unobtainable in Romania, this time due to production problems. Unfortunately patients and pharmacists were unaware of the pending delay, and so were unable to create a buffer stock of the product beforehand.
Myasthenia gravis patients in Romania have difficulties obtaining other medicinal products; in particular patients suffer from a lack of access to the immunoglobulins that are needed to stop major myasthenic crises. These products are not currently covered by insurance, but patients report that they cannot obtain them even if they are willing and able to pay. It has also been reported that imunnosupressive drugs are no longer available; methotrexate among them. Patients attribute the lack of access to the currency exchange rate, and the refusal or inability of the government to modify prices. The importers stop importation in order to avoid losing money.
Lessons learnt
The latest Mestinon crisis in Romania lasted two months and 20 days. Mestinon was once again available in Romania as of 21 March, though only in some pharmacies in Bucharest and another major city. The patient organisation has learnt from this episode and is now better prepared to confront the situation if and when it arises in the future. The patient association has created a stockpile with 200 bottles of 20 pills donated by the Hellenic Pasteur Institute of Athens, Greece, and another 60 bottles donated from the Association des Myastheniques Isoles et Solitaires in France and the Associazione Italiana Miastenia ONLUS. The Romanian Myasthenia Gravis Association was able to distribute emergency aid to patients in need, but hoped to be able to save a quantity of Mestinon as a buffer stock for further crises. The group is convinced that further crises will happen. Current law states that every three months the health ministry will renegotiate the drug price with the importers - following the fluctuating euro/Romanian leu exchange rate – and, according to the patient group, recent experience suggests that the importer will stop importation and sell the whole quantity of product before negotiations in order to avoid losing money. Thus the Romanian Myasthenia Gravis Association is intent on creating its own supplies. The group is also pressuring the government to apply a law that would have the state take over importation when an authorised product is not available for a significant period of time. In addition, the group is agitating to have Mestinon declared a “drug for special needs” in Romania. This would allow the government to import the product alongside the private-sector importer. Finally, the group is seeking alternative solutions, such as a second importer or a second medicinal product as a means to offset future crises. It is hoped that the national rare disease plan under construction in Romania will include provisions to ease access to Mestinon for rare disease patients. Recent actions on the part of the government demonstrate that Romania is a country working hard to improve conditions for its rare disease patients – including their medicinal needs.