Europe's equivalent of the FDA has advised that patients with Fabry disease receive the full label-recommended dosage of Genzyme's agalsidase-beta (Fabrazyme) despite the ongoing shortage of the drug, which is one of two enzyme replacement products available to treat the genetic disease.
A statement from the European Medicines Agency (EMA) indicated that patients receiving reduced dosages of Fabrazyme -- recommended in September 2009 as a way to stretch limited supplies of the drug -- had shown adverse events including pain and events affecting the heart, kidneys, and central nervous system.
"This pattern suggests a progression of Fabry disease," the statement said.
The agency's Committee for Medicinal Products for Human Use "is now recommending that physicians switch back to prescribing the full dose of Fabrazyme according to the authorized product information, depending on the availability of enzyme replacement therapy and the severity of the disease," according to the EMA.
Fabrazyme has been in short supply since June 2009, when bioreactors at a Genzyme manufacturing facility in Boston began acting up.
Genzyme was hit with $175 million in fines from the FDA because of the problems, which allowed viruses and bits of rubber and metal to contaminate products made at the facility.
The company indicated last month that Fabrazyme production at the plant had recently increased. Nevertheless, it still projected a substantial shortage until a new plant under construction in Framingham, Mass., is completed and cleared by the FDA, which Genzyme expects to happen in late 2011.
In September 2009, with Genzyme rationing its limited stock of Fabrazyme, a group of Fabry disease organizations developed temporary guidance providing for reduced dosing schedules, which the EMA endorsed. These schedules called for patients to receive as little as one-quarter of their normal dosage.
Fabry disease is a genetic condition in which the gene for the alpha-galactosidase enzyme is defective. The enzyme digests globotriaosylceramide, a byproduct of cellular metabolism that becomes toxic if not cleared from cells.
Another enzyme replacement product for Fabry disease is available, agalsidase-alfa (Replagal), even though it is not fully FDA approved. Its manufacturer, Shire, has applied for marketing approval, and the FDA has allowed it to sell limited quantities while the Fabrazyme shortage continues.
The EMA's statement noted that some patients appeared to have done well with the reduced Fabrazyme dosages, and it indicated that these patients could continue with low doses if they wish.
The agency also recommended against monitoring urine or plasma levels of globotriaosylceramide, which builds up in cells as a result of the Fabry defect. Such monitoring "does not appear to add value to the management of the patients while on a lower dose," it said.
The FDA has not provided special guidance to patients or clinicians for coping with the Fabrazyme shortage, except to allow sales of Replagal.