Stopgaps Avert Methotrexate and Doxil Shortages -- For Now

Roxanne Nelson

February 21, 2012

February 21, 2012 — In response to the critical shortages of several cancer drugs, the US Food and Drug Administration (FDA) has announced a series of steps being taken to increase the supply of methotrexate and doxorubicin (Doxil).

"Prevention of drug shortages must be a priority for all of us, and it is — including President Obama and Congress," said FDA Commissioner Margaret A. Hamburg, MD, during a press briefing. "To that end, the FDA has been actively and aggressively working with industry and other stakeholders to ensure that treatments and therapies always get into the hands of those who need them, when they need them."

The FDA has approved a new manufacturer of a preservative-free form of methotrexate: APP Pharmaceuticals. This company expects its product to be available in March. In addition, Hospira, the world's leading provider of injectable drugs and infusion technologies, has ramped up its production of this version of methotrexate.

"I'm thrilled to relay that, 24 hours ago, we began directly shipping 31,000 vials of new product — enough to address more than a month's worth of demand," said Hospira CEO F. Michael Ball during the briefing. "It is being received in hundreds of our nation's hospitals and treatment centers today."

Ball added that next week an additional 34,000 vials will be released. "And by mid-March, we'll have enough product not only to meet the full market demand, but also to begin establishing safety stock to ensure patients and families never have to face this type of fear again," he explained.

Importing Unapproved Agent

Arrangements have also been made to increase supplies of doxorubicin, which is used to treat diseases such as ovarian cancer after the failure of platinum-based chemotherapy, AIDS-related Kaposi's sarcoma, and multiple myeloma. The FDA has allowed the temporary importation of Lipo-Dox from the Indian manufacturer Sun Pharma Global. Dr. Hamburg explained that even though Lipo-Dox is not approved for use in the United States, the FDA can allow temporary and limited use of a foreign approved drug when there is a critical shortage that cannot be resolved quickly.

Dr. Hamburg noted that the problem of drug shortages is complex, and stems from an "interconnected series of factors," such as demand outpacing supply and other economic and legal issues.

Methotrexate Crisis

As previously reported by Medscape Medical News, the shortage of critical drugs has been an ongoing issue. According to the FDA, the number of drugs deemed to be in short supply has nearly tripled, from 61 in 2005 to 178 in 2010. In 2011, there were roughly 200 shortages reported. Many of the products in short supply are generics, primarily sterile injectables, and include cancer medications, anesthetics, and antibiotics.

Recently, supplies of preservative-free methotrexate have been dwindling, which created panic among pediatric oncologists. This version of the drug is critical in the treatment of children with acute lymphoblastic leukemia. In a joint letter, experts stated that without preservative-free methotrexate, "patients are at a dramatically heightened risk of dying."

This shortage of preservative-free methotrexate, and its impact on the treatment of childhood leukemia, was widely reported last week in the American media.

Dr. Hamburg pointed out that in response to President Obama's Executive Order on prescription drug shortages, which was issued in October 2011, the FDA issued draft guidance to industry on detailed requirements for both mandatory and voluntary notifications to the agency of issues that could result in a drug shortage or supply disruption. The increased awareness of the importance of early notification has resulted in a 6-fold increase in voluntary notifications by industry about potential shortages.

In 2011, 195 drug shortages were prevented; this year, the FDA has prevented 114 drug shortages, she said.

Guidance From ASCO

Although the crisis of drug shortages for children with cancers has captured the attention of the media, it is important to note that methotrexate and other drugs are also used in adult patients, said Michael Link, MD, president of the American Society of Clinical Oncology (ASCO).

"It is for all cancer patients that we must make permanent changes that address the root causes of the ongoing drug shortages," warned Dr. Link during the briefing. These "shortages not only jeopardize today's care, but they will slow the development of better treatment for tomorrow's cancer patients. We cannot continue to practice medicine from crisis to crisis."

ASCO has called on Congress to immediately appoint a bipartisan, bicameral working group to consider all possible solutions and develop comprehensive legislation.

During the briefing, Dr. Link described 3 essential elements that must be included in new legislation: the FDA should receive confidential notification from manufacturers of market withdrawals or manufacturing interruptions 6 months in advance, or as soon as problems become known; Congress should provide incentives for companies to develop contingency plans to address economic factors that have driven shortages of low-cost, generic medicines; and the FDA's authority should be expanded to collect user fees from generic drug manufacturers as part of the regulatory approval process, similar to the fees paid by branded drug makers.


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