FDA allows importation of methotrexate, doxorubicin

The agency moved to alleviate a shortage created when a US manufacturer suspended operations last year.

With a major manufacturer of methotrexate and doxorubicin temporarily shuttered because of quality concerns, the FDA announced that companies from Australia and India will be allowed to replenish the dwindling supply.

Hospira announced it would import more than 62,000 vials of preservative-free methotrexate from Australia by early March — two months supply for the country — and another 55,000 vials by the middle of the month. The agency also approved an application from APP Pharmaceuticals to manufacture methotrexate. That application was made in 2010.

Methotrexate is crucial for the treatment of acute lymphoblastic lymphoma, bone cancers, brain tumors and lymphomas. Doxorubicin is used to treat ovarian cancer, multiple myeloma and AIDS-related Kaposi’s sarcoma.

FDA commissioner Margaret A. Hamburg, MD, said the agency was allowing “temporary overseas importation” of the doxorubicin (Doxil) substitute Lipodox from India by Sun Pharma Global. Importation is rare, she said, but sometimes necessary when drugs are short supply.

“Lipodox remains unapproved by the FDA for the US market,” Hamburg said. “But when a critical drug is unavailable and the substitute can produce a comparable outcome and has been evaluated by us for quality and safety, we use our enforcement discretion to allow for its temporary and limited use.”

Ben Venue Laboratories of Bedford, Ohio, one of only four US manufacturers of methotrexate, voluntarily suspended operations in November after the FDA discovered “significant manufacturing and quality concerns.” The supply of methotrexate steadily dwindled since then as other manufacturers struggled to ramp up production to meet demand.

Max J. Coppes, MD, PhD, MBA, senior vice president of the Center for Cancer and Blood Disorders at Children’s National Medical Center in Washington, D.C., said the FDA should have looked outside the US sooner but still praised the agency for taking this step.

“It’s a laudable decision by the FDA based on the current shortages of drugs,” he said. “I would assume this is a one-time decision and I hope this will generate the discussion as to whether a process needs to exist that would allow importation to happen in other circumstances.”

Coppes, a HemOnc Today Editorial Board member, serves as an adviser to Health Canada, that country’s version of the FDA. Canada has an established plan to look internationally to address drug shortages, and Coppes said he would like to see the FDA establish a similar program.

“They have a process that allows physicians to request a special exempt status drug when there is a shortage. There’s a formal request reviewed by the Canadian government, and they can allow import of that drug from a different country,” Coppes said. “If drugs cannot be made in this country, patients should have access to life-saving drugs made elsewhere with the same standards we’re used to in the United States.”

Ben Venue announced on its website that it began releasing a limited supply of methotrexate to oncology clinics, hospitals and pediatric facilities on Feb. 16 and will continue during the next several weeks. The company is shipping methotrexate produced before the November shutdown.

The FDA had previously announced that the other manufacturers will increase production, and the agency is trying to find overseas suppliers.

Margaret R. O’Donnell, MD, associate clinical director of hematology and hematopoietic cell transplantation at City of Hope in Duarte, Calif., had about six weeks of methotrexate left when she spoke with HemOnc Today and expressed doubts about these solutions in the long term.

“The problem is that the US market is such a large market that I’m not sure foreign producers of these drugs can gear up to make five times what they usually make,” she said. “It’s something we should explore until we can get manufacturing alternatives in the US to pick up the slack.”

The problem goes beyond methotrexate. Ben Venue also manufactures the benzodiazepine midazolam (Versed), mitomycin (Mutamycin), metoclopramide (Reglan), prochlorperazine (Compazine), bortezomib (Velcade) in partnership with Millennium Pharmaceuticals, and doxorubicin (Caelyx) in partnership with Johnson & Johnson. Supplies of those drugs are running low as well.

City of Hope is out of metoclopramide and prochlorperazine, and a shortage of leucovorin has caused the hospital to switch to the much more expensive L-leucovorin. The oncology community has been dealing with shortages of various drugs from a variety of manufacturers for the past 2 years, O’Donnell said.

“We are constantly trying to piece together drug supplies or alternative dosing schedules or alternative regimens to compensate for what’s not available,” she said. “Almost every week, there is a note from our pharmacist saying some drug is in short supply”. – by Jason Harris

Disclosure: Drs. Coppes, Hamburg and O’Donnell report no relevant financial disclosures.

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