On February 21, 2012, the FDA announced a series of actions to deal with the severe shortages of Doxil (doxorubicin hydrochloride liposome injection; Janssen Research & Development, LLC) and preservative-free formulations of methotrexate. Doxorubicin is used to treat patients with ovarian cancer, multiple myeloma, and Kaposi’s sarcoma when first-line therapies have failed. Methotrexate is an antimetabolite used in both adults and children for the treatment of osteosarcoma, acute lymphoid leukemia, and lung cancer. It is also used to treat adults with gestational trophoblastic tumors, meningeal leukemia, breast cancer, head and neck cancer, advanced mycosis fungoides, and advanced non-Hodgkin lymphomas.
Doxorubicin Hydrochloride Liposome Injection Janssen, the sole supplier of Doxil in the United States, reported that the shortage is a result of manufacturing issues at its contracted manufacturer, Ben Venue Laboratories, which voluntarily suspended production on November 19, 2011, after problems occurred at its manufacturing facility in Bedford, Ohio. A Janssen spokeswoman stated there was “unplanned downtime due to equipment failure” at the facility. The facility had been cited by regulators for manufacturing deficiencies.
To increase the supplies of doxorubicin, the FDA is allowing the temporary importation and distribution of Lipodox. The FDA’s action is limited to Sun Pharma Global FZE and its authorized distributor, Caraco Pharmaceutical Laboratories Ltd—no other entities will be allowed to import or distribute doxorubicin. Sun Pharma’s Lipodox contains the same active ingredient and concentration as the doxorubicin hydrochloride liposome injection manufactured in the US (Doxil). Lipodox is manufactured at an FDA-inspected facility in India, and Caraco Pharmaceutical Laboratories is working with FDA to make Lipodox available to wholesalers in the US. The FDA stated Sun Pharma Global’s Lipodox remains unapproved for marketing in the US.
According to the FDA, “Temporary importation of foreign drugs is considered in rare cases when a shortage of an approved critical US drug exists and the shortage cannot be resolved by manufacturers of the approved drug in the immediate future.”
Preservative-Free Methotrexate
The FDA has approved a preservative-free methotrexate generic drug manufactured by APP Pharmaceuticals after a prioritized review. APP has a generic drug already approved by the FDA, and the approval for preservative-free methotrexate was based on a supplemental application.
The pharmaceutical companies that manufacture methotrexate slowed or stopped manufacturing for a variety of reasons, citing increased demand and manufacturing delays. Ben Venue Laboratories, one of the suppliers of the preservative-free formulation of methotrexate, voluntarily shut down production and distribution at its Ohio facility for issues related to maintenance and requalification of equipment. After confirming the safety of the already-manufactured preservative-free methotrexate, the FDA worked with Ben Venue to release its supply of the product. This supply is available for emergency distribution while APP and other manufacturers work to increase the production of preservative-free methotrexate.
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