Doxil Availability Once Again in Question

Access to Doxil has been inconsistent since mid-2011, when the drug's sole manufacturer announced a voluntary shutdown of production to address significant manufacturing and quality concerns.

In a continued uphill battle, Doxil (doxorubicin hydrochloride liposome injection) is once again expected to be in short supply. Access to the drug, which is distributed by Janssen Products, LP, has been inconsistent since mid-2011, when the third-party manufacturer, Ben Venue Laboratories, Inc, announced a voluntary shutdown at its Bedford, Ohio, plant to address significant manufacturing and quality concerns.

On September 25, a letter warning healthcare providers of an imminent shortage was sent by Janssen, citing continued difficulties with Ben Venue as the leading cause for the diminished supply. In a follow-up letter on October 14, the company announced that some distributors are starting to experience outages. The company did not indicate when the supply would resume, although some reports place this date in late 2014.

As Janssen was releasing these statements, Ben Venue announced the decision to permanently cease production by the end of 2013. Despite continued efforts to return the Ohio facility to working order, the company noted an inability to resume production in a sustainable fashion. To date, the manufacturer has spent more than $350 million in renovations and noted that it would require an additional $700 million investment to return the plant to working order. The FDA is working in collaboration with Ben Venue to minimize the impact of this closure, which will impact the supply of several medications in addition to Doxil.

In the announcement of the closure, Boehringer Ingelheim, the parent company of Ben Venue, emphasized the importance of the generic sterile injectable production at the plant and noted that it was exploring options to continue supplying these products. However, no mention was specifically made to the manufacture of Doxil in this statement.

Johnson & Johnson (J&J), the parent company of Janssen, and Ben Venue initially undertook the manufacturing agreement for Doxil in 2009. In the letter to healthcare providers, Janssen expressed that it was taking steps to acquire a new manufacturer for Doxil, and that the company would take measures to ensure that Ben Venue met its contractual obligations. These efforts have been under way since 2011, when Boehringer initially informed J&J that they wished to transition away from contract manufacturing services.

The original patent for Doxil expired in 2009; however, an orphan designation for the drug in combination with bortezomib (Velcade) for patients with multiple myeloma resulted in an exclusivity extension of this patent to May 17, 2014. Despite this, in February 2013, the FDA approved a generic version of the drug manufactured by Sun Pharma Global FZE, to help alleviate the shortage that began in 2011. This generic version is not approved to treat patients with multiple myeloma, as this exclusivity agreement is still intact. However, treatment with Doxil and its generic are both approved for patients with ovarian cancer following progression on platinum-based chemotherapy and for AIDS-related Kaposi’s sarcoma in patients after failure or intolerance to prior systemic chemotherapy.

The intravenous generic is available in 10-mg and 25-mg vials. In an announcement, the FDA noted that Sun Pharma, based in India, has sufficient supplies of its generic product to cover the US market. As part of the generic approval process, an agent must meet the same quality and strength requirements as the brandname drug. Additionally, the manufacturing process must also pass the same quality standards. In this announcement, no reference was made to LipoDox, which the FDA had temporarily approved for importation at previous dates to help alleviate shortages.

While other treatments for patients, specifically with ovarian cancer, are equivalent in terms of efficacy, the toxicity profiles vary greatly. Cardiac toxicity is a common side effect with conventional versions of doxorubicin hydrochloride (Adriamycin), since these treatments lack the liposomal encapsulation that makes Doxil unique. As a result, Janssen made the distinction in its letter to physicians that a milligram-per-milligram substitution of the two medications should not be made.