EU/3/01/059: Orphan designation for the treatment of anthracycline extravasations

Chemotherapeutic agents (medications that are used to treat various forms of cancers) are mostly given by intravenous administration. When given intravenously, there are few side effects at the site of injection. However, when injected or leaked outside the vein into the surrounding tissues, defined as extravasation, a tissue reaction spanning from irritation to necrosis (cell death) may arise. In particular, anthracycline (a chemotherapeutic agent) leaked outside the vein is continuously released from necrotic (dead) cells in the surrounding tissues and causes damage to adjacent healthy tissue. This leads to severe tissue damage and deep ulcerations (skin lesions) that progress slowly over several weeks. Anthracycline extravasation is chronically debilitating.

At the time of designation, anthracycline extravasation affected approximately 0.03 in 10,000 people in the European Union (EU). This was equivalent to a total of around 1,100 people*, and is below the threshold for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP).

*Disclaimer: For the purpose of the designation, the number of patients affected by the condition is estimated and assessed on the basis of data from the European Union. At the time of designation, this represented a population of 378,800,000 (Eurostat 2001).

At the time of submission of application for orphan-drug designation, there were no authorised products for the treatment of anthracycline extravasation in the European Union. However, several methods were used to prevent and treat anthracycline extravasation, such as elevation of the affected limb or cooling. In some cases dimethyl sulfoxide, hyberbaric oxygen or surgical intervention were used.

Dexrazoxane is structurally similar to ethylenediaminetetraacetic acid, a chelating agent (an agent that binds metal ions). It is believed to bind iron and conceal it from oxygen. Anthracycline induces the formation of free radicals (active molecular fragments containing a chemical charge) leading to breaks in the DNA (the genetic material in the cell). Although the mechanism of action of dexrazoxane in anthracycline extravastion is not completely understood, it is believed to inhibit formation of DNA breaks by scavenging iron and preventing free-radical formation. These effects are expected to protect against the toxic damages of tissues and cells caused by anthracyclines.

The effects of dexrazoxane have been evaluated in experimental models.

At the time of submission of the application for orphan designation, no clinical trials in patients with anthracycline extravasation had been initiated.

Dexrazoxane was not marketed anywhere worldwide for treatment of anthracycline extravasation, at the time of submission.

Orphan designation of dexrazoxane was granted in the United States for treatment of anthracycline extravasation during chemotherapy in 2004. Dexrazoxane has been authorised in the United States for the treatment of extravasation resulting from intravenous anthracycline chemotherapy since 2007.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 18 July 2001 recommending the granting of this designation.

Update: Dexrazoxane (Savene) was authorised in the EU on 28 July 2006 for for the treatment of anthracycline extravasation.

• the seriousness of the condition;
• the existence of alternative methods of diagnosis, prevention or treatment;
• and either the rarity of the condition (affecting not more than five in 10,000 people in the Community) or the insufficient returns on investment.

Designated orphan medicinal products are products that are still under investigation and are considered for orphan designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of the quality, safety and efficacy is necessary before a product can be granted a marketing authorisation.