FDA gives cancer drug Adcetris a stronger warning label

January 27, 2012

FDA and Seattle Genetics, which makes brentuximab vedotin (Adcetris), have updated the warning label on the company’s cancer drug after a second patient developed progressive multifocal leukoencephalopathy.

FDA and Seattle Genetics, which makes brentuximab vedotin (Adcetris), have updated the warning label on the company’s cancer drug after a second patient developed progressive multifocal leukoencephalopathy (PML).

Adcetris will carry a black-box warning stating that patients receiving Adcetris may be at risk of a John Cunningham viral infection resulting in PML, a rare but serious brain infection that can result in death. In addition, a contraindication will warn of the concomitant use of Adcetris and bleomycin because of pulmonary toxicity.

Adcetris was approved by FDA in August 2011 for the treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least 2 prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. The drug also was approved for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 prior multi-agent chemotherapy regimen.

At the time the drug was approved, 1 case of PML was described in the Warnings and Precautions section of the label. FDA and the company have said that 2 additional cases have now been reported. The company says it began working with FDA to develop the boxed warning in order to heighten awareness of the potential risk of PML.

The update to the contraindications has been prompted by data coming from a phase 1 clinical trial that suggests an increased risk of pulmonary toxicity related to the combination of Adcetris plus doxorubicin (Adriamycin, Bedford), bleomycin, vinblastine, and dacarbazine (ABVD) compared with the combination of Adcetris plus doxorubicin, vinblastine, and dacarbazine (AVD) as front-line therapy for HL.

According to the company and FDA, approximately 40% of patients (10 out of 25) in the Adcetris plus ABVD group had a pulmonary toxicity event compared with the 10% to 25% reported in the literature with bleomycin-based regimens (not containing Adcetris).

“No pulmonary toxicity has been observed thus far in the Adcetris plus AVD treatment group,” FDA said. “Patients have reported cough and dyspnea. Signs of interstitial infiltration have been observed on radiographs and computed tomographic imaging of the chest. Patients have responded to corticosteroid therapy.”

FDA makes the following recommendations to healthcare professionals:

Instruct patients to report changes in mood or usual behavior, confusion, problems thinking, loss of memory, changes in walking or talking, decreased strength or weakness on one side of the body, or changes in vision.

Consider a possible diagnosis of PML in any patient currently receiving or who has received Adcetris in the past, and who presents with new signs or symptoms of central nervous system abnormalities.

Hold Adcetris dosing for any suspected case of PML and discontinue Adcetris dosing if a diagnosis of PML is confirmed.

Report adverse events involving Adcetris to the FDA MedWatch program.

Peggy Pinkston, Senior Director of Corporate Communications for Seattle Genetics, said that the updated prescribing information for Adcetris is final and has been posted to the company’s website.

“Our first priority is patient safety,” she told Formulary  in an email, reinforcing earlier statements made by the company’s chief medical officer, Thomas C. Reynolds, MD, PhD. “Although PML in lymphoma patients can be caused by factors such as underlying disease and prior therapies that affect the immune system, a contributory role of Adcetris cannot be excluded.

“By developing these agreed upon label updates with the FDA regarding PML and the contraindication with bleomycin,” she continued, “we aim to heighten awareness among healthcare professionals in order to most safely treat their patients with Adcetris.”