Off-label use of bevacizumab raises medical and ethical concerns in Europe

VIENNA, Austria — Currently available safety and efficacy data do not provide sufficient evidence to justify the off-label use of bevacizumab in the treatment of age-related macular degeneration, according to a specialist speaking at the Euretina Congress here.

"The major portion of published data derives from small and short-term studies," Paolo Lanzetta, MD, said. In addition, "the availability of registered drugs such as ranibizumab (Lucentis, Genentech) and pegaptanib (Macugen, OSI/Pfizer) raises further ethical concerns."

Despite the initial assumption that full-length antibodies would not pass across the retina, several studies demonstrated that Avastin (bevacizumab, Genentech) is able to penetrate the retina after intravitreal injection, and a promising efficacy profile was proven for neovascular AMD. Also, in clinical practice, the incidence of local side effects did not seem to differ from other intraocular drugs. Electrophysiological studies showed no side effects on the retina, and in vitro and in vivo experiments excluded short-term negative effects on ocular cells and histological structures.

"However, a mitochondrial disruption in the inner layers of photoreceptors and apoptosis has been reported after high doses of bevacizumab administration in rabbit eyes. One reported side effect is the occurrence of retinal pigment epithelium tears (5% to 10%), usually subsequent to large and hemorrhagic pigment epithelium detachment. Rapid fluid resolution or contraction of the fibrous tissue has been suggested as potential causes," Dr. Lanzetta said.

In addition, in the absence of long-term randomized controlled trials, safety concerns with systemic side effects are not yet entirely dispelled, he said. Bevacizumab accesses the systemic circulation, and this may explain the biological effects observed in the contralateral eye and the significantly elevated blood pressure levels reported in some patients after intravitreal injection, Dr. Lanzetta said. On the other hand, a recent 1-year prospective study of 60 eyes reported no ocular or systemic side effects.

The lack of coherent, evidence-based data makes the use of bevacizumab professionally hazardous and an ethically questionable practice, he said.

"The off-label use of a product within the medical profession is not illegal in any part of the world, but physicians have the responsibility to base its use on firm scientific rationale and medical evidence," he said.