Biotech Values

[DewDiligence]

Avastin's "Black Box" warnings re bowel perforations, impaired wound healing, and hemorrhage:

[Because Avastin is an anti-angiogenic agent, one would expect wound healing to be a concern for patients receiving treatment. “lflc”, an oncologist who posts on the IMCL message board, suggested that Avastin be given *before* routine colorectal surgery so that wound healing is not in progress when the drug is administered. However, the FDA warning below shows that there are potential problems no matter how Avastin is scheduled. If a patient needs immediate surgery to fix a problem caused by Avastin itself (e.g. a bowel perforation), you have a real dilemma because wound healing is impaired for several weeks following Avastin treatment. Yet a bowel perforation can be life-threatening, so one must operate anyhow. Thanks to corky6900_2000 for this reference. Annotations below in italics by Dew.]

http://www.fda.gov/cder/foi/label/2004/125085lbl.pdf

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U.S. BLA Amendment: Bevacizumab—Genentech

WARNING

Gastrointestinal Perforations/Wound Healing Complications

Gastrointestinal perforation and wound dehiscence, complicated by intra-abdominal abscesses, occurred at an increased incidence in patients receiving AVASTIN as compared to controls. AVASTIN has also been shown to impair wound healing in pre-clinical animal models. In Study 1, one of 396 (0.3%) patients receiving bolus-IFL plus placebo, six of 392 (2%) patients receiving bolus-IFL plus AVASTlN, and four of 109 (4%) patients receiving 5-FU/LV plus AVASTIN developed gastrointestinal perforation, in some instances with fatal outcome. [It is unclear why the perforation rate should be higher in the Avastin patients who took 5FU/LV *without* Irinotecan than in the Avastin patients who took IFL, which is 5FU/LV *with* Irinotecan. This is presumably a statistical fluke.] These episodes occurred with or without intra-abdominal abscesses and at various time points during treatment. The typical presentation was reported as abdominal pain associated with symptoms such as constipation and vomiting.

In addition, two of 396 (0.5%) patients receiving bolus-IFL plus placebo, four of 392 (1%) patients receiving bolus-IFL plus AVASTIN, and one of 109 (1%) patients receiving 5-FU/LV plus AVASTIN developed a wound dehiscence during study treatment. The appropriate interval between surgery and subsequent initiation of AVASTIN required to avoid the risks of impaired wound healing has not been determined. In Study 1, the clinical protocol did not permit initiation of AVASTIN for at least 28 days following surgery. There was one patient (among 501 patients receiving AVASTIN on Study 1) in whom an anastomotic dehiscence occurred when AVASTIN was initiated per protocol. In this patient, the interval between surgery and initiation of AVASTIN was greater than 2 months.

Similarly, the appropriate interval between termination of AVASTIN and SUBSEQUENT [emphasis added] elective surgery required to avoid the risks of impaired wound healing has not been determined. In Study 1, 39 patients who were receiving bolus-IFL plus AVASTIN underwent surgery following AVASTIN therapy and, of these patients, six (15%) had wound healing/bleeding complications. In the same study, 25 patients in the bolus-IFL arm underwent surgery and, of these patients, one of 25 (4%) had wound healing/bleeding complications. The longest interval between last dose of study drug and dehiscence was 56 days; this occurred in a patient on the bolus-IFL plus AVASTIN arm. The interval between termination of AVASTIN and subsequent elective surgery should take into consideration the calculated half-life of AVASTIN (approximately 20 days). AVASTIN therapy should be discontinued in patients with gastrointestinal perforation or wound dehiscence requiring medical intervention.

Hemorrhage

[This section pertains mostly to lung cancer, an unapproved indication.] Two distinct patterns of bleeding have occurred in patients receiving AVASTIN. The first is minor hemorrhage, most commonly Grade 1 epistaxis. The second is serious, and in some cases fatal, hemorrhagic events. Serious hemorrhagic events occurred primarily in patients with non–small cell lung cancer, an indication for which AVASTIN is not approved. In a randomized study in patients with nonsmall cell lung cancer receiving chemotherapy with or without AVASTIN, four of 13 (31%) AVASTIN-treated patients with squamous cell histology and two of 53 (4%) AVASTIN-treated patients with non-squamous histology experienced life-threatening or fatal pulmonary hemorrhage as compared to none of the 32 (0%) patients receiving chemotherapy alone. Of the patients experiencing events of life-threatening pulmonary hemorrhage, many had cavitation and/or necrosis of the tumor, either pre-existing or developing during AVASTIN therapy. These serious hemorrhagic events occurred suddenly and presented as major or massive hemoptysis. The risk of central nervous system (CNS) bleeding in patients with CNS metastases receiving AVASTIN has not been evaluated because these patients were excluded from Genentech-sponsored studies following development of CNS hemorrhage in a patient with a CNS metastasis in Phase 1 studies. Other serious bleeding events reported in patients receiving AVASTIN were uncommon and included gastrointestinal hemorrhage, subarachnoid hemorrhage, and hemorrhagic stroke. Patients with serious hemorrhage i.e., requiring medical intervention, should have AVASTIN treatment discontinued and receive aggressive medical management. Patients with recent hemoptysis should not receive AVASTIN.
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