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J Oral Maxillofac Surg70:765-767, 2012

Adverse Events Reported After the Use ofRecombinant Human BoneMorphogenetic Protein 2

Emily Jane Woo, MD, MPH*

Purpose: The US Food and Drug Administration has approved recombinant human bone morpho-genetic protein 2 (rhBMP-2) (Infuse Bone Graft; Medtronic Sofamor Danek, Minneapolis, MN) as analternative to autogenous bone graft for sinus augmentations and for localized alveolar ridgeaugmentations for defects associated with extraction sockets. The objective of this analysis was tocharacterize adverse events reported after the use of rhBMP-2 in oral and maxillofacial procedures.

Materials and Methods: The US Food and Drug Administration’s Manufacturer and User FacilityDevice Experience database contains reports of adverse events involving medical devices. The publiclyavailable version of the database was searched for reports for the brand name Infuse Bone Graft.Descriptive statistics were used to summarize the procedures and adverse events.

Results: As of April 30, 2011, the Manufacturer and User Facility Device Experience database contained83 reports of adverse events after oral and maxillofacial operations involving rhBMP-2. Of these reports,55 (66.3%) described off-label uses, such as reconstruction of the mandible after fracture or cancer oralveolar cleft repair. The most commonly reported adverse events included local reactions, graft failure,infections, and other wound complications. Of the reports, 25 (30.1%) stated that the patient requiredadditional surgery to address the reported adverse event.

Conclusions: Serious adverse events, some of which may require a second operation, can occur afterthe use of rhBMP-2 in oral and maxillofacial procedures. In this analysis graft, failure and pseudarthrosiswere more commonly reported after off-label uses of rhBMP-2 than approved uses.This is a US government work. There are no restrictions on its use. Published by Elsevier Inc on behalfof the American Association of Oral and Maxillofacial Surgeons.

J Oral Maxillofac Surg 70:765-767, 2012

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n March 9, 2007, the US Food and Drug Administra-ion (FDA) approved recombinant human bone mor-hogenetic protein 2 (rhBMP-2) (Infuse Bone Graft;edtronic Sofamor Danek, Minneapolis, MN) as an

lternative to autogenous bone graft for sinus aug-entations and for localized alveolar ridge augmenta-

*Medical Officer, US Food and Drug Administration, Rockvi-

lle, MD.

There was no external funding source. The author does not have

any commercial association with the pharmaceutical industry. The

views expressed in this article are the author’s own and do not

reflect the official policy or position of the US Food and Drug

Administration.

Address correspondence and reprint requests to Dr Woo: US

Food and Drug Administration, HFM-222, 1401 Rockville Pike,

Rockville, MD 20852; e-mail: jane.woo@fda.hhs.gov

This is a US government work. There are no restrictions on its use.

Published by Elsevier Inc on behalf of the American Association of Oral and

Maxillofacial Surgeons

0278-2391/12/7004-0$36.00/0

doi:10.1016/j.joms.2011.09.008

765

ions for defects associated with extraction sockets.1

Infuse Bone Graft is contraindicated in patients with aknown hypersensitivity to rhBMP-2, bovine type Icollagen, or other components of the formulation; inpatients with any active malignancy or patients un-dergoing treatment for a malignancy; in skeletallyimmature patients; in pregnant women; or in patientswith an active infection at the operative site.2 Itshould not be used in the vicinity of a resected orextant tumor.2 The manufacturer’s package insertlso includes warnings about potential adverse effectsuring pregnancy and lactation; warnings about boneesorption, fluid formation, and edema; precautionsegarding the potential for ectopic, heterotopic, orxuberant bone formation; and a statement that theroduct has not been studied in extraction sites asso-iated with molars or in the mandible.2

Postmarketing surveillance may reveal importantinformation about adverse events that were not ob-served in clinical trials. The objective of this analysiswas to characterize adverse events reported to the

FDA after oral and maxillofacial procedures in which

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766 ADVERSE EVENTS WITH RECOMBINANT HUMAN BMP-2

rhBMP-2 was used, as well as the types of operationsduring which the product was applied.

Materials and Methods

The FDA’s Manufacturer and User Facility DeviceExperience (MAUDE) database contains reports ofadverse events involving medical devices.3 Reports donot necessarily reflect a conclusion by the party sub-mitting the report or by the FDA that the devicecaused or contributed to the adverse event.3 Thepublicly available version of the MAUDE database wassearched for reports for the brand name Infuse BoneGraft. Adverse events were reviewed and summa-rized. The public dataset does not include demo-graphic information (age, gender, and so on), medicalhistory, clinical and radiologic records related to thereported adverse event, or follow-up information re-garding complications and long-term outcomes.

For this analysis, the guidelines of the HelsinkiDeclaration do not apply, and institutional reviewboard approval was not required. The analysis tookplace after surgery and exposure to rhBMP-2. Further-more, the public dataset does not contain any patientidentifiers, so there is no risk to confidentiality.

Table 1. OPERATIONS IN WHICH rhBMP-2WAS USED

Operation n (%)

pproved indications 28 (33.7)Sinus augmentation 20 (24.1)Alveolar ridge augmentation 8 (9.6)ff-label uses 44 (53.0)Mandibular reconstruction 25 (30.1)Alveolar cleft repair 19 (22.9)ther or unspecified oral and maxillofacial

surgery 11 (13.3)

Woo. Adverse Events with Recombinant Human BMP-2. J OralMaxillofac Surg 2012.

Table 2. ADVERSE EVENTS REPORTED AFTER USE OF rh

Principal Adverse EventApproved

Use [n (%)]O

Us

ocal edema/erythema/pain 15 (53.6) 1urgical site infections/wound

complications 8 (44.4)raft failure 3 (17.6) 1seudarthrosis 0ther* 2 (13.3)

Other reported events included hardware complications (32), gastrointestinal distress (1), giant cell granuloma (1), hy1), respiratory distress (1), and unintentional injury (1).

Woo. Adverse Events with Recombinant Human BMP-2. J Oral Maxillof

Results

Through April 30, 2011, MAUDE has received 929reports of adverse events involving rhBMP-2, of which83 (8.9%) described oral and maxillofacial operations.Of these, 28 (33.7%) described procedures in whichrhBMP-2 was used in accordance with the approvedindication (Table 1). Off-label uses included recon-struction of the mandible after fracture or cancer (25reports) and alveolar cleft repair (19 reports). Table 2summarizes the adverse events reported after use ofrhBMP-2 in oral and maxillofacial surgery. Three clin-ical categories together accounted for 76% of re-ported adverse events: local reactions, surgical siteinfections and other wound complications, and graftfailure. Of all the reports, 25 (30.1%) stated that thepatient required additional surgery to address the re-ported adverse event. Seven reports described the useof rhBMP-2 at the site of a resected tumor. There wereno reports of rhBMP-2 use in pregnant/lactatingwomen or in persons with known hypersensitivity toany of the device components. No deaths after oraland maxillofacial surgery involving rhBMP-2 werereported.

Discussion

Encompassing 4 years of postmarketing experi-ence, this article summarizes all adverse reports re-ported to MAUDE after oral and maxillofacial proce-dures involving rhBMP-2. Fifty-three percent ofreports explicitly described off-label uses; an addi-tional 11 reports did not state whether the operationinvolved an approved use, so the percentage of off-label uses may have been even higher. Although themanufacturer’s package insert states that Infuse BoneGraft has not been studied in the mandible,2 manyeports described its use in operations to addressandibular reconstruction. Similarly, the prescribing

nformation specifies that the use of Infuse Bone Graft

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Type of Use CouldNot Be Determined [n (%)]

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is contraindicated at the site of a resected or extanttumor,2 yet MAUDE received numerous reports stat-ing that rhBMP-2 had been used in such a manner.The package insert further states that rhBMP-2 is in-dicated for skeletally mature patients,2 but some ofhe procedures in this analysis, such as alveolar cleftepair, are generally performed in children and ado-escents. Local reactions, infections and other woundomplications, and graft failure were among the mostommonly reported adverse events. Because the pub-ic version of the MAUDE database does not includeollow-up information, it was not possible to evaluateisk factors and alternative etiologies of the reportedomplications.The findings reported in this article do not neces-

arily reflect the true range or proportions of adversevents that can occur after oral and maxillofacial op-rations involving rhBMP-2. The number of patientsho have been exposed to rhBMP-2 is not known.

nsurance claims data could be used to estimate the

enominator, but it would not be appropriate to com-ine MAUDE results and claims data to calculate inci-ence rates of adverse events. Conclusions about theisk of adverse events after approved and off-labelses cannot be drawn. Nevertheless, results from pas-ive surveillance data are useful for detecting new andnexpected safety concerns. Serious adverse events,ome of which may require a second operation, canccur after the use of rhBMP-2 in oral and maxillofa-ial procedures. In this analysis, graft failure and pseu-arthrosis were more commonly reported after off-

abel uses of rhBMP-2 than approved uses.

References1. PMA P050053, original application. Available from: URL: http://

www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm.Accessed September 1, 2011.

2. Available from: URL: https://www.infusebonegraft.com/omf_package_insert.pdf. Accessed September 1, 2011.

3. Available from: URL: http://www.fda.gov/medicaldevices/

deviceregulationandguidance/postmarketrequirements/reportingadverseevents/ucm127891.htm. Accessed September 1, 2011.