MLリソース：骨形成不全症

　日本語版註）dibotermin alfa (欧InductOs[Wyeth];米INFUSE(R) Bone Graft[Wyeth; Medtronic])
　【別名】rhBMP-2; Bone Morphogenetic Protein骨形成タンパク　【開発元】Medtronic,Inc & Wyeth　 [DBR_ID]x
　【化学名】dibotermin alfa (recombinant human Bone Morphogenetic Protein-2; rhBMP-2) is a human protein derived from a recombinant Chinese Hamster Ovary (CHO) cell line.
　【承認】FDA申請=、FDA承認=2-Jul-2002(脊椎固定術処置)　、FDA承認=30-Apr-2004(急性開放脛骨骨幹部骨折の治療)　、FDA承認=9-Mar-2007(抜歯後骨欠損) ;　【製剤】INFUSE Bone Graft consists of two parts - a solution containing rhBMP-2 (recombinant human Bone Morphogenetic Protein 2) and the ACS (absorbable collagen sponge). The protein is a manufactured (genetically engineered) version of a natural protein normally found in small quantities in the body.　【適応】1)[整外](l4-s1から1つのレベルで椎間板変性症(ddd)の骨格が成熟した患者における脊椎固定術処置)indicated for spinal fusion procedures in skeletally mature patients with degenerative disc disease (ddd) at one level from l4-s1　2)[整外](切な傷処置後の髄内釘固定術で安定化させた急性開放脛骨骨幹部骨折の治療) indicated for treating acute, open tibial shaft fractures that have been stabilized with im nail fixation after appropriate wound management.　3)[歯科](抜歯窩治癒過程に伴う骨欠損に対する上顎洞底挙上術および局所的な歯槽堤形成術で自家骨移植の代替) indicated as an alternative to autogenous bone graft for sinus augmentations, and for localized alveolar ridge augmentations for defects associated with extraction sockets　【用法用量】
　【作用】Dibotermin alfa is an osteoinductive protein that results in the induction of new bone tissue at the site of implantation. Dibotermin alfa binds to receptors on the surface of mesenchymal cells and causes cells to differentiate into cartilage- and bone-forming cells. The differentiated cells form trabecular bone as the matrix is degraded, with vascular invasion evident at the same time. The bone formation process develops from the outside of the implant towards the center until the entire InductOs implant is replaced by trabecular bone.　【特徴】
　【製品情報】INFUSE BoneGraft.com　【添付文書】INFUSE_tibia　　
【EU】InductOs INN: dibotermin alfa[Wyeth]MA=9 September 2002　【製剤～EU】One vial contains 12 mg dibotermin alfa*. After reconstitution, InductOs contains 1.5 mg/ml dibotermin alfa　【適応～EU】InductOs is indicated for single-level (L4 - S1) anterior lumbar spine fusion as a substitute for autogenous bone graft in adults with degenerative disc disease who have had at least 6 months of nonoperative treatment for this condition. InductOs is indicated for the treatment of acute tibia fractures in adults, as an adjunct to standard care using open fracture reduction and intramedullary nail fixation.　【用法用量～EU】　【製品情報～EU】　【添付文書～EU】InductOs-PI
　【日本】YM484[アステラス製薬] P2中止？　【その他】

Harvesting of autogenous bone, most commonly from the iliac crest, for use as the interbody graft in spinal fusion procedures has been standard practice, but is associated with a high rate of morbidity, including graft site pain, infection, fracture, bleeding and damage to the femoral nerve. Use of recombinant human bone morphogenetic protein (rhBMP-2; Infuse Bone Graft － Medtronic) was first approved by the FDA in 2002 for single-level anterior lumbar spinal fusion in adults with degenerative disc disease who had not responded to at least 6 months of nonoperative treatment. Now it has also been approved for treatment of open tibial fractures and for use in oral and maxillofacial bone grafting procedures.

The device consists of three components spilt among two parts -- [part 1] a metallic tapered spinal fusion cage (known as the LT-CAGE Lumbar Tapered Fusion Device); and [part 2] a bone graft substitute (InFUSE Bone Graft) which consists of a genetically-engineered human cytokine (rhBMP-2) and a carrier/scaffold for the cytokine (manufactured from bovine [cow] Type I collagen), that is placed inside of the fusion cage. The fusion cage component maintains the spacing and temporarily stabilizes the diseased region of the spine, while the InFUSE Bone Graft component is used to form bone which would permanently stabilize (fuse) this portion of the spine. The InFUSE Bone Graft component is used instead of the patient’s own bone (autograft bone).

The device consists of three components split among two parts: a metallic tapered spinal fusion cage (known as the LT-CAGE lumbar tapered fusion device) and a bone graft substitute (known as the InFUSE Bone Graft). The InFUSE Bone Graft consists of a genetically engineered human protein (rhBMP-2) and a carrier/scaffold for the protein (manufactured from bovine [cow] Type 1 collagen) that are placed inside the fusion cage.

The fusion cage maintains the spacing and temporarily stabilizes the diseased region of the spine, while the InFUSE Bone Graft is used to form bone that would permanently stabilize (fuse) this portion of the spine.

The InFUSE Bone Graft component is used instead of the patient's own bone (autograft bone). Device labeling explicitly states that the components are only to be used as a single system and that the InFUSE Bone Graft should not be used alone for this or other purposes.

FDA based its decision to approve the InFUSE Bone Graft/LT-CAGE lumbar tapered fusion device on the results of a clinical study that demonstrated the use of this device is safe and effective for promoting spinal fusion. The study also showed that the device is as safe and as effective as the same fusion cage component filled with the autograft bone. Both the InFUSE Bone Graft/LT-CAGE device and the same fusion cage component filled with the autograft bone produced fusion in approximately 90% of patients.

The study was performed at multiple sites and consisted of a randomized arm which included 143 patients who were given the InFUSE Bone Graft/LT-CAGE device and 136 patients who were treated with the cage and standard bone graft. Another 134 patients were enrolled in a non-randomized study arm and also received the new device. The primary study endpoint was the rate of spinal fusion at 24 months.

The InFUSE Bone Graft/LT-CAGE lumbar tapered fusion device should not be used if patients are pregnant or are suspected to be pregnant since potential adverse effects of the genetically engineered human protein (rhBMP-2) on a developing fetus are currently not well understood.

The other risks associated with the use of the device are those normally associated with spinal surgery, which were not seen in greater numbers than expected in the clinical trial, and the potential for exuberant bone formation. The manufacturer of the device, Medtronic Sofamor Danek, of Memphis, Tenn., will monitor for any long-term immunological or other side effects that may be associated with the use of the device.

It is estimated that more than 350,000 bone grafting procedures to generate or regenerate bone in sinus augmentations and localized alveolar ridge augmentations for defects associated with extraction sockets are performed in the United States each year. Autogenous bone grafts, or bone harvested from other parts of the patient such as the tibia (shin), ilium (hip) or chin, are currently the standard grafting procedure used for these patients. INFUSE Bone Graft offers surgeons and their patients an alternative to autogenous bone grafting, possibly reducing patients’ pain, limiting scarring and reducing surgical time. INFUSE Bone Graft is also an alternative for bone grafting procedures that do not commonly use autogenous bone grafts such as for alveolar ridge augmentation associated with extraction site procedures.

INFUSE Bone Graft is recombinant human bone morphogenetic protein-2 (rhBMP-2) applied to an absorbable collagen sponge carrier. The purpose of the protein, which occurs naturally in the body, is to stimulate bone formation. It has been previously approved by the FDA for use in certain lumbar spine fusion and tibial fracture repair procedures. Implanted into a bone-deficient site, INFUSE Bone Graft works with the body’s own biology to induce normal bone formation.

“Patients come to see us with a multitude of problems and it’s our job to help patients discover methods to achieve their goals,” said Daniel Spagnoli, Ph.D., DDS, an oral and maxillofacial surgeon with University Oral and Maxillofacial Surgery in Charlotte, North Carolina. “When we talk to an individual, we have to think about more than the structural problem. We also consider the psychological and social aspects of missing teeth. INFUSE Bone Graft encourages bone growth to make it possible for them to have the corrective dental work that gives my patients a chance to have confidence, to feel good about their smile, to function well and to be able to enjoy a meal,” he added.

FDA approval for the selected use of INFUSE Bone Graft for certain oral maxillofacial and dental regeneration applications was based on five clinical studies involving 312 patients. This is the largest amount of clinical trial data for any similar product to date. In 2005, two of the studies supporting INFUSE Bone Graft approval were published in the journals of the professional associations of Oral and Maxillofacial Surgeons and Periodontists. Each study won the highest peer-granted awards of the respective professional groups, the Daniel M. Laskin Award and the E. Bud Tarrson Research Award, for the best clinical research paper of the year.

“I know of no other studies on any oral maxillofacial applications that had such rigorous testing. INFUSE Bone Graft (rhBMP-2/ACS) has the most comprehensive, multi-centered, randomized Level I clinical data of any bone growing protein currently available,” said Gilbert Triplett, Ph.D., DDS, chairman of the Dentistry Department at Baylor University Medical Center in Dallas.

Medtronic expects to have product available for surgeons trained in the indicated procedures by March 26. Patients and surgeons can learn more about the uses of INFUSE Bone Graft at www.infusebonegraft.com.

"This unique protein represents a breakthrough in orthopedic surgery as it can help improve fracture healing, while reducing the chances of infection," says Joseph Camardo, M.D., Senior Vice President of Global Medical Affairs and Medical Director for Wyeth Pharmaceuticals North America. "It clearly represents a novel approach to orthopedic surgeons facing a serious tibia fracture."

Recombinant human Bone Morphogenetic Protein-2 (rhBMP-2, or dibotermin alfa), a recombinant version of a naturally occurring human protein, was discovered and developed by Genetics Institute, now part of Wyeth. The protein is manufactured at a Wyeth biopharmaceutical facility in Andover, Massachusetts.

The data package Wyeth submitted to the FDA was based on one of the largest orthopedic fracture clinical trials ever conducted. The use of rhBMP-2/ACS 1.5 mg/mL in more than 400 patients during surgery, significantly improved the probability of fracture healing as evidenced by a reduced need for secondary procedures to promote fracture healing, when compared to the standard of care, fracture repair using an intramedullary nail.

In 2002, the European Commission approved the Marketing Authorization Application (MAA) for rhBMP-2/ACS for use in the treatment of acute tibia fractures in adults in the European Union (EU). Marketed under the name InductOs^(TM), this product was introduced in the EU in July 2003.

Medtronic Sofamor Danek (MSD) will be marketing the product for tibia fractures, while purchasing the rhBMP-2 from Wyeth. Wyeth will receive royalties and milestone payments from MSD.

Wyeth and MSD reached agreement to expand Medtronic’s marketing rights for rhBMP-2/ACS in the United States, Canada, Australia, Latin America and other countries, for spine and tibia fracture indications. Medtronic will also have global marketing rights for the tibia fracture indication.

rhBMP-2/ACS must be applied within 14 days after the initial fracture. Like all implanted medical devices, rhBMP-2/ACS may have side effects. The most frequent side effects included: abnormal healing at the surgical site; abnormal lab tests which included those related to pancreas and liver function, anemia, and decreased concentrations of calcium and potassium; constipation; nausea and vomiting; allergic reactions at the surgical site; infections at the surgical site; local and surgical site inflammation; altered mental status; altered sensations at the surgical site; and respiratory difficulties.

Some patients in the clinical trial who were treated with rhBMP-2/ACS 1.5 mg/mL had an antibody response to either rhBMP-2 (9 patients) or the ACS (29 patients). Because of the small numbers of patients who developed antibodies, it was not possible to determine if there was a connection between the antibody formation and the need for additional treatment to heal their fracture.

Trade Name	Applicant	PMA Number	Decision Date
INFUSE BONE GRAFT	medtronic sofamor da	P000054 S019	01/20/2010
[整外]Approval for an additional supplier of bovine achilles tendon for the manufacture of the absorbable collagen sponge (acs) component of the infuse bone graft.
INFUSE BONE GRAFT/LT- CAGE LUMBAR TAPERED FUSION DEVICE	medtronic sofamor da	P000058 S030	01/20/2010
invertebral lumbar device[整外]Approval for an additional supplier of bovine achilles tendon for the manufacture of the absorbable collagen sponge (acs) component of the infuse bone graft.
INFUSE BONE GRAFT	medtronic inc.	P050053 S010	01/20/2010
[歯科]Approval for an additional supplier of bovine achilles tendon for the manufacture of the absorbable collagen sponge (acs) component of the infuse bone graft.
INFUSE BONE GRAFT	medtronic inc.	P050053 S013	01/14/2010
[歯科]製法変更Approval for the removal of ellmanACs assay and sds-page silver stain tests from the rhbmp-2 drug substance release specification
INFUSE BONE GRAFT	medtronic sofamor da	P000054 S023	01/14/2010
[整外]製法変更Approval for the removal of ellmanACs assay and sds-page silver stain tests from the rhbmp-2 drug substance release specification
INFUSE BONE GRAFT/LT-CAGE LUMBAR TAPERED FUSION DEVICE	medtronic sofamor da	P000058 S034	01/14/2010
[整外]製法変更Approval for the removal of ellmanACs assay and sds-page silver stain tests from the rhbmp-2 drug substance release specification.
INFUSE BONE GRAFT	medtronic sofamor da	P000054 S022	10/21/2009
[整外]製法変更Approval for a change to the kitting and storage location for infuse@� bone graft and is indicated for treating acute, open tibial shaft fractures that have been stabilized with im nail fixation after appropriate wound management, an alternative to autogenous bone graft for sinus augmentations, and for localized alveolar ridge augmentations for defects associated with extraction sockets, and for spinal fusion procedures in skeletally mature patients with degenerative disc disease at one level from l4-s1.
INFUSE BONE GRAFT/LT-CAGE LUMBAR TAPERED FUSION DEVICE	medtronic sofamor da	P000058 S033	10/21/2009
invertebral lumbar device[整外]製法変更Approval for a change to the kitting and storage location for infuse@� bone graft and is indicated for treating acute, open tibial shaft fractures that have been stabilized with im nail fixation after appropriate wound management, an alternative to autogenous bone graft for sinus augmentations, and for localized alveolar ridge augmentations for defects associated with extraction sockets, and for spinal fusion procedures in skeletally mature patients with degenerative disc disease at one level from l4-s1.
INFUSE BONE GRAFT	medtronic inc.	P050053 S012	10/21/2009
[歯科]製法変更Approval for a change to the kitting and storage location for infuse@� bone graft and is indicated for treating acute, open tibial shaft fractures that have been stabilized with im nail fixation after appropriate wound management, an alternative to autogenous bone graft for sinus augmentations, and for localized alveolar ridge augmentations for defects associated with extraction sockets, and for spinal fusion procedures in skeletally mature patients with degenerative disc disease at one level from l4-s1
INFUSE BONE GRAFT/LT-CAGE LUMBAR TAPERED FUSION DEVICE	medtronic sofamor da	P000054 S021	05/13/2009
[整外]ラベル変更Approval for a modification to the package inserts. Specifically, adding text to one of the warnings to address aes and potential surgical interventions associated with improper use of the rhbmp-2/acs components of the products.
INFUSE BONE GRAFT/LT-CAGE LUMBAR TAPERED FUSION DEVICE	medtronic sofamor da	P000058 S032	05/13/2009
[整外]ラベル変更Approval for a modification to the package inserts. Specifically, adding text to one of the warnings to address aes and potential surgical interventions associated with improper use of the rhbmp-2/acs components of the products.
INFUSE BONE GRAFT	medtronic sofamor da	P000054 S020	02/20/2009
[整外]包装変更Approval for changes in the exterior cartons used to ship one or more units of infuse bone graft.
INFUSE BONE GRAFT/LT-CAGE LUMBER TAPERED FUSION DEVICE	medtronic sofamor da	P000058 S031	02/20/2009
[整外]包装変更Approval for changes in the exterior cartons used to ship one or more units of infuse bone graft.
INFUSE BONE GRAFT	medtronic inc.	P050053 S011	02/20/2009
[歯科]包装変更Approval for changes in the exterior cartons used to ship one or more units of infuse bone graft.
INFUSE BONE GRAFT	medtronic sofamor da	P000054 S017	12/04/2008
[整外]製法変更Approval for a change in the specific activity specification range of dibotermin alfa drug substance and drug product.
INFUSE BONE GRAFT/LT-CAGE LUMBAR TAPERED FUSION DEVICE	medtronic sofamor da	P000058 S028	12/04/2008
[整外]製法変更Approval for a change in the specific activity specification range of dibotermin alfa drug substance and drug product
INFUSE BONE GRAFT	medtronic inc.	P050053 S006	12/04/2008
[歯科]製法変更Approval for a change in the specific activity specification range of dibotermin alfa drug substance and drug product.
INFUSE BONE GRAFT	medtronic sofamor da	P000054 S018	11/24/2008
[整外]製法変更Approval for additional treatment processing vessels, upgrades to process equipment and automation of a test method.
INFUSE BONE GRAFT / LT-CAGE LUMBAR TAPERED FUSION DEVICE	medtronic sofamor da	P000058 S029	11/24/2008
[整外]製法変更Approval for additional treatment processing vessels, upgrades to process equipment and automation of a test method.
INFUSE BONE GRAFT	medtronic inc.	P050053 S009	11/24/2008
[歯科]製法変更Approval for additional treatment processing vessels, upgrades to process equipment and automation of a test method.
INFUSE BONE GRAFT	medtronic sofamor da	P000054 S015	08/15/2008
[整外]製法変更Approval for a manufacturing site located at integra neurosciences pr, inc. , anasco, puerto rico, and a sterilizing site at steritech, inc. , salinas, puerto rico.
INFUSE BONE GRAFT/LT-CAGE LUMBAR TAPERED FUSION DEVICE	medtronic sofamor da	P000058 S026	08/15/2008
[整外]製造所変更Approval for a manufacturing site located at integra neurosciences pr, inc. , anasco, puerto rico, and a sterilizing site at steritech, inc. , salinas, puerto rico.
INFUSE BONE GRAFT	medtronic inc.	P050053 S005	08/15/2008
[歯科]製造所変更Approval for a manufacturing site located at integra neurosciences pr, inc. , anasco, puerto rico, and a sterilizing site at steritech, inc. , salinas, puerto rico.
INFUSE BONE GRAFT	medtronic inc.	P050053 S008	05/13/2008
[歯科]ラベル変更Approval for labeling modifications to address warnings about improper preparation of infuse bone graft and overfilling of bone defects.
INFUSE BONE GRAFT/LT-CAGE LUMBAR TAPERED FUSION DEVICE	medtronic sofamor da	P000058 S027	03/21/2008
[整外]ラベル変更Approval for the following modifications to the package insert: 1) inclusion of warnings related to localized, transient bone resorption and possible nerve compression due to ectopic bone formation prompted by a labeling modification required by the eu as a result of an analysis of reported adverse events; 2) inclusion of clinical and adverse event data resulting from the clinical post approval study; 3) inclusion of a warning related to adverse events potentially associated with over stuffing the scaffold component into a small volume or hyperconcentrating the recombinant human protein component; 4) inclusion of references to previously approved xs and xxs kits; and 5) strengthening the language stating that the components of the product may only be used together and not with other devices or components, e. G. , scaffolds other than the acs.
INFUSE BONE GRAFT	medtronic sofamor da	P000054 S016	03/17/2008
[整外]ラベル変更Approval for inclusion of a warning related to localized, transient bone resorption in the package insert. The inclusion of this additional warning was prompted by a labeling modification required by the eu as a result of an analysis of reported adverse events.
INFUSE BONE GRAFT	medtronic inc.	P050053 S001	03/06/2008
[歯科]design/components/specifications等の変更Approval for the addition of the xs and xxs infuse bone graft kits to the approved dental bone grafting material.
INFUSE BONE GRAFT	medtronic inc.	P050053 S007	02/14/2008
[歯科]製法変更Change in test methodology for the device.
INFUSE BONE GRAFT	medtronic sofamor da	P000054 S013	01/14/2008
[整外]製法変更Approval for the addition of a new validated cross-linking chamber.
INFUSE BONE GRAFT/LT-CAGE LUMBAR TAPERED FUSION DEVICE	medtronic sofamor da	P000058 S025	01/14/2008
invertebral lumbar device[整外]製法変更Approval for the addition of a new validated cross-linking chamber
INFUSE BONE GRAFT	medtronic inc.	P050053 S004	01/14/2008
[歯科]製法変更Approval for the addition of a new validated cross-linking chamber.
INFUSE BONE GRAFT	medtronic sofamor da	P000054 S009	12/21/2007

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S020	12/21/2007

INFUSE BONE GRAFT/ LT-CAG	medtronic sofamor da	P000058 S022	12/20/2007

INFUSE BONE GRAFT	medtronic sofamor da	P000054 S011	10/05/2007

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S023	10/05/2007

INFUSE BONE GRAFT	medtronic inc.	P050053 S002	10/05/2007

INFUSE BONE GRAFT	medtronic sofamor da	P000054 S010	07/03/2007

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S021	07/03/2007

INFUSE BONE GRAFT	medtronic sofamor da	P000054 S008	03/23/2007

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S019	03/23/2007

INFUSE BONE GRAFT	medtronic inc.	P050053	03/09/2007
[歯科]Approval for the infuse bone graft. The device is indicated as an alternative to autogenous bone graft for sinus augmentations, and for localized alveolar ridge augmentations for defects associated with extraction sockets./装置は、抜歯窩治癒過程に伴う骨欠損に対する上顎洞底挙上術および局所的な歯槽堤形成術で自家骨移植の代替としての適応症。
INFUSE BONE GRAFT	medtronic sofamor da	P000054 S003	08/22/2005

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S014	08/22/2005

INFUSE BONE GRAFT	medtronic sofamor da	P000054 S004	04/20/2005

INFUSE BONE GRAFT	medtronic sofamor da	P000054 S005	04/20/2005

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S009	04/20/2005

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S016	04/20/2005

INFUSE BONE GRAFT	medtronic sofamor da	P000054 S006	03/11/2005

INFUSE BONE-GRAFT/LT-CAGE	medtronic sofamor da	P000058 S017	03/11/2005

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S015	02/04/2005

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S005	12/27/2004

INFUSE BONE GRAFT	medtronic sofamor da	P000054 S002	08/09/2004

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S002	07/29/2004

INFUSE BONE GRAFT	medtronic sofamor da	P000054 S001	06/10/2004

INFUSE BONE GRAFT-LT-CAGE	medtronic sofamor da	P000058 S010	06/10/2004

INFUSE BONE GRAFT	medtronic sofamor da	P000054	04/30/2004
[整外]Approval for the infuse bone graft. The device is indicated for treating acute, open tibial shaft fractures that have been stabilized with im nail fixation after appropriate wound management. Infuse bone graft must be applied within 14 days after the initial fracture. Prospective patients should be skeletally mature. /装置は、適切な傷処置後の髄内釘固定術で安定化させた急性開放脛骨骨幹部骨折の治療を適応とする。　Infuse bone graft は骨折の14日以内に用いる。　予定の患者は、骨格上成熟いているべきである。
INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S008	04/16/2004

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S007	03/30/2004

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S004	12/01/2003

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S006	09/17/2003

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S003	06/24/2003

INFUSE BONE GRAFT/LT-CAGE	medtronic sofamor da	P000058 S001	10/04/2002

INFUSE BONE GRAFT/LT-CAGE LUMBAR TAPERED FUSION DEVICE	medtronic sofamor da	P000058	07/02/2002
[整外]Approval for the infuse bone graft/lt-cage lumbar tapered fusion device. This device is indicated for spinal fusion procedures in skeletally mature patients with degenerative disc disease (ddd) at one level from l4-s1. Ddd is defined as discogenic back pain with degeneration of the disc confirmed by patient history, function deficit and/or neurological deficit and radiographic studies. These ddd patients may also have up to grade i spondylolisthesis at the involved level. Infuse bone graft/lt-cage devices are to be implanted via an anterior open or an anterior laparoscopic approach. Patients receiving the infuse bone graft/lt-cage lumbar tapered fusion device should have had at least six months of nonoperative treatment prior to treatment with the infuse bone graft/lt-cage device. /本承認はthe infuse bone graft/lt-cage lumbar tapered fusion device(注入骨移植/ lt -ケージ腰部テープ融合装置)に関するもの。　この装置は、l4-s1から1つのレベルで椎間板変性症(ddd)の骨格が成熟した患者における脊椎固定術処置の適応となる。　Dddは、患者歴、機能損傷および(または)神経学上の損傷およびX線写真術の研究によって確認された椎間板変性を伴うdiscogenicな腰背痛として定義される。　これらのddd患者はまた罹患レベルで脊椎分離すべり症を持っているかもしれない。　Infuse bone graft/lt-cage devicesは腹腔鏡下前開または前方のアプローチによって移植する。　the infuse bone graft/lt-cage lumbar tapered fusion deviceを受ける患者は、治療に先立って少なくとも6ヶ月の外科手術を行わないこと。

Among the less frequent side effects, some patients (6 percent) treated with rhBMP-2/ACS had abnormal bone healing at the fracture site.

Wyeth (NYSE: WYE) and Yamanouchi Europe B.V., the European organization of Yamanouchi Pharmaceutical Co., Ltd., today announced that the European Commission has approved a Marketing Authorization Application (MAA) for InductOs(TM) (rhBMP-2/ACS) for use in the treatment of acute tibia fractures in adults, as an adjunct to standard care, using open fracture reduction and intramedullary nail fixation. Wyeth and Yamanouchi Europe B.V., who are partners for the development and marketing of InductOs(TM) in Europe, expect the product to be available in early 2003.

Wyeth (NYSE: WYE) today announced that the FDA has approved rhBMP-2/ACS (recombinant human Bone Morphogenetic Protein-2/Absorbable Collagen Sponge), a novel protein device that enhances bone healing, for use in the treatment of acute, open tibia shaft fractures in adults. The device consists of rhBMP-2 placed on an absorbable collagen sponge. It will be used after stabilization with an intramedullary nail (a metal rod inserted into the bone) by orthopedic surgeons, after appropriate wound management.

これまで、日本におけるrhBMP-2製剤の臨床開発は山之内製薬が進めてきており、適応症の絞込みとともに今後の商業化方針などについて検討を続けてきた。他方、欧州では山之内製薬の欧州子会社とWyeth（米国ニュージャージー州）の欧州子会社との間で設立したパートナーシップが、脛骨の開放骨折を適応症として「InductOsTM」の商品名で2002年9月に承認を取得。その後、MDTの欧州子会社であるメドトロニックヨーロッパに独占的な販売促進権が付与されている。このように欧州において提携関係にある両社は、日本においてもrhBMP-2の製品価値最大化を図るための商業化方針につき協議を続け、このたびの契約締結に至ったものである。

MDTは、埋め込み型医療機器等を取扱う世界有数の医療機器メーカーであり、製品の販売促進に専門的な知識や経験を有している。米国においてはrhBMP-2を脊椎変性疾患の適応症で既に販売しているほか、欧州でも「InductOsTM」の発売準備が進められている。

なお、rhBMP-2はWyethにより創製され、Wyethと山之内製薬により共同開発された。原体はWyethが製造している。

Determination of bisphosphonate active pharmaceutical ingredients in pharmaceuticals and biological material: A review of analytical methods.

J Pharm Biomed Anal. 2008 Jul 1. [Epub ahead of print]

PMID: 18599247 [PubMed - as supplied by publisher]

2: D'Eufemia P, Finocchiaro R, Celli M, Zambrano A, Tetti M, Villani C, Persiani P, Mari E, Zicari A.

High levels of serum prostaglandin E2 in children with osteogenesis imperfecta are reduced by neridronate treatment.

Pediatr Res. 2008 Feb;63(2):203-6.

PMID: 18091347 [PubMed - indexed for MEDLINE]

3: Rugolotto S, Monti E, Carli M, Pietrobelli A, Antoniazzi F, Tato L.

Pulmonary function tests in an infant with osteogenesis imperfecta and early biphosphonate treatment.

Acta Paediatr. 2007 Dec;96(12):1856-7. No abstract available.

PMID: 18001342 [PubMed - indexed for MEDLINE]

4: Quarta L, Corrado A, Melillo N, Trotta A, Scotto G, d'Onofrio F, Santoro N, Cantatore FP.

Combined effect of Neridronate and specific antibiotic therapy in a case of tuberculous spondylodiscitis.

Rheumatol Int. 2008 Mar;28(5):495-8. Epub 2007 Sep 26.

PMID: 17899089 [PubMed - in process]

5: Merlotti D, Gennari L, Martini G, Valleggi F, De Paola V, Avanzati A, Nuti R.

Comparison of different intravenous bisphosphonate regimens for Paget's disease of bone.

J Bone Miner Res. 2007 Oct;22(10):1510-7.

PMID: 17605632 [PubMed - indexed for MEDLINE]

6: Nicolin V, Bareggi R, Baldini G, Bortul R, Martinelli B, Narducci P.

Effects of neridronic acid on osteoclasts derived by physiological dual-cell cultures.

Acta Histochem. 2007;109(5):397-402. Epub 2007 Jun 15.

PMID: 17574655 [PubMed - indexed for MEDLINE]

7: Saviola G, Abdi Ali L, Shams Eddin S, Manfredi M, Benucci M.

Can neridronate be effective in the treatment of osteoporosis in hypogonadic men?

Clin Exp Rheumatol. 2007 Mar-Apr;25(2):340. No abstract available.

PMID: 17543167 [PubMed - indexed for MEDLINE]

8: Corrado A, Quarta L, Errico S, Cantatore FP.

Successful treatment of avascular bone necrosis of the knee with neridronate: a case report.

Rheumatol Int. 2007 Jul;27(9):891-3. Epub 2007 Feb 7. No abstract available.

PMID: 17285278 [PubMed - indexed for MEDLINE]

9: D'Eufemia P, Finocchiaro R, Zambrano A, Tetti M, Ferrucci V, Celli M.

Reduction of plasma taurine level in children affected by osteogenesis imperfecta during bisphosphonate therapy.

Biomed Pharmacother. 2007 May;61(4):235-40. Epub 2006 Dec 29.

PMID: 17275249 [PubMed - indexed for MEDLINE]

10: Spreafico A, Frediani B, Capperucci C, Gambera D, Ferrata P, Baldi F, Chellini F, Niccolini S, Bocchi L, Marcolongo R.

[Anabolic effects and inhibition of interleukin 6 production induced by neridronate on human osteoblasts]

Reumatismo. 2006 Oct-Dec;58(4):288-300. Italian.

PMID: 17216018 [PubMed - indexed for MEDLINE]

11: Benhamou CL.

Effects of osteoporosis medications on bone quality.

Joint Bone Spine. 2007 Jan;74(1):39-47. Epub 2006 Nov 28. Review.

PMID: 17196423 [PubMed - indexed for MEDLINE]

12: Pittari G, Costi D, Raballo M, Maulucci L, Baroni MC, Mangoni M.

Intravenous neridronate for skeletal damage treatment in patients with multiple myeloma.

Acta Biomed. 2006 Aug;77(2):81-4.

PMID: 17172186 [PubMed - indexed for MEDLINE]

13: Casolaro M, Casolaro I, Spreafico A, Capperucci C, Frediani B, Marcolongo R, Margiotta N, Ostuni R, Mendichi R, Samperi F, Ishii T, Ito Y.

Novel therapeutic agents for bone resorption. Part 1. Synthesis and protonation thermodynamics of poly(amido-amine)s containing bis-phosphonate residues.

Biomacromolecules. 2006 Dec;7(12):3417-27.

PMID: 17154470 [PubMed - indexed for MEDLINE]

14: Ribatti D, Nico B, Mangieri D, Maruotti N, Longo V, Vacca A, Cantatore FP.

Neridronate inhibits angiogenesis in vitro and in vivo.

Clin Rheumatol. 2007 Jul;26(7):1094-8. Epub 2006 Nov 15.

PMID: 17106617 [PubMed - indexed for MEDLINE]

15: Antoniazzi F, Zamboni G, Lauriola S, Donadi L, Adami S, Tato L.

Early bisphosphonate treatment in infants with severe osteogenesis imperfecta.

J Pediatr. 2006 Aug;149(2):174-9.

PMID: 16887429 [PubMed - indexed for MEDLINE]

16: Ferlazzo V, Sferrazza C, Caccamo N, Di Fede G, Di Lorenzo G, D'Asaro M, Meraviglia S, Dieli F, Rini G, Salerno A.

In vitro effects of aminobisphosphonates on Vgamma9Vdelta2 T cell activation and differentiation.

Int J Immunopathol Pharmacol. 2006 Apr-Jun;19(2):309-17.

PMID: 16831298 [PubMed - indexed for MEDLINE]

17: Cacace E, Salis G, Ruggiero V, Perpignano G.

Systemic mast cell disease: a rare cause of osteoporosis.

Clin Exp Rheumatol. 2006 Mar-Apr;24(2):210. No abstract available.

PMID: 16762162 [PubMed - indexed for MEDLINE]

18: Benucci M, Dolenti S, Saviola G, Manfredi M.

[Modifications of markers of bone resorption in patients affected by glucocorticoid induced osteoporosis (GIOP) treated with neridronate]

Recenti Prog Med. 2006 Jan;97(1):24-7. Italian.

PMID: 16535926 [PubMed - indexed for MEDLINE]

19: Corrado A, Cantatore FP, Grano M, Colucci S.

Neridronate and human osteoblasts in normal, osteoporotic and osteoarthritic subjects.

Clin Rheumatol. 2005 Sep;24(5):527-34. Epub 2005 Aug 10.

PMID: 16091841 [PubMed - indexed for MEDLINE]

20: Muller S, Migianu E, Lecouvey M, Kraemer M, Oudar O.

Alendronate inhibits proliferation and invasion of human epidermoid carcinoma cells in vitro.

Anticancer Res. 2005 Jul-Aug;25(4):2655-60.

PMID: 16080508 [PubMed - indexed for MEDLINE]

21: Gatti D, Viapiana O, Lippolis I, Braga V, Prizzi R, Rossini M, Adami S.

Intravenous bisphosphonate therapy increases radial width in adults with osteogenesis imperfecta.

J Bone Miner Res. 2005 Aug;20(8):1323-6. Epub 2005 Mar 14.

PMID: 16007328 [PubMed - indexed for MEDLINE]

22: Cascella T, Musella T, Orio F Jr, Palomba S, Bifulco G, Nappi C, Lombardi G, Colao A, Tauchmanova L.

Effects of neridronate treatment in elderly women with osteoporosis.

J Endocrinol Invest. 2005 Mar;28(3):202-8. Erratum in: J Endocrinol Invest. 2005 May;28(5):IV.

PMID: 15952402 [PubMed - indexed for MEDLINE]

23: Miller PD.

Optimizing the management of postmenopausal osteoporosis with bisphosphonates: the emerging role of intermittent therapy.

Clin Ther. 2005 Apr;27(4):361-76. Review.

PMID: 15922811 [PubMed - indexed for MEDLINE]

24: Magno C, Anastasi G, Morabito N, Gaudio A, Maisano D, Franchina F, Gali A, Frisina N, Melloni D.

Preventing bone loss during androgen deprivation therapy for prostate cancer: early experience with neridronate.

Eur Urol. 2005 May;47(5):575-80; discussion 580-1.

PMID: 15826746 [PubMed - indexed for MEDLINE]

25: Gatti D, Antoniazzi F, Prizzi R, Braga V, Rossini M, Tato L, Viapiana O, Adami S.

Intravenous neridronate in children with osteogenesis imperfecta: a randomized controlled study.

J Bone Miner Res. 2005 May;20(5):758-63. Epub 2004 Dec 20.

PMID: 15824848 [PubMed - indexed for MEDLINE]

26: Morabito N, Gaudio A, Lasco A, Catalano A, Atteritano M, Trifiletti A, Anastasi G, Melloni D, Frisina N.

Neridronate prevents bone loss in patients receiving androgen deprivation therapy for prostate cancer.

J Bone Miner Res. 2004 Nov;19(11):1766-70. Epub 2004 Aug 23.

PMID: 15476575 [PubMed - indexed for MEDLINE]

27: Frediani B, Spreafico A, Capperucci C, Chellini F, Gambera D, Ferrata P, Baldi F, Falsetti P, Santucci A, Bocchi L, Marcolongo R.

Long-term effects of neridronate on human osteoblastic cell cultures.

Bone. 2004 Oct;35(4):859-69.

PMID: 15454093 [PubMed - indexed for MEDLINE]

28: La Montagna G, Malesci D, Tirri R, Valentini G.

Successful neridronate therapy in transient osteoporosis of the hip.

Clin Rheumatol. 2005 Feb;24(1):67-9. Epub 2004 Aug 19.

PMID: 15322945 [PubMed - indexed for MEDLINE]

29: Sartori L, Adami S, Filipponi P, Crepaldi G.

Injectable bisphosphonates in the treatment of postmenopausal osteoporosis.

Aging Clin Exp Res. 2003 Aug;15(4):271-83. Review.

PMID: 14661816 [PubMed - indexed for MEDLINE]

30: Braga V, Gatti D, Colapietro F, Battaglia E, Righetti D, Prizzi R, Rossini M, Adami S.

Intravenous intermittent neridronate in the treatment of postmenopausal osteoporosis.

Bone. 2003 Sep;33(3):342-5.

PMID: 13678775 [PubMed - indexed for MEDLINE]

31: Adami S, Gatti D, Colapietro F, Fracassi E, Braga V, Rossini M, Tato L.

Intravenous neridronate in adults with osteogenesis imperfecta.

J Bone Miner Res. 2003 Jan;18(1):126-30.

PMID: 12510813 [PubMed - indexed for MEDLINE]

32: Mazzantini M, Di Munno O, Metelli MR, Bulleri M, Giordani R.

Single infusion of neridronate (6-amino-1-hydroxyhexylidene-1,1-bisphosphonate) in patients with active rheumatoid arthritis: effects on disease activity and bone resorption markers.

Aging Clin Exp Res. 2002 Jun;14(3):197-201.

PMID: 12387527 [PubMed - indexed for MEDLINE]

33: Neves M, Gano L, Pereira N, Costa MC, Costa MR, Chandia M, Rosado M, Fausto R.

Synthesis, characterization and biodistribution of bisphosphonates Sm-153 complexes: correlation with molecular modeling interaction studies.

Nucl Med Biol. 2002 Apr;29(3):329-38.

PMID: 11929703 [PubMed - indexed for MEDLINE]

34: Adami S, Bevilacqua M, Broggini M, Filipponi P, Ortolani S, Palummeri E, Ulivieri F, Nannipieri F, Braga V.

Short-term intravenous therapy with Neridronate in Paget's disease.

Clin Exp Rheumatol. 2002 Jan-Feb;20(1):55-8.

PMID: 11892710 [PubMed - indexed for MEDLINE]

35: Hadjipavlou AG, Gaitanis LN, Katonis PG, Lander P.

Paget's disease of the spine and its management.

Eur Spine J. 2001 Oct;10(5):370-84. Review.

PMID: 11718191 [PubMed - indexed for MEDLINE]

36: Adami S, Braga V, Guidi G, Gatti D, Gerardi D, Fracassi E.

Chronic intravenous aminobisphosphonate therapy increases high-density lipoprotein cholesterol and decreases low-density lipoprotein cholesterol.

J Bone Miner Res. 2000 Mar;15(3):599-604.

PMID: 10750576 [PubMed - indexed for MEDLINE]

37: Gandolfi MG, Pugnaloni A, Mattioli-Belmonte M, Muzzarelli R, De Benedittis A, Mengucci P, Zucchini C, Tesei M, Caudarella R, Biagini G.

Osteoblast behaviour in the presence of bisphosphonates: ultrastructural and biochemical in vitro studies.

Clin Exp Rheumatol. 1999 May-Jun;17(3):327-33.

PMID: 10410266 [PubMed - indexed for MEDLINE]

38: Filipponi P, Cristallini S, Policani G, Casciari C, Gregorio F.

Paget's disease of bone: benefits of neridonate as a first treatment and in cases of relapse after clodronate.

Bone. 1998 Dec;23(6):543-8.

PMID: 9855463 [PubMed - indexed for MEDLINE]

39: Mian M, Benetti D, Aloisi R, Rosini S, Fantozzi R, Savarino L, Stea S, Donati ME, Paganetto G, Pizzoferrato A.

Effects of orally administered bisphosphonates on bone loss in a disuse osteopenia model involving the rat.

Clin Exp Rheumatol. 1996 Nov-Dec;14(6):619-24.

PMID: 8978956 [PubMed - indexed for MEDLINE]

40: Tobias JH, Laversuch CV, Wilson N, Robins SP.

Neridronate preferentially suppresses the urinary excretion of peptide-bound deoxypyridinoline in postmenopausal women.

Calcif Tissue Int. 1996 Nov;59(5):407-9.

PMID: 8849410 [PubMed - indexed for MEDLINE]

41: Tobias JH, Laversuch CJ, Chambers TJ, Gallagher AC.

Aminohexane bisphosphonate suppresses bone turnover in postmenopausal women more rapidly than oestrogen-gestagen therapy.

Br J Rheumatol. 1996 Jul;35(7):636-41.

PMID: 8670596 [PubMed - indexed for MEDLINE]

42: Mian M, Benetti D, Aloisi R, Rosini S, Fantozzi R.

Effects of bisphosphonate derivatives on macrophage function.

Pharmacology. 1994 Nov;49(5):336-42.

PMID: 7862746 [PubMed - indexed for MEDLINE]

43: O'Rourke NP, McCloskey EV, Rosini S, Coleman RE, Kanis JA.

Treatment of malignant hypercalcaemia with aminohexane bisphosphonate (neridronate).

Br J Cancer. 1994 May;69(5):914-7.

PMID: 8180023 [PubMed - indexed for MEDLINE]

44: Delmas PD, Chapuy MC, Edouard C, Meunier PJ.

Beneficial effects of aminohexane diphosphonate in patients with Paget's disease of bone resistant to sodium etidronate.

Am J Med. 1987 Aug;83(2):276-82.

PMID: 3113247 [PubMed - indexed for MEDLINE]

45: McCloskey EV, Yates AJ, Beneton MN, Galloway J, Harris S, Kanis JA.

Comparative effects of intravenous diphosphonates on calcium and skeletal metabolism in man.

Bone. 1987;8 Suppl 1:S35-41.

PMID: 2825741 [PubMed - indexed for MEDLINE]

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★1327-28★25/25-26★09.12.14/28★099★骨形成タンパク質（Infuse Bone Graft）/2p●MLリソース：骨形成不全症

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作成：2008.8.5　最終更新:2010.4.26　小菅博之

The Medical Letter日本語版
●追加メモ to 1327-28
On Drugs and Therapeutics

このページは［The Medical Letter日本語版］の補足データとして添付しています。　［The Medical Letter］は新薬の厳正な評価誌であり、ここに収録される製品は新しくＦＤＡ承認された新薬に対する評価を中心としています。

　企画意図の第一は、収録製品についての米国内・世界での背景情報です。　例えば、各製品の承認関連データ、競合品との、あるいは市場での位置づけ、疫学データなど。　第二は、日本での該当製品や市場の情報。　市場の主要製品売上、開発中の治験薬等。　調査項目としては、■製品■解説■データ■臨床ガイドラインなど■総説記事・文献■ニュース・トピックス■リンク■主要サイト

製品	億円 (2007)	単位	2008	2007	2006	2005	2004	2003	2002	2001	2000	1999	備考
●骨形成蛋白
rhBMP-2 [Wyeth]	352 (396)	$000	389,621(+8.6)	358,886(+16.5)	307,940(+30.5)	236,291(+43.0)	165,279	58,100	66,500				/[米特許]2014迄;骨形成誘導
米国内		$000	376,426(+7.4)	350,572(+15.4)	303,905(+29.4)	234,802(+42.8)	164,449	57,939
米国外		$000	13,195(+58.7)	8,314(+106.0)	4,035(+171.0)	1,489(+79.4)	830	161

Registered Name	Company	Status	Indication	備考
Alendronic acid	Istituto Gentili(Originator)/Gador(Originator)/Merck & Co(Licensee)	米申請準備	Osteogenesis imperfecta
		米

製品	組成	適応症	用法用量	備考
ヒューマトロープC6mg,C12mg[製造販売元／日本イーライリリー株式会社]Humatrope 発売2000年7月	1筒中ソマトロピン（遺伝子組換え）6.56mg,13.13mg	1)骨端線閉鎖を伴わない軟骨異栄養症（軟骨無形成症・軟骨低形成症）における低身長　2)骨端線閉鎖を伴わない下垂体性小人症　3)骨端線閉鎖を伴わないターナー症候群における低身長　4)成人成長ホルモン分泌不全症	[軟骨異栄養症]通常1週間に体重kg当たり、ソマトロピン（遺伝子組換え）として0.35mgを6～7回に分けて皮下に注射する。
ノルディトロピンS注5mg,10mg[製造販売元／ノボノルディスクファーマ株式会社]NORDITROPIN S 発売2000年7月	皮下注用1カートリッジ中ソマトロピン（遺伝子組換え）　5mg,10mg	1)骨端線閉鎖を伴わない軟骨異栄養症における低身長　2)骨端線閉鎖を伴わない下垂体性小人症　3)骨端線閉鎖を伴わないターナー症候群における低身長
ノルディトロピン　ノルディフレックス注5mg,10mg,15mg[製造販売元／ノボノルディスクファーマ株式会社]Norditropin NordiFlex 2004年7月[10mg]発売2006年7月[15mg]	皮下注用1カートリッジ中ソマトロピン（遺伝子組換え）　5mg,10mg	皮下注用1筒中ソマトロピン（遺伝子組換え）　5mg,10mg,15mg

整理番号	医療技術の名称	使用する医療機器の製品名等	対象疾患（処置等）	要望学会	海外での承認				適応疾患の重篤性	医療上の有用性
整理番号	医療技術の名称	使用する医療機器の製品名等	対象疾患（処置等）	要望学会	ＦＤＡ	米国承認年月	ＥＵ	ＥＵ承認年月	Ａ：疾病の致命率が高いＢ：疾病の致命率は低いが日常生活への著しい影響ありＣ：その他	Ａ：既存の方法なしＢ：欧米で普及かつ、及び既存の方法より優れてる影響ありＣ：その他
18	コラーゲンスポンジ複合体（骨補填材）	Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) /コラーゲンスポンジ・複合体(米国での製品名： Infuse Bone Graft)	脊椎変性疾患、脊椎変形、脊椎外傷、脊椎炎症性疾患等	日本整形外科学会	あり	2002,7	あり	2002,9外傷 2005,3脊椎	Ｂ	Ｂ

No.	提出者	成分名	販売名	要望内容（効能効果等の概略）	小児に関係
2	日本口腔外科学会	rhBＭＰ-2含有骨充填剤	ＩnＦＵＳＥ BoneGraft/InductOs	歯科インプラント前処置としてのサイナスリフト時の骨を誘導

APPLICATION NUMBER / DATE of APPROVAL	DEVICE TRADE NAME	COMPANY NAME CITY, STATE, & ZIP	DEVICE DESCRIPTION / INDICATIONS
●PMA Original Approvals
●PMA Supplemental Approvals
★October 2009 PMA Approvals
P000054/S022 10/21/09 135-Day	INFUSE Bone Graft@�	Medtronic Sofamor Danek, Inc.,Memphis, TN38132	Approval for a change to the kitting and storage location for INFUSE@� Bone Graft and is indicated for treating acute, open tibial shaft fractures that have been stabilized with IM nail fixation after appropriate wound management, an alternative to autogenous bone graft for sinus augmentations, and for localized alveolar ridge augmentations for defects associated with extraction sockets, and for spinal fusion procedures in skeletally mature patients with degenerative disc disease at one level from L4-S1.
P000058/S033 10/21/09 135-Day	INFUSE Bone Graft@�/LT-Cage Lumber Tapered Fusion Device	Medtronic Sofamor Danek, Inc. Memphis, TN38132	Approval for a change to the kitting and storage location for INFUSE@� Bone Graft and is indicated for treating acute, open tibial shaft fractures that have been stabilized with IM nail fixation after appropriate wound management, an alternative to autogenous bone graft for sinus augmentations, and for localized alveolar ridge augmentations for defects associated with extraction sockets, and for spinal fusion procedures in skeletally mature patients with degenerative disc disease at one level from L4-S1.
P050053/S012 10/21/09 135-Day	INFUSE Bone Graft@�	Medtronic Sofamor Danek, Inc.Memphis, TN38132	Approval for a change to the kitting and storage location for INFUSE@� Bone Graft and is indicated for treating acute, open tibial shaft fractures that have been stabilized with IM nail fixation after appropriate wound management, an alternative to autogenous bone graft for sinus augmentations, and for localized alveolar ridge augmentations for defects associated with extraction sockets, and for spinal fusion procedures in skeletally mature patients with degenerative disc disease at one level from L4-S1.
★February 2009 PMA Approvals
P000054/S020 2/20/09 Real-Time	INFUSEmV Bone Graft/LT-Cage Lumbar Tapered Fusion Device	Medtronic Sofamor Danek,Memphis , TN 38132	Approval for changes in the exterior cartons used to ship one or more units of INFUSE Bone Graft.
P000058/S031 2/20/09 Real-Time	InFusemV Bone Graft/LT-Cage Lumbar Tapered Fusion Device	Medtronic Sofamor Danek,Memphis , TN 38132	Approval for changes in the exterior cartons used to ship one or more units of InFuse Bone Graft.
P050053/S011 2/20/09 Real-Time	InFuse@� Bone Graft	Medtronic, Inc. Memphis , TN 38132	Approval for changes in the exterior cartons used to ship one or more units of InFuse Bone Graft.

ML	開催日	議題	備考
	2002.11.21	Wyeth BMP-2 Collagen Sponge For TIbial Fractures※キャンセル

($000)	2009	2008	2007	2006	2005	2004	2003	2002	2001	2000	1999	備考
rhBMP-2[旧W]		389,621(+8.6)	358,886(+16.5)	307,940(+30.5)	236,291(+43.0)	165,279	58,100	66,500				/[米特許]2014迄;骨形成誘導
米国内		376,426(+7.4)	350,572(+15.4)	303,905(+29.4)	234,802(+42.8)	164,449	57,939
米国外		13,195(+58.7)	8,314(+106.0)	4,035(+171.0)	1,489(+79.4)	830	161

(Eur 000)	2007	2006	2005	2004	2003	2002	2001
売上高	65,364	72,190.58	69,130.31	69,410.20

内Pharma	47,820[73.15%]	57,136.18	53,996.36	49,290.60	42,200	36,300	34,400
Manufacturing	12,880[19.72%]	11,846.84	12,277.79	15,207.90	12,600	10,700	10,700
Royalty&Down payment	4,660[7.13%]	3,207.56	1,856.16	4,911.70	12,000	7,600	13,950

EBITDA		7,640	8,961
EBIT		2,687.28	2,814.94	2,672.57
純利益		(639.24)	(1,017.69)	(478.72)
従業員数[連結]			369

製品名	薬効	ライセンス先	備考
alendronate(Alendros)	骨粗鬆症	米Merck & Co
Lyophilised bacterial lysates(Broncho Munal)		瑞O.M.
Calcium dobesilate(Doxium/Doxiproct Plus)		瑞O.M.
E.Coli Bacteria exts(Uro Munal)		瑞O.M.
diacerein(Fisiodar)		瑞Tran Bussan
aceclofenac(Gladio)	NSAIDs	西Almirall Prodesfarma
tecalcitol(Vellutan)		帝人
octopirox/sebomina/Norgel(Kourilles)		伊Farmaka
clotiazepam(Tienor)		伊Farmaka
lyophilised collagene(Condress)		伊Euroresearch
xibornol(Bornilene)		伊Euphar
clarithromycin(Soriclar)	マクロライド抗生物質	伊Abbott

製品名	成分	薬効	段階	備考
CL-I.A.	clodronate	変形性関節症	P3
Nerixia	neridronate	骨粗鬆症・Algodistrophy	P3
BTG1640	isoxazoline誘導体	不安症・パニック障害	P2
TALL 104	Human cytotoxic cell line	癌	P1
Combotox	MOAB-Anti-CD19 Toxin MOAB-Anti-CD22 Toxin	非ホジキンリンパ腫	P1
IMTOX 22	MOAB-Anti-CD22 Toxin	非ホジキンリンパ腫	P1