Novartis Pharmaceuticals Corporation

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East Hanover, NJ 07936

Appendix 4:\
ONJ in Clinical Studies

Zometa^®^ (zoledronic acid) Injection

and

Aredia^®^ (pamidronate disodium) Injection

Submitted: February 1, 2005

Oncologic Drugs Advisory Committee Meeting

March 4, 2005

Property of Novartis Pharmaceuticals Corporation\
All rights reserved\
**Available for public disclosure without redaction**

###### Table 1 - Pivotal bone metastases studies included in the search for terms related to ONJ using MedDRA terms

  ------------------- ---------------- ------------ ------------ -------- -------- -------- --------------- -----------
  **Phase I\          **Indication**   **No.        **Study      **Zol\   **Zol\   **Zol\   **Zol/Aredia\   **Aredia\
  Study No.**                          patients**   duration**   0.4/8    2/8 mg** 4/8 mg** 90 mg**         90 mg**
                                                                 mg**                                       

  CZOL4460007+E^1)^   BCa, MM          288          9mo/21mo     62       62       59       30              75
  ------------------- ---------------- ------------ ------------ -------- -------- -------- --------------- -----------

+----------------+--------+-----+------+------+------+------+------+
| **Phase III    | **     | **  | **S  | **T  |      |      |      |
| randomized\    | Indica | No. | tudy | reat |      |      |      |
| Study No.**    | tion** | p   | du   | ment |      |      |      |
|                |        | ati | rati | Gr   |      |      |      |
|                |        | ent | on** | oups |      |      |      |
|                |        | s** |      | (No. |      |      |      |
|                |        |     |      | pat  |      |      |      |
|                |        |     |      | ient |      |      |      |
|                |        |     |      | s)** |      |      |      |
+----------------+--------+-----+------+------+------+------+------+
|                |        |     |      | **   | *    | *    | **P  |
|                |        |     |      | Zol\ | *Zol | *Are | lace |
|                |        |     |      | 4    | 8    | dia\ | bo** |
|                |        |     |      | mg** | mg/\ | 90   |      |
|                |        |     |      |      | 4    | mg** |      |
|                |        |     |      |      | mg** |      |      |
+----------------+--------+-----+------+------+------+------+------+
| ZOMETA studies |        |     |      |      |      |      |      |
+----------------+--------+-----+------+------+------+------+------+
| CZOL4460010+E  | MM,    | 1   | 25   | 564  | 526  | 558  | NA   |
|                | BCa    | 648 | mo   |      |      |      |      |
+----------------+--------+-----+------+------+------+------+------+
| CZOL4460011+E  | Solid  | 773 | 21   | 257  | 266  | NA   | 250  |
|                | tumors |     | mo   |      |      |      |      |
|                | (      |     |      |      |      |      |      |
|                | except |     |      |      |      |      |      |
|                | BC     |     |      |      |      |      |      |
|                | a+PCa) |     |      |      |      |      |      |
+----------------+--------+-----+------+------+------+------+------+
| CZOL4460039+E  | PCa    | 643 | 24   | 214  | 221  | NA   | 208  |
|                |        |     | mo   |      |      |      |      |
+----------------+--------+-----+------+------+------+------+------+
| CZOL4460704    | PCa    | 405 | 38.7 | 49   | 155  | NA   | 201  |
|                |        |     | mo   |      |      |      |      |
|                |        |     | ^2)^ |      |      |      |      |
+----------------+--------+-----+------+------+------+------+------+
| Total Zometa   |        | 3,  |      | 1    | 1    | 558  | 659  |
| studies        |        | 469 |      | ,084 | ,168 |      |      |
+----------------+--------+-----+------+------+------+------+------+
|                |        |     |      |      |      |      |      |
+----------------+--------+-----+------+------+------+------+------+
| AREDIA studies |        |     |      |      |      |      |      |
+----------------+--------+-----+------+------+------+------+------+
| CARD233AP12    | MM     | 392 | 21   | NA   | NA   | 203  | 189  |
|                |        |     | mo   |      |      |      |      |
+----------------+--------+-----+------+------+------+------+------+
| CARD233AP18    | BCa    | 371 | 24   | NA   | NA   | 182  | 189  |
|                |        |     | mo   |      |      |      |      |
+----------------+--------+-----+------+------+------+------+------+
| CARD233AP19    | BCa    | 382 | 24   | NA   | NA   | 185  | 197  |
|                |        |     | mo   |      |      |      |      |
+----------------+--------+-----+------+------+------+------+------+
| **Total Aredia |        | **1 |      |      |      | **5  | **5  |
| studies**      |        | ,14 |      |      |      | 70** | 75** |
|                |        | 5** |      |      |      |      |      |
+----------------+--------+-----+------+------+------+------+------+
| **TOTAL (Z+A   |        | **4 |      | *    | *    | *    | *    |
| Phase III)**   |        | ,61 |      | *1,0 | *1,1 | *1,1 | *1,2 |
|                |        | 4** |      | 84** | 68** | 28** | 34** |
+----------------+--------+-----+------+------+------+------+------+
| ^1)^ After the |        |     |      |      |      |      |      |
| 9 month core   |        |     |      |      |      |      |      |
| study patients |        |     |      |      |      |      |      |
| who entered    |        |     |      |      |      |      |      |
| the extension  |        |     |      |      |      |      |      |
| study were     |        |     |      |      |      |      |      |
| switched from  |        |     |      |      |      |      |      |
| lower Zometa   |        |     |      |      |      |      |      |
| doses to 8 mg  |        |     |      |      |      |      |      |
| Zometa or      |        |     |      |      |      |      |      |
| Aredia.        |        |     |      |      |      |      |      |
| Patients in    |        |     |      |      |      |      |      |
| the Aredia     |        |     |      |      |      |      |      |
| group          |        |     |      |      |      |      |      |
| continued to   |        |     |      |      |      |      |      |
| receive        |        |     |      |      |      |      |      |
| Aredia.        |        |     |      |      |      |      |      |
|                |        |     |      |      |      |      |      |
| ^2)^ Study was |        |     |      |      |      |      |      |
| terminated     |        |     |      |      |      |      |      |
| earlier. The   |        |     |      |      |      |      |      |
| maximum        |        |     |      |      |      |      |      |
| duration on    |        |     |      |      |      |      |      |
| study was 38.7 |        |     |      |      |      |      |      |
| months.        |        |     |      |      |      |      |      |
+----------------+--------+-----+------+------+------+------+------+

###### Table 2 -- Pivotal Zometa hypercalcemia studies included in the search for terms related to ONJ using MedDRA

  ----------- ---------------- ------------ ------------ --------- --------- --------- --------- ---------
  **Phase I\  **Indication**   **No.        **Study      **Zol\    **Zol\    **Zol\    **Zol\    **Zol\
  Study No.**                  patients**   duration**   0.002     0.005     0.01      0.02      0.04
                                                         mg/kg**   mg/kg**   mg/kg**   mg/kg**   mg/kg**

  CHJC1^1)^   Cancer           33           5 weeks      3         3         4         5         18
  ----------- ---------------- ------------ ------------ --------- --------- --------- --------- ---------

  ------------------- ---------------- ------------ ------------ --------- --------- -----------
  **Phase II\         **Indication**   **No.        **Study      **Zol\    **Zol\    **Aredia\
  Study No.**                          patients**   duration**   4 mg**    8 mg**    90 mg**

  CZOL446036^2)^      Cancer           144          Max. 3 mo    46        48        50

  CZOL446037^2)^      Cancer           138          Max. 3 mo    40        47        51

  **Total Phase 2**                    **282**                   **84**    **95**    **101**

  ^1)^Single                                                                         
  infusion\                                                                          
  ^2)^Hypercalcemia                                                                  
  of malignancy (HCM)                                                                
  study: patients                                                                    
  received a single                                                                  
  dose of Zometa 4 mg                                                                
  or 8 mg or Aredia.                                                                 
  Patients with HCM                                                                  
  that was refractory                                                                
  or had relapsed                                                                    
  after the first                                                                    
  dose received a                                                                    
  second infusion of                                                                 
  Zometa 8 mg                                                                        
  ------------------- ---------------- ------------ ------------ --------- --------- -----------

###### Table 3 -- Non-pivotal bone metastases studies included in the search for terms related to ONJ using MedDRA

<table>
<colgroup>
<col style="width: 16%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 10%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 8%" />
</colgroup>
<thead>
<tr class="header">
<th><strong>Phase I –III<br />
Study No.</strong></th>
<th><strong>Indication</strong></th>
<th><strong>No. patients</strong></th>
<th><strong>Study duration</strong></th>
<th><strong>Zol<br />
≤ 2 mg</strong></th>
<th><strong>Zol<br />
4 mg</strong></th>
<th><strong>Zol<br />
8/4 mg</strong></th>
<th><strong>Zol<br />
8 mg</strong></th>
<th><strong>Zol<br />
16 mg</strong></th>
<th><strong>Are<br />
90 mg</strong></th>
<th><strong>Placebo</strong></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td>CZOL4460001<sup>1)</sup></td>
<td>M. Paget</td>
<td>16</td>
<td>14 d</td>
<td>16</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="even">
<td>CZOL4460002<sup>1)</sup></td>
<td>M. Paget</td>
<td>175</td>
<td>3 mo</td>
<td>140</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>35</td>
</tr>
<tr class="odd">
<td>CZOL4460003+E</td>
<td>Cancer</td>
<td>59</td>
<td>3mo/48mo</td>
<td>45</td>
<td>7</td>
<td>NA</td>
<td>7</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="even">
<td>CZOL4460035+E</td>
<td>NSCLC, PCa</td>
<td>42</td>
<td>2mo/ max. 31.6 mo</td>
<td>16</td>
<td>8</td>
<td>NA</td>
<td>8<sup>2)</sup></td>
<td>10<sup>3)</sup></td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="odd">
<td>CZOL4460503+E</td>
<td>Cancer</td>
<td>36</td>
<td>1 mo/~3 y</td>
<td>NA</td>
<td>12</td>
<td>NA</td>
<td>12</td>
<td>12</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="even">
<td>CZOL4460506+E</td>
<td>Cancer</td>
<td>19</td>
<td>3 mo/2 yrs</td>
<td>NA</td>
<td>19</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="odd">
<td>CZOL4460510</td>
<td>MM, PCa</td>
<td>20</td>
<td>6 mo/1 y</td>
<td colspan="5"><p>Core: 1x4 mg, 2x8mg, 2x12 mg, 1x4mg sequentially</p>
<p>Extention: 4 mg (investigator may decide to give 8 or 12 mg)</p></td>
<td>NA</td>
<td>NA</td>
</tr>
<tr class="even">
<td>CZOL4460705</td>
<td>PCa</td>
<td>106</td>
<td>12 mo</td>
<td>NA</td>
<td>55</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>NA</td>
<td>51</td>
</tr>
<tr class="odd">
<td>CZOL446IA03</td>
<td>MM, BCa</td>
<td>240</td>
<td>15-20 weeks</td>
<td>NA</td>
<td>NA</td>
<td>115</td>
<td>NA</td>
<td>NA</td>
<td>125</td>
<td>NA</td>
</tr>
<tr class="even">
<td><strong>Total</strong></td>
<td></td>
<td><strong>713</strong></td>
<td></td>
<td><strong>217</strong></td>
<td><strong>101<sup>4)</sup></strong></td>
<td><strong>115<sup>4)</sup></strong></td>
<td><strong>27<sup>4)</sup></strong></td>
<td><strong>22<sup>4)</sup></strong></td>
<td><strong>125</strong></td>
<td><strong>86</strong></td>
</tr>
</tbody>
</table>

+----------------+------------+----------------+----------------------+
| **Phase IV\    | **In       | **Zometa 4 mg\ | **Study Duration**   |
| Single Arm\    | dication** | No. of         |                      |
| Study No.**    |            | Patients**     |                      |
+----------------+------------+----------------+----------------------+
| CZOL446EDE02   | Cancer     | 604            | 36-48 weeks          |
|                |            |                | (follow-up until     |
|                |            |                | week 60)             |
+----------------+------------+----------------+----------------------+
| CZOL446EIT01   | BCa        | 312            | 48 weeks             |
+----------------+------------+----------------+----------------------+
| CZOL446EAU05   | PCa        | 184            | 36-48 weeks          |
+----------------+------------+----------------+----------------------+
| CZOL446EAU07   | MM         | 11             | 16 weeks             |
+----------------+------------+----------------+----------------------+
| CZOL446GAU09   | MM         | 2              | 12 months            |
+----------------+------------+----------------+----------------------+
| CZOL446EGB01   | BCa        | 101            | 9 months             |
+----------------+------------+----------------+----------------------+
| CZOL446EIN01   | Cancer     | 73             | 3 months             |
+----------------+------------+----------------+----------------------+
| CZOL446EPH01   | BCa, PCa,  | 70             | 6 months             |
|                | MM         |                |                      |
+----------------+------------+----------------+----------------------+
| CZOL446GFR02   | BCa        | 102            | 12 months            |
+----------------+------------+----------------+----------------------+
| CZOL446EUS24   | PCa        | 257            | 12 months            |
+----------------+------------+----------------+----------------------+
| **Total**      | **1,716**  |                |                      |
+----------------+------------+----------------+----------------------+
| ^1)^Zometa     |            |                |                      |
| administered   |            |                |                      |
| as single dose |            |                |                      |
|                |            |                |                      |
| ^2)^After the  |            |                |                      |
| 8-26 months 5  |            |                |                      |
| patients       |            |                |                      |
| switched from  |            |                |                      |
| 8 mg Zometa to |            |                |                      |
| 4 mg Zometa    |            |                |                      |
|                |            |                |                      |
| ^3)^2 patients |            |                |                      |
| from the 16 mg |            |                |                      |
| Zometa group   |            |                |                      |
| switched to    |            |                |                      |
| Aredia after   |            |                |                      |
| 18 months      |            |                |                      |
|                |            |                |                      |
| ^4)^Patient    |            |                |                      |
| numbers of     |            |                |                      |
| study          |            |                |                      |
| CZOL4460510    |            |                |                      |
| are not        |            |                |                      |
| included due   |            |                |                      |
| to non-uniform |            |                |                      |
| dose regimem   |            |                |                      |
+----------------+------------+----------------+----------------------+

###### Table 4 -- Osteonecrosis/osteomyelitis cases (related to jaw or with unknown location) reported in pivotal bone metastases and hypercalcemia trials

+-----+-----+----+---+-----+---------+----------+------+------------+
| **  | **  | *  | * | **D | **Di    | **S      | **AE | **Possible |
| Cen | Ind | *T | * | ate | agnosis | tart/end | re   | risk       |
| ter | ica | re | N | Fi  | /       | date**   | port | fac        |
| /** | tio | at | o | rst | Loc     |          | ing/ | tors^2)^** |
|     | n** | me | . | I   | ation** |          | s    |            |
| **  |     | nt | i | nfu |         |          | tudy |            |
| Sub |     | ** | n | sio |         |          | drug |            |
| jec |     |    | f | n** |         |          | re   |            |
| t** |     | *  | . |     |         |          | lati |            |
|     |     | *G | ^ |     |         |          | onsh |            |
|     |     | ro | 1 |     |         |          | ip** |            |
|     |     | up | ) |     |         |          |      |            |
|     |     | ** | ^ |     |         |          |      |            |
|     |     |    | * |     |         |          |      |            |
|     |     |    | * |     |         |          |      |            |
+=====+=====+====+===+=====+=========+==========+======+============+
| **  |     |    |   |     |         |          |      |            |
| CZO |     |    |   |     |         |          |      |            |
| L44 |     |    |   |     |         |          |      |            |
| 6G0 |     |    |   |     |         |          |      |            |
| 007 |     |    |   |     |         |          |      |            |
| (n= |     |    |   |     |         |          |      |            |
| 288 |     |    |   |     |         |          |      |            |
| )** |     |    |   |     |         |          |      |            |
+-----+-----+----+---+-----+---------+----------+------+------------+
| 60  | Mu  | Z  | 2 | 4N  | Aseptic | Mar      | Not  | Che        |
| 9/2 | lti | ol | 8 | ov1 | n       | 1999/    | ser  | motherapy; |
| 023 | ple | 0  |   | 996 | ecrosis |          | ious | cortic     |
|     | m   | .4 | ( |     | bone /  | Data not | /    | o­steroids; |
|     | yel | m  | 1 |     | m       | a        | not  | candidal   |
|     | oma | g/ | 0 |     | andible | vailable | s    | infection  |
|     |     |    | + |     |         |          | uspe | (          |
|     |     | Ar | 1 |     |         |          | cted | 4Dec1996); |
|     |     | ed | 8 |     |         |          |      | tooth      |
|     |     | ia | ) |     |         |          |      | abscess    |
|     |     | 90 |   |     |         |          |      | (          |
|     |     | mg |   |     |         |          |      | 12Aug1997) |
|     |     | ^3 |   |     |         |          |      |            |
|     |     | )^ |   |     |         |          |      |            |
+-----+-----+----+---+-----+---------+----------+------+------------+
| 62  | Mu  | Z  | 1 | 24O | Osteom  | 9        | Not  | Che        |
| 7/2 | lti | ol | 7 | ct1 | yelitis | Apr1998/ | ser  | motherapy; |
| 382 | ple | 4  |   | 996 | (tend   |          | ious | cortic     |
|     | m   | /8 | ( |     | erness) | c        | /    | o­steroids; |
|     | yel | mg | 1 |     | /       | ontinued | not  | 1 cm       |
|     | oma |    | 0 |     |         |          | s    | ra         |
|     |     |    | + |     | mandi   |          | uspe | diolucency |
|     |     |    | 7 |     | ble^4)^ |          | cted | at         |
|     |     |    | ) |     |         |          |      | mandible   |
|     |     |    |   |     |         |          |      | seen on a  |
|     |     |    |   |     |         |          |      | radiograph |
|     |     |    |   |     |         |          |      | of the     |
|     |     |    |   |     |         |          |      | skull      |
|     |     |    |   |     |         |          |      | (3         |
|     |     |    |   |     |         |          |      | 1Jul1997); |
|     |     |    |   |     |         |          |      | jaw        |
|     |     |    |   |     |         |          |      | infection  |
|     |     |    |   |     |         |          |      | (start     |
|     |     |    |   |     |         |          |      | date       |
|     |     |    |   |     |         |          |      | unknown);  |
|     |     |    |   |     |         |          |      | oste       |
|     |     |    |   |     |         |          |      | oarthritis |
|     |     |    |   |     |         |          |      | (medical   |
|     |     |    |   |     |         |          |      | histor     |
|     |     |    |   |     |         |          |      | y/ongoing) |
+-----+-----+----+---+-----+---------+----------+------+------------+
| **  |     |    |   |     |         |          |      |            |
| CZO |     |    |   |     |         |          |      |            |
| L44 |     |    |   |     |         |          |      |            |
| 6G0 |     |    |   |     |         |          |      |            |
| 010 |     |    |   |     |         |          |      |            |
| (   |     |    |   |     |         |          |      |            |
| n=1 |     |    |   |     |         |          |      |            |
| 648 |     |    |   |     |         |          |      |            |
| )** |     |    |   |     |         |          |      |            |
+-----+-----+----+---+-----+---------+----------+------+------------+
| 2   | Mu  | Z  | 2 | 10M | Ost     | 5        | Not  | Che        |
| 264 | lti | ol | 8 | ay1 | eomyeli | Mar2001/ | ser  | motherapy; |
| /11 | ple | 4  |   | 999 | tis^5)^ | c        | ious | cortic     |
| 160 | m   | mg |   |     | / Jaw   | ontinued | /    | o­steroids; |
|     | yel |    |   |     |         |          | not  | ulcer      |
|     | oma |    |   |     |         |          | s    | mouth      |
|     |     |    |   |     |         |          | uspe | (Oct2000); |
|     |     |    |   |     |         |          | cted | cyst under |
|     |     |    |   |     |         |          |      | chin       |
|     |     |    |   |     |         |          |      | (Apr2000); |
|     |     |    |   |     |         |          |      | infection  |
|     |     |    |   |     |         |          |      | of the gum |
|     |     |    |   |     |         |          |      | and teeth, |
|     |     |    |   |     |         |          |      | lesions in |
|     |     |    |   |     |         |          |      | the        |
|     |     |    |   |     |         |          |      | mandible   |
|     |     |    |   |     |         |          |      | (not       |
|     |     |    |   |     |         |          |      | related to |
|     |     |    |   |     |         |          |      | myeloma,   |
|     |     |    |   |     |         |          |      | no exposed |
|     |     |    |   |     |         |          |      | bone       |
|     |     |    |   |     |         |          |      | (5Mar2001) |
+-----+-----+----+---+-----+---------+----------+------+------------+
| 2   | Mu  | Z  | 1 | 27M | Oste    | 17       | Not  | Che        |
| 346 | lti | ol | 2 | ay1 | onecros | Apr2000/ | ser  | motherapy; |
| /10 | ple | 8  |   | 999 | is,bone |          | ious | corti      |
| 594 | m   | /4 | ( |     | n       | c        | /    | co­steroids |
|     | yel | mg | 1 |     | ecrosis | ontinued | not  |            |
|     | oma |    | 2 |     | / not   |          | s    |            |
|     |     |    | + |     | specif  |          | uspe |            |
|     |     |    | 0 |     | ied^6)^ |          | cted |            |
|     |     |    | ) |     |         |          |      |            |
+-----+-----+----+---+-----+---------+----------+------+------------+
| 2   | Bre | Z  | 2 | 14J | Oste    | 18       | Not  | Radiation  |
| 346 | ast | ol | 2 | un1 | oradio­n | Dec2000/ | ser  | (date      |
| /20 | can | 8  |   | 999 | ecrosis |          | ious | unknown);  |
| 593 | cer | /4 | ( |     | / jaw   | c        | /    | tooth      |
|     |     | mg | 1 |     |         | ontinued | not  | extraction |
|     |     |    | 4 |     |         |          | s    | (1         |
|     |     |    | + |     |         |          | uspe | 6Apr1999); |
|     |     |    | 8 |     |         |          | cted | mouth      |
|     |     |    | ) |     |         |          |      | sores      |
|     |     |    |   |     |         |          |      | (Jul1999); |
|     |     |    |   |     |         |          |      | p          |
|     |     |    |   |     |         |          |      | eriodontal |
|     |     |    |   |     |         |          |      | disease    |
|     |     |    |   |     |         |          |      | (28Jan00); |
|     |     |    |   |     |         |          |      | che        |
|     |     |    |   |     |         |          |      | motherapy; |
|     |     |    |   |     |         |          |      | corti      |
|     |     |    |   |     |         |          |      | co­steroids |
+-----+-----+----+---+-----+---------+----------+------+------------+
| **  |     |    |   |     |         |          |      |            |
| CZO |     |    |   |     |         |          |      |            |
| L44 |     |    |   |     |         |          |      |            |
| 6G0 |     |    |   |     |         |          |      |            |
| 704 |     |    |   |     |         |          |      |            |
| (n= |     |    |   |     |         |          |      |            |
| 398 |     |    |   |     |         |          |      |            |
| )** |     |    |   |     |         |          |      |            |
+-----+-----+----+---+-----+---------+----------+------+------------+
| 052 | Pr  | Z  | 2 | 29D | Osteom  | 26       | Not  | Dental     |
| 1/0 | ost | ol | 0 | ec1 | yelitis | Mar2002/ | ser  | abscess    |
| 002 | ate | 8  |   | 999 | /       |          | ious | (          |
|     | can | /4 | ( |     |         | co       | /    | 8Nov2001), |
|     | cer | mg | 7 |     | jaw     | ntinuing | not  | tooth      |
|     |     |    | + |     |         |          | s    | extraction |
|     |     |    | 1 |     |         |          | uspe | (date      |
|     |     |    | 3 |     |         |          | cted | unknown);  |
|     |     |    | ) |     |         |          |      | oral       |
|     |     |    |   |     |         |          |      | fistula    |
|     |     |    |   |     |         |          |      | (2         |
|     |     |    |   |     |         |          |      | 6Mar2002); |
|     |     |    |   |     |         |          |      | arthritis  |
|     |     |    |   |     |         |          |      | (1994,     |
|     |     |    |   |     |         |          |      | active     |
|     |     |    |   |     |         |          |      | problem);  |
|     |     |    |   |     |         |          |      | hormone    |
|     |     |    |   |     |         |          |      | therapy    |
+-----+-----+----+---+-----+---------+----------+------+------------+
| **C |     |    |   |     |         |          |      |            |
| ARD |     |    |   |     |         |          |      |            |
| 233 |     |    |   |     |         |          |      |            |
| AP1 |     |    |   |     |         |          |      |            |
| 2** |     |    |   |     |         |          |      |            |
| (   |     |    |   |     |         |          |      |            |
| n=3 |     |    |   |     |         |          |      |            |
| 92) |     |    |   |     |         |          |      |            |
+-----+-----+----+---+-----+---------+----------+------+------------+
| M6  | MM  | Ar | 1 | 20A | Osteom  | 21       | Not  | Che        |
| 596 |     | ed | 4 | ug1 | yelitis | Oct1992/ | ser  | motherapy; |
| P/6 |     | ia |   | 991 | /       |          | ious | cortic     |
|     |     | 90 |   |     |         | ongoing  | /    | o­steroids; |
|     |     | mg |   |     | jaw     |          | not  | dentition  |
|     |     |    |   |     |         |          | s    | poor       |
|     |     |    |   |     |         |          | uspe | (1         |
|     |     |    |   |     |         |          | cted | 0Jul1992); |
|     |     |    |   |     |         |          |      | denuded    |
|     |     |    |   |     |         |          |      | bone in    |
|     |     |    |   |     |         |          |      | posterior  |
|     |     |    |   |     |         |          |      | aspect of  |
|     |     |    |   |     |         |          |      | mandible   |
|     |     |    |   |     |         |          |      | (          |
|     |     |    |   |     |         |          |      | 15Sep1992) |
+-----+-----+----+---+-----+---------+----------+------+------------+
| *   |     |    |   |     |         |          |      |            |
| *CA |     |    |   |     |         |          |      |            |
| RD2 |     |    |   |     |         |          |      |            |
| 33A |     |    |   |     |         |          |      |            |
| P19 |     |    |   |     |         |          |      |            |
| (n= |     |    |   |     |         |          |      |            |
| 380 |     |    |   |     |         |          |      |            |
| )** |     |    |   |     |         |          |      |            |
+-----+-----+----+---+-----+---------+----------+------+------------+
| M   | BCa | P  | 3 | 7O  | Osteom  | 30N      | Not  | Che        |
| 748 |     | la |   | ct1 | yelitis | ov1992/2 | ser  | motherapy; |
| 8U/ |     | ce |   | 992 | / not   | 9Dec1992 | ious | hormone    |
| 101 |     | bo |   |     | sp      |          | /    | therapy;   |
|     |     |    |   |     | ecified |          | not  | sepsis     |
|     |     |    |   |     |         |          | s    | (          |
|     |     |    |   |     |         |          | uspe | 19Oct1992) |
|     |     |    |   |     |         |          | cted |            |
+-----+-----+----+---+-----+---------+----------+------+------------+
| *   |     |    |   |     |         |          |      |            |
| *CZ |     |    |   |     |         |          |      |            |
| OL4 |     |    |   |     |         |          |      |            |
| 460 |     |    |   |     |         |          |      |            |
| 037 |     |    |   |     |         |          |      |            |
| (H  |     |    |   |     |         |          |      |            |
| ype |     |    |   |     |         |          |      |            |
| rca |     |    |   |     |         |          |      |            |
| lce |     |    |   |     |         |          |      |            |
| mia |     |    |   |     |         |          |      |            |
| )** |     |    |   |     |         |          |      |            |
+-----+-----+----+---+-----+---------+----------+------+------------+
| M1  | SSC | Zo | 1 | 16J | Osteon  | 28       | Not  | Ch         |
| 694 | Hea | me |   | ul1 | ecrosis | Jul1999/ | seri | emotherapy |
| E/1 | d&N | ta |   | 992 | /       |          | ous/ |            |
| 303 | eck | 8  |   |     | Maxilla | ongoing  | not  |            |
|     |     | mg |   |     | (cancer |          | s    |            |
|     |     |    |   |     | r       |          | uspe |            |
|     |     |    |   |     | elated) |          | cted |            |
+-----+-----+----+---+-----+---------+----------+------+------------+
| ^   |     |    |   |     |         |          |      |            |
| 1)^ |     |    |   |     |         |          |      |            |
| Num |     |    |   |     |         |          |      |            |
| ber |     |    |   |     |         |          |      |            |
| of  |     |    |   |     |         |          |      |            |
| inf |     |    |   |     |         |          |      |            |
| usi |     |    |   |     |         |          |      |            |
| ons |     |    |   |     |         |          |      |            |
| re  |     |    |   |     |         |          |      |            |
| cei |     |    |   |     |         |          |      |            |
| ved |     |    |   |     |         |          |      |            |
| bef |     |    |   |     |         |          |      |            |
| ore |     |    |   |     |         |          |      |            |
| dia |     |    |   |     |         |          |      |            |
| gno |     |    |   |     |         |          |      |            |
| sis |     |    |   |     |         |          |      |            |
| of  |     |    |   |     |         |          |      |            |
| o   |     |    |   |     |         |          |      |            |
| ste |     |    |   |     |         |          |      |            |
| omy |     |    |   |     |         |          |      |            |
| eli |     |    |   |     |         |          |      |            |
| tis |     |    |   |     |         |          |      |            |
| /ne |     |    |   |     |         |          |      |            |
| cro |     |    |   |     |         |          |      |            |
| sis |     |    |   |     |         |          |      |            |
|     |     |    |   |     |         |          |      |            |
| ^2) |     |    |   |     |         |          |      |            |
| ^In |     |    |   |     |         |          |      |            |
| m   |     |    |   |     |         |          |      |            |
| edi |     |    |   |     |         |          |      |            |
| cal |     |    |   |     |         |          |      |            |
| h   |     |    |   |     |         |          |      |            |
| ist |     |    |   |     |         |          |      |            |
| ory |     |    |   |     |         |          |      |            |
| or  |     |    |   |     |         |          |      |            |
| as  |     |    |   |     |         |          |      |            |
| c   |     |    |   |     |         |          |      |            |
| urr |     |    |   |     |         |          |      |            |
| ent |     |    |   |     |         |          |      |            |
| con |     |    |   |     |         |          |      |            |
| dit |     |    |   |     |         |          |      |            |
| ion |     |    |   |     |         |          |      |            |
|     |     |    |   |     |         |          |      |            |
| ^   |     |    |   |     |         |          |      |            |
| 3)^ |     |    |   |     |         |          |      |            |
| The |     |    |   |     |         |          |      |            |
| p   |     |    |   |     |         |          |      |            |
| ati |     |    |   |     |         |          |      |            |
| ent |     |    |   |     |         |          |      |            |
| re  |     |    |   |     |         |          |      |            |
| cei |     |    |   |     |         |          |      |            |
| ved |     |    |   |     |         |          |      |            |
| 10  |     |    |   |     |         |          |      |            |
| inf |     |    |   |     |         |          |      |            |
| usi |     |    |   |     |         |          |      |            |
| ons |     |    |   |     |         |          |      |            |
| of  |     |    |   |     |         |          |      |            |
| Zom |     |    |   |     |         |          |      |            |
| eta |     |    |   |     |         |          |      |            |
| 0.4 |     |    |   |     |         |          |      |            |
| mg  |     |    |   |     |         |          |      |            |
| bef |     |    |   |     |         |          |      |            |
| ore |     |    |   |     |         |          |      |            |
| swi |     |    |   |     |         |          |      |            |
| tch |     |    |   |     |         |          |      |            |
| ing |     |    |   |     |         |          |      |            |
| to  |     |    |   |     |         |          |      |            |
| Are |     |    |   |     |         |          |      |            |
| dia |     |    |   |     |         |          |      |            |
| (18 |     |    |   |     |         |          |      |            |
| i   |     |    |   |     |         |          |      |            |
| nfu |     |    |   |     |         |          |      |            |
| sio |     |    |   |     |         |          |      |            |
| ns) |     |    |   |     |         |          |      |            |
|     |     |    |   |     |         |          |      |            |
| ^4) |     |    |   |     |         |          |      |            |
| ^Ex |     |    |   |     |         |          |      |            |
| cis |     |    |   |     |         |          |      |            |
| ion |     |    |   |     |         |          |      |            |
| of  |     |    |   |     |         |          |      |            |
| ri  |     |    |   |     |         |          |      |            |
| ght |     |    |   |     |         |          |      |            |
| m   |     |    |   |     |         |          |      |            |
| and |     |    |   |     |         |          |      |            |
| ibu |     |    |   |     |         |          |      |            |
| lar |     |    |   |     |         |          |      |            |
| b   |     |    |   |     |         |          |      |            |
| one |     |    |   |     |         |          |      |            |
| and |     |    |   |     |         |          |      |            |
| s   |     |    |   |     |         |          |      |            |
| oft |     |    |   |     |         |          |      |            |
| tis |     |    |   |     |         |          |      |            |
| sue |     |    |   |     |         |          |      |            |
| m   |     |    |   |     |         |          |      |            |
| ass |     |    |   |     |         |          |      |            |
| (   |     |    |   |     |         |          |      |            |
| 26. |     |    |   |     |         |          |      |            |
| Apr |     |    |   |     |         |          |      |            |
| .20 |     |    |   |     |         |          |      |            |
| 01) |     |    |   |     |         |          |      |            |
|     |     |    |   |     |         |          |      |            |
| ^5  |     |    |   |     |         |          |      |            |
| )^T |     |    |   |     |         |          |      |            |
| erm |     |    |   |     |         |          |      |            |
| not |     |    |   |     |         |          |      |            |
| i   |     |    |   |     |         |          |      |            |
| den |     |    |   |     |         |          |      |            |
| tif |     |    |   |     |         |          |      |            |
| ied |     |    |   |     |         |          |      |            |
| in  |     |    |   |     |         |          |      |            |
| CRF |     |    |   |     |         |          |      |            |
|     |     |    |   |     |         |          |      |            |
| ^6) |     |    |   |     |         |          |      |            |
| ^No |     |    |   |     |         |          |      |            |
| a   |     |    |   |     |         |          |      |            |
| dve |     |    |   |     |         |          |      |            |
| rse |     |    |   |     |         |          |      |            |
| eve |     |    |   |     |         |          |      |            |
| nts |     |    |   |     |         |          |      |            |
| i   |     |    |   |     |         |          |      |            |
| ndi |     |    |   |     |         |          |      |            |
| cat |     |    |   |     |         |          |      |            |
| ing |     |    |   |     |         |          |      |            |
| jaw |     |    |   |     |         |          |      |            |
| in  |     |    |   |     |         |          |      |            |
| vol |     |    |   |     |         |          |      |            |
| vem |     |    |   |     |         |          |      |            |
| ent |     |    |   |     |         |          |      |            |
+-----+-----+----+---+-----+---------+----------+------+------------+

######  Table 5 -- ONJ cases reported in ongoing beone metastases studies

+------+-----+-----+-----+-----+------+------+------+-------------+
| **C  | **  | *   | **  | **D | **D  | **S  | **AE | **Possible  |
| ente | Ind | *Tr | No. | ate | iagn | tart | re   | risk        |
| r/** | ica | eat | i   | Fi  | osis | /end | port | fa          |
|      | tio | men | nf. | rst | /    | da   | ing/ | ctors^2)^** |
| **S  | n** | t** | ^1) | I   | Lo   | te** | s    |             |
| ubje |     |     | ^** | nfu | cati |      | tudy |             |
| ct** |     |     |     | sio | on** |      | drug |             |
|      |     |     |     | n** |      |      | re   |             |
|      |     |     |     |     |      |      | lati |             |
|      |     |     |     |     |      |      | onsh |             |
|      |     |     |     |     |      |      | ip** |             |
+------+-----+-----+-----+-----+------+------+------+-------------+
| **   |     |     |     |     |      |      |      |             |
| CZOL |     |     |     |     |      |      |      |             |
| 446G |     |     |     |     |      |      |      |             |
| 2408 |     |     |     |     |      |      |      |             |
| (    |     |     |     |     |      |      |      |             |
| ongo |     |     |     |     |      |      |      |             |
| ing, |     |     |     |     |      |      |      |             |
| 1036 |     |     |     |     |      |      |      |             |
| pati |     |     |     |     |      |      |      |             |
| ents |     |     |     |     |      |      |      |             |
| e    |     |     |     |     |      |      |      |             |
| nrol |     |     |     |     |      |      |      |             |
| led, |     |     |     |     |      |      |      |             |
| 6Ja  |     |     |     |     |      |      |      |             |
| n200 |     |     |     |     |      |      |      |             |
| 5)** |     |     |     |     |      |      |      |             |
+------+-----+-----+-----+-----+------+------+------+-------------+
| 1/10 | Bre | Zom | M   | 2   | O    | May  | Ser  | Ch          |
| 0055 | ast | eta | ax. | 6Ja | steo | 2004 | ious | emotherapy; |
|      | can | 4   | 4   | n04 | necr |      | /    | corti       |
|      | cer | mg  |     |     | osis |      | s    | costeroids; |
|      |     |     |     |     | /    |      | uspe | gingival    |
|      |     |     |     |     | jaw  |      | cted | infection   |
|      |     |     |     |     |      |      |      | (9Feb2004); |
|      |     |     |     |     |      |      |      | dental      |
|      |     |     |     |     |      |      |      | extraction  |
|      |     |     |     |     |      |      |      | (16Feb2004) |
+------+-----+-----+-----+-----+------+------+------+-------------+
| **   |     |     |     |     |      |      |      |             |
| CZOL |     |     |     |     |      |      |      |             |
| 446E |     |     |     |     |      |      |      |             |
| DE07 |     |     |     |     |      |      |      |             |
| (    |     |     |     |     |      |      |      |             |
| ongo |     |     |     |     |      |      |      |             |
| ing, |     |     |     |     |      |      |      |             |
| 309  |     |     |     |     |      |      |      |             |
| pati |     |     |     |     |      |      |      |             |
| ents |     |     |     |     |      |      |      |             |
| e    |     |     |     |     |      |      |      |             |
| nrol |     |     |     |     |      |      |      |             |
| led, |     |     |     |     |      |      |      |             |
| 14Ja |     |     |     |     |      |      |      |             |
| n200 |     |     |     |     |      |      |      |             |
| 5)** |     |     |     |     |      |      |      |             |
+------+-----+-----+-----+-----+------+------+------+-------------+
| 20/9 | Pr  | Zom | M   | 2   | O    | Alr  | Ser  | Preexisting |
|      | ost | eta | ax. | 5Fe | steo | eady | ious | os          |
|      | ate | 4   | 9   | b03 | myel | pre  | /    | teomyelitis |
|      | can | mg  |     |     | itis | sent | not  | of the jaw  |
|      | cer |     |     |     | /    | at   | s    |             |
|      |     |     |     |     | jaw  | s    | uspe |             |
|      |     |     |     |     |      | tudy | cted |             |
|      |     |     |     |     |      | e    |      |             |
|      |     |     |     |     |      | ntry |      |             |
+------+-----+-----+-----+-----+------+------+------+-------------+
| **CZ |     |     |     |     |      |      |      |             |
| OL44 |     |     |     |     |      |      |      |             |
| 6EDE |     |     |     |     |      |      |      |             |
| KR02 |     |     |     |     |      |      |      |             |
| (    |     |     |     |     |      |      |      |             |
| ongo |     |     |     |     |      |      |      |             |
| ing, |     |     |     |     |      |      |      |             |
| 40   |     |     |     |     |      |      |      |             |
| pati |     |     |     |     |      |      |      |             |
| ents |     |     |     |     |      |      |      |             |
| enro |     |     |     |     |      |      |      |             |
| lled |     |     |     |     |      |      |      |             |
| Ja   |     |     |     |     |      |      |      |             |
| n200 |     |     |     |     |      |      |      |             |
| 5)** |     |     |     |     |      |      |      |             |
+------+-----+-----+-----+-----+------+------+------+-------------+
| 1/11 | Bre | Zom | M   | 2   | O    | A    | Ser  | Ch          |
|      | ast | eta | ax. | 5Ju | steo | fter | ious | emotherapy; |
|      | can | 4   | 4   | l03 | myel | 6Jan | /    | chronic     |
|      | cer | mg  |     |     | itis | 2004 | not  | gingivitis  |
|      |     |     |     |     | /    |      | s    | (6Jan2004); |
|      |     |     |     |     | jaw  |      | uspe | seq         |
|      |     |     |     |     |      |      | cted | uestrectomy |
|      |     |     |     |     |      |      |      | (20Apr2004) |
+------+-----+-----+-----+-----+------+------+------+-------------+
| **   |     |     |     |     |      |      |      |             |
| CZOL |     |     |     |     |      |      |      |             |
| 446E |     |     |     |     |      |      |      |             |
| DE01 |     |     |     |     |      |      |      |             |
| (    |     |     |     |     |      |      |      |             |
| ongo |     |     |     |     |      |      |      |             |
| ing, |     |     |     |     |      |      |      |             |
| 101  |     |     |     |     |      |      |      |             |
| pati |     |     |     |     |      |      |      |             |
| ents |     |     |     |     |      |      |      |             |
| e    |     |     |     |     |      |      |      |             |
| nrol |     |     |     |     |      |      |      |             |
| led, |     |     |     |     |      |      |      |             |
| 14Ja |     |     |     |     |      |      |      |             |
| n200 |     |     |     |     |      |      |      |             |
| 5)** |     |     |     |     |      |      |      |             |
+------+-----+-----+-----+-----+------+------+------+-------------+
| ?    | Mu  | Zom | ?   | ?   | O    | ?    | Not  | ?           |
|      | lti | eta |     |     | steo |      | ser  |             |
|      | ple | 4   |     |     | necr |      | ious |             |
|      | m   | mg  |     |     | osis |      | / ?  |             |
|      | yel |     |     |     | /    |      |      |             |
|      | oma |     |     |     | jaw  |      |      |             |
+------+-----+-----+-----+-----+------+------+------+-------------+