Novartis Pharmaceuticals Corporation

59 Route 10

East Hanover, NJ 07936

Appendix 6:\
Summary of ONJ Cases from Retrospective Chart Review at MD Anderson
Cancer Center

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**

**Summary of ONJ Cases from Retrospective Chart Review at MD Anderson
Cancer Center**

<table>
<colgroup>
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<col style="width: 12%" />
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</colgroup>
<thead>
<tr class="header">
<th><strong>ID</strong></th>
<th><strong>Gender/<br />
Age</strong></th>
<th><strong>Diagnosis</strong></th>
<th><strong>Date of DX</strong></th>
<th><strong>BP (Type/#)</strong></th>
<th><strong>Date of DX ON</strong></th>
<th><strong>BP Duration (mos)</strong></th>
<th><strong>Predisposing factors</strong></th>
<th><strong>Clinical presentation</strong></th>
<th><strong>Onco Treatments</strong></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td><p>1</p>
<p>(A)</p></td>
<td>F/54</td>
<td>MTC, hypothyroidism</td>
<td><p>12/97</p>
<p>Bone mets 5/99</p></td>
<td><p>Aredia 4/00 qmo</p>
<p>In 2003 was on Zometa (date N/A)</p>
<p>Rx’d in Georgia</p></td>
<td>01/03</td>
<td><p><u>33mos</u></p>
<p>A: 33mos</p>
<p>(Z: N/A)</p></td>
<td>Trauma to jaw/anesthesia in 12/02</td>
<td><p>Trauma never healed</p>
<p>10/03 pain right mandible with exposed bone</p>
<p>Progressive with extension to maxilla</p></td>
<td><p>DTIC</p>
<p>Anti-CEA antibody/Adria</p></td>
</tr>
<tr class="even">
<td><p>2</p>
<p>(AZ)</p></td>
<td>M/58</td>
<td>MM, COPD, HTN, DM, smoking</td>
<td>10/96</td>
<td><p>MDA pharmacy</p>
<p>A - 1/98-2/02</p>
<p>Z - 3/02-9/04</p></td>
<td>09/02</td>
<td><p><u>57 mos</u></p>
<p>A: 50 mos</p>
<p>Z: 7 mos</p></td>
<td><p>Gingivitis 6/02</p>
<p>Dental decay 6/02</p>
<p>Periodontal dz 6/02</p>
<p>Dental Extraction</p>
<p>7/02 (7 teeth)</p>
<p>Dentures XRT to maxilla 7/02</p></td>
<td><p>Right maxilla pain and poor healing/exposed bone 9/02</p>
<p>3/03 several areas of exposed bone</p>
<p>6/03 necrotic bone</p>
<p>9/03 larger areas 4x2 cm bilaterally + ant. bone exposure 1/x0.5
cm-debrid.</p>
<p>10/03, 11/03 debridements</p></td>
<td><p>Melphalan, prednisone, decadron hyper/cvad, interferon,
thiothepa, busulfan, cyclophosphamide, thalidomide, arsenic autologous
BMT X2</p>
<p>Ianoxin, vioxx, protonox, codeine, xanax, klonopin, prilosec, buspar,
hydrocodone</p></td>
</tr>
<tr class="odd">
<td><p>3</p>
<p>(AZ)</p></td>
<td>F/79</td>
<td>MM, DVT, HTN</td>
<td>5/01</td>
<td><p>A – 5/01 – 6/02</p>
<p>Z – 7/02 – 4/04 *see CRF</p></td>
<td>8/03</td>
<td><p><u>26 mos</u></p>
<p>A: 13 mos</p>
<p>Z: 13 mos</p></td>
<td>Several dental extractions 9/02 Mandibular tori</td>
<td><p>Pain left mandible 8/03 (2x1 cm lesion)</p>
<p>Debridements 8/03, 10/03, 11/03, cephalexin, clindamycin,</p>
<p>1/04 worse ON 4/04 1/5 cm lesion</p></td>
<td>Melphalan, DEX, cyclophosphamide, cytoxan, thalidomide, coumadin,
velcade, procrit, darbepoetin</td>
</tr>
<tr class="even">
<td><p>4</p>
<p>(AZ)</p></td>
<td>F/47</td>
<td>MM, DM, Renal failure</td>
<td>3/97</td>
<td><p>A - ?</p>
<p>Z - ?</p></td>
<td>6/02</td>
<td>Unknown</td>
<td><p>Dental extraction in 6/01 tooth #20 left mandible</p>
<p>2/02 (outside MDA) – sequestrec-</p>
<p>tomy to remove necrotic bone. Mod. Periodontal dz</p></td>
<td><p>Pain left mandible since 2/02</p>
<p>Panorex</p>
<p>6/02: lesion left mandible 2/03 debridement</p>
<p>3/03 hyperbaric O2 Rx</p>
<p>4/03 worsening of necrosis (1.5 cm)</p>
<p>9/03 stable</p></td>
<td>Hyper-CVAD (cytoxan, mesna, adryamycin, vincristine, decradron,
cyclophosphamide, decardron, thalidomide, arsenic, melphalan,
velcade.</td>
</tr>
<tr class="odd">
<td><p>5</p>
<p>(Z)</p></td>
<td>F/60</td>
<td>Breast ca, Bone mets 12/02</td>
<td>10/99</td>
<td><p>No A</p>
<p>Z – 5/03-7/03</p></td>
<td>5/04</td>
<td><p>Z: 2 doses</p>
<p>Latency 12 months</p></td>
<td>None</td>
<td><p>Pain right mandible/exposed bone (1x1cm)</p>
<p>Biopsy: necrotic bone</p>
<p>Sequestrectomy 5/04</p>
<p>Controlled with treatment</p></td>
<td>Aryamycin, Cyclophosphamide, Paclitaxel, Tamoxifen, Docetaxel,
Arimidex, Exemestane, bellerga, xanax, elavil, melatonin, prilosec</td>
</tr>
<tr class="even">
<td><p>6</p>
<p>(AZ)</p></td>
<td>F/70</td>
<td>Breast ca</td>
<td>1/30/98</td>
<td><p>A - 22 inf (90 mg q mo)</p>
<p>Z – 28 infus. (4mg q mo) 5/02</p>
<p>A – 8/00-4/02</p>
<p>Z – 5/02-9/04</p>
<p>(22 doses of A, 28 doses of Z</p></td>
<td>4/04</td>
<td><p><u>45 mos</u></p>
<p>A: 21 mos</p>
<p>Z: 24 mos</p></td>
<td><p>Dental extraction</p>
<p>Dentures</p></td>
<td>Pain right mandible, Poor healing, exposed bone – Infection?</td>
<td>5-FU, adryamycin, cyclophosphamide, tamoxifen, arimidex, exemestane,
capecitabine, TAS-108, vinorelbine, gleevec, trastuzumab, paclitaxel
01/03-4/03, dexamethasone 10mg weekly 01/03</td>
</tr>
<tr class="odd">
<td><p>7</p>
<p>(AZ)</p></td>
<td>M/67</td>
<td>MM, osteoporosis</td>
<td>8/98</td>
<td><p>A-7/99 – 4/02</p>
<p>Z-6/02 – 9/04</p></td>
<td>2/04</td>
<td><p><u>53 mos</u></p>
<p>A: 32 mos</p>
<p>Z: 21 mos</p></td>
<td><p>Moderate periodontal disease</p>
<p>Mandibular Tori</p></td>
<td><p>6/99: good dentition</p>
<p>2/04 - pain right mandible: 3mmX4mm bone exposure</p>
<p>6/04: lesion healed</p></td>
<td><p>Hyper-CVAD (1/99) autologous BMT (6/99)</p>
<p>Serial dex 8/99</p>
<p>Thalidomide + dexamelphalan</p>
<p>Revimid</p></td>
</tr>
<tr class="even">
<td><p>8</p>
<p>(Z)</p></td>
<td>F/42</td>
<td>Breast ca</td>
<td>9/98</td>
<td>Zometa started 10/03 with DX of bone mets</td>
<td>5/04</td>
<td><p><u>7 mos</u></p>
<p>Z: 7 mos</p></td>
<td>Dental extraction (1/04), Torus mandibularis, Slow healing and dry
socket after extraction</td>
<td>Pain tooth #30, Poor healing, Infection, Bone exposure right
mandible 5/04</td>
<td>Cytoxan, 5-Fu, methotrexate, tamoxifen, evista, adryamycin/ cytoxan,
Taxol (7/03), Arimidex, Faslodex (5/7/04), Prozac, bextra, ambient,
cipro, calcium, clindamycin, vicoprofen, XRT chest wall 1999, XRT
mediastinum 12/01</td>
</tr>
<tr class="odd">
<td><p>9</p>
<p>(AZ)</p>
<p>9 cont.</p></td>
<td>F/44</td>
<td>Breast ca</td>
<td>10/99</td>
<td><p>A: 11/00 – 2/02</p>
<p>Z: 12/01 – 8/03</p></td>
<td>11/02</td>
<td><p><u>27 mos</u></p>
<p>A: 16 mos</p>
<p>Z: 11 mos</p></td>
<td>Mandibular Tori</td>
<td><p>12/99 – dental visit: mand. tori</p>
<p>11/02: pain right mandible – exposed bone</p>
<p>4/03: stable</p>
<p>10/03: stable</p>
<p>11/03: necrotic area larger</p>
<p>12/03: debridement</p></td>
<td><p>Paclitaxel, FAC, tamoxifen, Herceptin (11/02), navelbine, xeloda,
dexamethasone (10/01</p>
<p>XRT: left hip, WBRT, Lspine, chest wall, axilla</p></td>
</tr>
<tr class="even">
<td><p>10</p>
<p>(A)</p></td>
<td>M/60</td>
<td>MM</td>
<td>1/99</td>
<td>A: 1/99-4/00</td>
<td>5/99</td>
<td><p><u>4 mos</u></p>
<p>A: 4 mos</p></td>
<td>Bone exostosis, Dental extraction 5/99, Periodontal disease 5/99,
smoking – 34 years</td>
<td>5/99: exposed bone after dental extraction (no pain) in maxilla and
mandible; Treated with debridement and antibiotic: resolved 4/04.</td>
<td>Dexamethasone, Cytoxan, Melphalan, Holmium, Pepcid, Valium</td>
</tr>
<tr class="odd">
<td><p>11</p>
<p>(A)</p></td>
<td>F/61</td>
<td>Breast cancer</td>
<td>4/92</td>
<td><p>A : 3/99 – 12/01</p>
<p>Z: 4/02-5/03</p></td>
<td>8/00</td>
<td><p><u>17 mos</u></p>
<p>A: 17 mos</p></td>
<td>Dentures, Dental decay, Periodontal disease, Dental extraction 5/00
with poor healing</td>
<td><p>8/00: gum pain, exposed bone left mandible and maxilla</p>
<p>Controlled with treatment</p></td>
<td>FAC ’92, Methotrexate ’92, Vinblastine ’92, Tamoxifen 10/99,
Exemestane 2/01, Fulvestrant 8/02, Megestrol 6/04, MVI, Celebrex,
Hydrocodone</td>
</tr>
<tr class="even">
<td><p>12</p>
<p>(AZ)</p></td>
<td>F/69</td>
<td>Breast ca, Melamona 1962, Bone mets 9/00</td>
<td>10/97</td>
<td><p>A: 11/00-7/02</p>
<p>Z: 8/02-9/04</p></td>
<td>11/04</td>
<td><p><u>46 mos</u></p>
<p>A: 21 mos</p>
<p>Z: 25 mos</p></td>
<td>Dental decay 5/04, Dental extraction 5/04</td>
<td>Poor healing after extraction, infection, no pain, exposed bone
(11/04) left mandible</td>
<td>Tamoxifen 3/98, Anastrozole, Vioxx, Hydrocodone, Lasix, Bactrim,
Clindamycin</td>
</tr>
<tr class="odd">
<td><p>13</p>
<p>(AZ)</p></td>
<td>F/46</td>
<td>Breast ca</td>
<td>7/01 Bone mets</td>
<td><p>A: 8/01-11/02</p>
<p>Z: 11/02-10/04</p></td>
<td>8/04</td>
<td><p><u>37 mos</u></p>
<p>A: 15 mos</p>
<p>Z: 22 mos</p></td>
<td>Gingivitis, advanced periodontal DZ, dental infection</td>
<td>8/04: pain right mandible, spontaneous bone exposure</td>
<td>Taxol 9/01, Herceptin 2/02, Taxoxifen 2/02, Prilosec, Decadron,
Darvon</td>
</tr>
<tr class="even">
<td><p>14</p>
<p>(AZ)</p></td>
<td>F/61</td>
<td>Breast ca, hypothyroidism</td>
<td>2/00 bone mets</td>
<td><p>A: 2/00-10/02 (~37 doses)</p>
<p>Z: 11/02-10/04 (~23 doses)</p></td>
<td>10/04</td>
<td><p><u>58 mos</u></p>
<p>A: 34 mos</p>
<p>Z: 24 mos</p></td>
<td>Gingivitis, Manipulation of right mandible, implants with poor
healing and infection</td>
<td><p>4/04: right mandible pain – bone exposure</p>
<p>9/04: mand. implants removed, 10/04: 2X1x1.5cm bone exposure site,
Healing well with irrigation, slicept</p></td>
<td>Tamoxifen, arimidex, celebrex</td>
</tr>
<tr class="odd">
<td><p>15</p>
<p>(Z)</p></td>
<td>F/71</td>
<td>MM, DM, Hyperlipidemia, ETOH use</td>
<td>1/00</td>
<td><p>Alendronate (4/00-11/01)</p>
<p>Z: 4/03, 7/03, 8/03, 11/03, 1/04</p></td>
<td>6/04</td>
<td>5 doses, latency 14 months</td>
<td>Dentures (traumatic wound)</td>
<td><p>Gum/jaw pain 4/04, Gingivitis, oseomyelitis, bone exposure</p>
<p>6/04: Eikenella corrodens, Rx’d</p>
<p>7/04: 2X1cm</p>
<p>8/04: debrid</p>
<p>11/04: 0.2X0.7cm</p></td>
<td><p>*steroids – induced diabetes</p>
<p>Dexamethasone 9/00, Valcade 4/03, Revimid 4/03, Interferon 9/00,
Vioxx, Prevacid, Lortab, Zocor, Zoloft, Xanax, Neurontin</p></td>
</tr>
<tr class="even">
<td><p>16</p>
<p>(AZ)</p></td>
<td>F/60</td>
<td>Breast ca, melanoma</td>
<td><p>5/80 bone mets</p>
<p>2/99 last visit to MDA: 9/04 (dead)</p></td>
<td><p>A: 3/99-10/01</p>
<p>Z: 12/01-6/04</p></td>
<td>12/03</td>
<td><p><u>56 mos</u></p>
<p>A: 31 mos</p>
<p>Z: 25 mos</p></td>
<td><p>Periodontal dz, Dental extraction 6/03, slow healing 7/03</p>
<p>*Rx’d with clindamycin, salicept, debridement</p></td>
<td><p>7/03 slow healing: debridement</p>
<p>8/03: debridement</p>
<p>12/03: bone exposure</p>
<p>2/04 dental at MDA: ONJ 2.5x2cm right mandible (biopsy proven)</p>
<p>¾ : 3/2 cm-debridement</p>
<p>¾ healing</p>
<p>5/04: debridement</p>
<p>6/04: healing</p></td>
<td><p>XRT: chest, nodes, L-spine, and brain 7/04.</p>
<p>Taxotere 3/99, Cytoxan 3/99, Cyclophosphamide 3/99, Adriamycin 3/99,
Tamoxifen 6/99, G-CSF 6/99, FEC 5/01, Xeloda 5/01, Aptosyn 5/01,
Navelbine 8/01, Gemcitabine 8/01, Doxil 5/02, Faslodex 5/03, CPT-11
6/04, CMF 6/04, Augmentin, Cipro</p></td>
</tr>
<tr class="odd">
<td><p>17</p>
<p>(Z)</p></td>
<td>F/78</td>
<td>Breast ca, Osteoporosis, Atrial Arrhythmia, anemia</td>
<td><p>4/83 bone mets</p>
<p>8/02</p></td>
<td>Z: 9/02-1/05 (qmo)</td>
<td>10/04</td>
<td><p><u>26 mos</u></p>
<p>Z: 26 mos</p></td>
<td></td>
<td>Being treated outside MDA??</td>
<td>Femara, Tamoxifen, faslodex</td>
</tr>
<tr class="even">
<td><p>18</p>
<p>(Z)</p></td>
<td>F/63</td>
<td>Breast ca, degenerative joint disease,asthma</td>
<td><p>10/02</p>
<p>bone mets 11/02</p></td>
<td><p>Z: started 4/03 outside MDACC</p>
<p>Last Zometa qmo. @MDACC 2/04</p></td>
<td>12/04</td>
<td><p><u>9 mos</u></p>
<p>Z: 9 mos</p></td>
<td>Periodontal disease and tooth extraction 2/04</td>
<td>Facial pain and swelling. Extraction of tooth root 10/04,
pain/swelling and purulent drainage @ extraction site 12/04, poor
fitting denture – trauma 12/04, osteomyelitis left maxilla 12/04.</td>
<td>Femara 10/02, Capecitabine 7/03, Adriamycin 1/04, Cytoxan 1/04,
Fasoldex 7/04, Albuterol, Wellbutrin, Singular, Equagesic, Aleve and
Cipro</td>
</tr>
</tbody>
</table>