1. CP-1 Osteonecrosis of the Jaw (ONJ) and Bisphosphonates Oncologic Drugs Advisory Committee March 4, 2005 Novartis Pharmaceuticals Oncologic Drugs Advisory Committee March 4, 2005 Novartis Pharmaceuticals

2. CP-2 Novartis Presentation ONJ Reported in Bisphosphonate-Treated Patients — An Overview D. Young, MD Novartis Pharmaceuticals Corp Clinical Benefit of Bisphosphonates in Cancer Patients With Metastatic Bone Disease J. Berenson, MD Institute for Myeloma & Bone Cancer Research ONJ Reported in Bisphosphonate-Treated Patients — An Overview D. Young, MD Novartis Pharmaceuticals Corp Clinical Benefit of Bisphosphonates in Cancer Patients With Metastatic Bone Disease J. Berenson, MD Institute for Myeloma & Bone Cancer Research

3. CP-3 External Advisors* James Berenson, MD Medical & Scientific Director Institute for Myeloma and Bone Cancer Research Ana Hoff, MD Assistant Professor Department of Endocrinology University of Texas, MD Anderson Cancer Center Regina Landesberg, DMD, PhD Assistant Professor Department of Oral/Maxillofacial Surgery Columbia University Lloyd Fisher, PhD Professor Emeritus Biostatistics Department University of Washington Salvatore Ruggiero, DMD, MD Chief, Division of Oral & Maxillofacial Surgery Long Island Jewish Medical Center * The views expressed by these individuals are their own and not necessarily those of Novartis Oncology.

4. CP-4 Summary of Presentation (1) Zometa ® and Aredia ® are important medications that reduce complications of bone metastases in patients with solid tumors and multiple myeloma Novartis has actively examined issue of ONJ since first spontaneous reports received in Dec 2002 –ONJ remains poorly understood –Frequency estimates variable; however, ONJ appears to be an infrequent occurrence –Insufficient evidence to support difference between Zometa and Aredia Zometa ® and Aredia ® are important medications that reduce complications of bone metastases in patients with solid tumors and multiple myeloma Novartis has actively examined issue of ONJ since first spontaneous reports received in Dec 2002 –ONJ remains poorly understood –Frequency estimates variable; however, ONJ appears to be an infrequent occurrence –Insufficient evidence to support difference between Zometa and Aredia

5. CP-5 Summary of Presentation (2) Novartis is committed to –Ensuring patient safety –Enhancing understanding of ONJ through additional clinical investigation –Continuing dissemination of evolving information and guidance to health-care providers and patients Balance of benefit-risk for Zometa ® and Aredia ® remains favorable Novartis is committed to –Ensuring patient safety –Enhancing understanding of ONJ through additional clinical investigation –Continuing dissemination of evolving information and guidance to health-care providers and patients Balance of benefit-risk for Zometa ® and Aredia ® remains favorable

6. CP-6 1. Jemal A, et al. CA Cancer J Clin. (2005) 2. Coleman RE. Cancer Treat Rev. (2001) 3. DeVita VT, et al. Cancer Principles & Practice of Oncology. Lippincott Williams & Wilkins. NY (2005) 4. Shoup M, et al. J Am Coll Surg. (2003) Annual estimate new cases - US, x1000 1 Incidence of bone metastases, % 2 Median survival, months 2-4 Myeloma 1670 - 9550 - 67 Renal 3620 - 258 - 21 Melanoma 60 14 - 45 5 - 31 Bladder 63 40 9 - 20 Thyroid 26 60 49 Lung 17330 - 40 17 - 33 Breast 213 65 - 7518 - 24 Prostate 23265 - 7516 - 24 Metastatic Bone Disease is an Important Clinical Problem in Cancer Patients

7. CP-7 Zometa ® and Aredia ® in Metastatic Bone Disease Effective in the prevention of complications of bone metastases in breast cancer and multiple myeloma Zometa is effective in prostate cancer, whereas Aredia is not. Unlike Aredia, Zometa was tested and showed efficacy in other tumor types such as lung, renal, colorectal, and bladder cancer Benefit-risk profile is well established, with known, manageable renal adverse events Recommended in ASCO guidelines for the management of multiple myeloma and metastatic breast cancer patients with bone lesions*, † * Hillner, et al. J Clin Oncol. 2003;21:4042-4057. † Berenson, et al. J Clin Oncol. 2002;20:3719-3736.

8. CP-8 Osteonecrosis (ON): Background Etiology and pathogenesis not well understood –Impaired blood supply leading to ischemia proposed as pathologic process preceding ON* Most commonly seen in hip † Multiple risk factors suspected, including cancer and cancer treatments Bisphosphonates used to treat ON with some success ‡ (NS10-02) Zometa Core presentation ONJ (CO).ppt * Glueck et al (1997). In: Urbaniak JR and Jones JP, eds. Osteonecrosis, AAOS, 105-116 † Assouline-Dayan et al (2002). Semin Arthritis Rheum; 32:94-124. ‡ Agarwala S et al. Rheumatology (Oxford). 2002. * Glueck et al (1997). In: Urbaniak JR and Jones JP, eds. Osteonecrosis, AAOS, 105-116 † Assouline-Dayan et al (2002). Semin Arthritis Rheum; 32:94-124. ‡ Agarwala S et al. Rheumatology (Oxford). 2002.

9. CP-9 Osteonecrosis of the Jaw (ONJ) Involves portion of jaw bone (maxilla or mandible) –No consensus on diagnostic criteria for ONJ Incidence unknown Pathogenesis not understood –Similar risk factors to ON suggested Risk factors specific to jaw bones may play a role –Exposure to external environment through teeth –Risk of trauma from repeated dental procedures Involves portion of jaw bone (maxilla or mandible) –No consensus on diagnostic criteria for ONJ Incidence unknown Pathogenesis not understood –Similar risk factors to ON suggested Risk factors specific to jaw bones may play a role –Exposure to external environment through teeth –Risk of trauma from repeated dental procedures (NS3-19) July15,2004FDAONImeetingslides.doc

10. CP-10 ONJ in Cancer Patients Awareness was limited, now growing ONJ incidence in cancer patients unknown Few literature reports before 2003 1-3 –Most often reported - osteoradionecrosis (ORN) following head and neck radiation Reported incidence of 8.2% 4 Novartis received first spontaneous report of ONJ in IV BP-treated cancer patient in Dec 2002 Awareness was limited, now growing ONJ incidence in cancer patients unknown Few literature reports before 2003 1-3 –Most often reported - osteoradionecrosis (ORN) following head and neck radiation Reported incidence of 8.2% 4 Novartis received first spontaneous report of ONJ in IV BP-treated cancer patient in Dec 2002 1. Winer et al. J Am Dent Assoc. (1972) 2. Schwartz. Head Neck Surg. ( 1982) 3. Sung et al. Spec Care Dent. (2002) 4. Reuther et al. Oral Max Surgery. (2003) (NS10-04) Zometa Core presentation ONJ (CO).ppt - Slide 4

11. CP-11 Review of Available Data on ONJ Clinical trials Spontaneous reports to Novartis Literature MD Anderson Cancer Center study Clinical trials Spontaneous reports to Novartis Literature MD Anderson Cancer Center study

12. CP-12 Limitations in Existing Datasets Available Datasets Controlled clinical trials –Most meaningful, quality assured, source verified, reliable –Lack of awareness of ONJ, follow-up to be updated Spontaneous reports (Novartis database) –Incomplete case data –Diagnostic, selection, and reporting biases Literature –Reports: anecdotal, completeness of data unknown –Web survey: uncontrolled, anonymous, selection bias, QA, and source verification MDACC –Planned retrospective review –Ongoing, 25% completed Controlled clinical trials –Most meaningful, quality assured, source verified, reliable –Lack of awareness of ONJ, follow-up to be updated Spontaneous reports (Novartis database) –Incomplete case data –Diagnostic, selection, and reporting biases Literature –Reports: anecdotal, completeness of data unknown –Web survey: uncontrolled, anonymous, selection bias, QA, and source verification MDACC –Planned retrospective review –Ongoing, 25% completed

13. CP-13 Review of Available Data on ONJ Clinical trials Spontaneous reports to Novartis Literature MD Anderson Cancer Center study

14. CP-14 Screening for Potential ONJ Cases Novartis Databases Lack of clear definition poses a challenge No current MedDRA term Novartis used a wide net of 18 MedDRA terms: Bone debridement Jaw lesion excision Jaw operation Mandibulectomy Maxillofacial operation Oral surgery Aseptic necrosis bone Bone infarction Necrosis Osteomyelitis acute Osteomyelitis chronic Osteomyelitis drainage OsteomyelitisOsteonecrosis Primary sequestrum Secondary sequestrum Sequestrectomy Tertiary sequestrum Screening results medically reviewed to identify ONJ

15. CP-15 Novartis Current “Case Definition” Any case or report suggestive of the following to maxillofacial area was considered “ONJ” –Osteonecrosis –Osteomyelitis –Exposed bone –Bone necrosis –Sequestrum –Impaired healing post-dental procedure

16. CP-16 Pivotal Trials: Study Design and Follow-up (1) TrialPatient populationTreatment, mgN Follow-up Median, mo Cum dose Median, mgONJ P12MMA 902051814851, MM Placebo187150 P18BC-hormonalA 90182171440 Placebo190150 P19BC-ChemotherapyA 90185131440 Placebo197100 007MM and BCZ 0.4/862104 Z 2/8621020 Z 4/85910401, MM Z/A*3040N/A1, MM A 907510N/A 036HCMZ 44614 Z 85118 A 9052190 037HCMZ 44014 Z 847181, H&N A 9051190 25 *Dose of Zometa ® is variable, Aredia ® dose 90 mg. N/A = Not available; Z = Zometa; A = Aredia.

17. CP-17 Pivotal Trials: Study Design and Follow-up (2) TrialPatient populationTreatment, mg N Follow-up Median, mo Cum dose Median, mgONJ 010BC and MMZ 456314561, MM Z 8/452413104 A 90556131,260 011Lung cancer and other solid tumors (-BC/PC) Z 4254624 Z 8/4265540 Placebo24750 039HRPC with bone metastases Z 42141358 Z 8/42181096 Placebo208100 704HRPC without bone metastases Z 4491654 Z 8/4152241101, PC Placebo197240 Open label phase 1151336 1501BCZ 41141352 Placebo113130 25 Z = Zometa ® ; A = Aredia ®.

18. CP-18 Pivotal Trials: ONJ Cases* Treatment Number of patients Number of ONJ casesTumor type Aredia ® 90 mg13342†2†MM Zometa ® (total)2730 4 mg12841MM 8 mg2191H & N 8 + 4 mg12272PC MM Placebo13470 (NS4-13) Zometa Briefing Document January 2005.doc Table 4-4 * Trials included in search: Zometa trial: 007, 010, 011, 039, 704, 036, 037 and 1501 Aredia: P12, P18, P19 †Includes 1 patient who received Zometa 0.4 mg ×10 * Trials included in search: Zometa trial: 007, 010, 011, 039, 704, 036, 037 and 1501 Aredia: P12, P18, P19 †Includes 1 patient who received Zometa 0.4 mg ×10

19. CP-19 ONJ Cases in Pivotal Trials (1) Case Diagnosis/ site YearDrug, mgTTERisk factors CTC grade/ outcome 1. MMASN/Mandible 1999 Z 0.4 A 90 28 moTooth abscess, HZV, Candida, steroids, chemo Grade 2-3 Mandibular fracture 2. MMOM/Jaw 1992 A 9014 moPoor dentition, steroids, chemo Grade 2 Unknown 3. MMOM/Jaw 2001 Z 422 moDental infection, chemo, steroids Grade 1 Continued MM = Multiple myeloma; H&N = Head and neck cancer; PC = Prostate cancer. OM = Osteomyelitis, ON = Osteonecrosis, ASN = aseptic necrosis MM = Multiple myeloma; H&N = Head and neck cancer; PC = Prostate cancer. OM = Osteomyelitis, ON = Osteonecrosis, ASN = aseptic necrosis

20. CP-20 ONJ Cases in Pivotal Trials (2) Case Diagnosis/ site YearDrug, mgTTERisk factors CTC grade/ outcome 4. H&NON/Maxilla 1999 Z 813 daysChemoGrade 2 Continued 5. PCOM/Jaw 2002 Z 8/427 moDental abscess, tooth extraction Grade 2 Unknown 6. MMOM/Mandible 1998 Z 4/818 moJaw infection, steroids, chemo Grade 2 - 3 R. mand. excision MM = Multiple myeloma; H&N = Head and neck cancer; PC = Prostate cancer. OM = Osteomyelitis, ON = Osteonecrosis, ASN = aseptic necrosis MM = Multiple myeloma; H&N = Head and neck cancer; PC = Prostate cancer. OM = Osteomyelitis, ON = Osteonecrosis, ASN = aseptic necrosis

21. CP-21 ONJ Cases: Other Trials Completed trials: no ONJ cases as of Jan 2005* –23 trials in Zometa ® program (N = 3428) –Zometa3217 –Aredia125 –Placebo86 –26 trials in Aredia ® program (N = 1401) –Aredia1214 –Placebo187 Ongoing trials: 4 ONJ cases reported –> 10,000 patients enrolled Completed trials: no ONJ cases as of Jan 2005* –23 trials in Zometa ® program (N = 3428) –Zometa3217 –Aredia125 –Placebo86 –26 trials in Aredia ® program (N = 1401) –Aredia1214 –Placebo187 Ongoing trials: 4 ONJ cases reported –> 10,000 patients enrolled *Except for 1 case of osteomyelitis of the jaw (OMJ) that existed prior to study entry.

22. CP-22 ONJ Cases in Ongoing Zometa ® Trials* (NS4-13) Zometa Briefing Document January 2005.doc Table 4-4 Zometa trialPatients, N ONJ cases, nDiagnosis Infusions prior to event, n Tumor typeRisk factor 2408 † 10361Osteonecrosis4BCDental infection, extraction, chemo, steroids DE073091**Osteomyelitis9PCPre-existing OM of jaw KR02401Osteomyelitis12BCChronic dental infection DE011011Osteonecrosis15MMSpontaneous tooth loss, tooth extraction, dental abscess † This study is not sponsored by Novartis. * All studies use Zometa 4 mg. ** Patient had pre-existing osteomyelitis of the jaw at study entry.

23. CP-23 Review of Available Data on ONJ Clinical trials Spontaneous reports to Novartis Literature MD Anderson Cancer Center study

24. CP-24 (NS4-8) Zometa Briefing Document January 2005.doc Table 4-2 Spontaneous Reports Of ONJ* Zometa ® or Aredia ® † As of 07 Dec 04 Total 610 ‡ Total patients exposed DrugAredia Zometa Both 119 248 243 1.9 million 1 million CountriesUS Non-US 440 170 IndicationMultiple myeloma Breast Other 218 125 267 * Includes reportable cases from the literature. † The number of reported cases from generic pamidronate is unknown. ‡ 91% of patients diagnosed with ONJ and 28% diagnosed with osteomyelitis.  As of 22 Feb 2005, total reports = 875

25. CP-25 Spontaneous Reports Of ONJ Reported Risk Factors Reported risk factorsReports, n (%) At least 1 risk factor in addition to cancer450 (74) Corticosteroids † 230 (38) Chemotherapy † 315 (52) Hormonal therapy63 (10) Radiotherapy to head and neck28 (5) Anemia89 (15) Thalidomide89 (15) Transplant57 (9) Other ‡ 263 (43) †In 188 (31%) reports the patients had received both corticosteroids and chemotherapy. ‡Broad criteria used, including all conditions and medications with potential impact on bone metabolism. Includes 3 patients with herpes virus infection of the maxillofacial area. (NS9-12) Zometa Mar 4, 05 ODAC Meeting Briefing Appx 3.doc

26. CP-26 Spontaneous Reports Of ONJ Reported Dental Events At least 50% of cases (n = 303) reported dental events preceding the diagnosis of ONJ (NS9-11) Zometa Mar 4, 05 ODAC Meeting Briefing Appx 3.doc Dental eventsn (%) Prior extraction252 (83) Dental problems, procedures (other than extraction) 26 (9) Other (eg, tooth abscess, trauma)16 (5) Denture trauma9 (3)

27. CP-27 Spontaneous Reports Of ONJ Reported Outcomes Outcome Bisphosphonates ContinuedDiscontinuedTotal ‡ Recovered/Improved § 133245 No change2186107 Deteriorated71017 Unknown94655 Total50174224 ‡ 224/610 reports assessable for outcome analysis. § Also includes recovered with sequelae.

28. CP-28 Spontaneous Reports: Time to Onset of ONJ Direct comparison of time to onset between Zometa ® & Aredia ® is not feasible –No common definition of ONJ –Aredia available since 1991, Zometa since 2001 –Utilization of Aredia has declined significantly since 2001 (including generic introduction) –Recent awareness could have accelerated diagnosis of ONJ –Concurrent therapy has changed significantly over time with contribution unknown Direct comparison of time to onset between Zometa ® & Aredia ® is not feasible –No common definition of ONJ –Aredia available since 1991, Zometa since 2001 –Utilization of Aredia has declined significantly since 2001 (including generic introduction) –Recent awareness could have accelerated diagnosis of ONJ –Concurrent therapy has changed significantly over time with contribution unknown

29. CP-29 Review of Available Data on ONJ Clinical trials Spontaneous reports to Novartis Literature MD Anderson Cancer Center study

30. CP-30 (NS4-7) Zometa Briefing Document January 2005.doc Table 4-1 Literature Reports of ONJ Author ONJ patients reported, nJournalMethodology de Almeida, de Araujo, and Pire 5Rev Bras Oncologia Clinica (Brazil), 2004 Case report Bagan10J Oral Pathol Med, 2004Case report, manuscript Durie62Blood, 2004Abstract, anonymous Web-based survey Thakkar14Blood, 2004Case reports, abstract Van Poznack6San Antonio Breast Cancer Symposium, 2004 Clinical database review, abstract Ruggiero et al.63J Oral Maxillofac Surg, 2004 Case reports Marx36J Oral Maxillofac Surg, 2003 Letter to the editor case reports

31. CP-31 Literature Report of ONJ: Ruggiero et al. 2004 * 63 cases between Feb 01- Nov 03 –MM (28), BC (20), prostate (3), other (5), no cancer (7) –Pamidronate (57%), zoledronic acid (31%), oral BP (12%) –71% female –Mandible (63%), maxilla (37%) –Typical presentation: pain, non-healing extraction socket, exposed bone –Other treatments: chemotherapy –Previous dental procedure: 86% –Majority required surgical removal of involved bone 63 cases between Feb 01- Nov 03 –MM (28), BC (20), prostate (3), other (5), no cancer (7) –Pamidronate (57%), zoledronic acid (31%), oral BP (12%) –71% female –Mandible (63%), maxilla (37%) –Typical presentation: pain, non-healing extraction socket, exposed bone –Other treatments: chemotherapy –Previous dental procedure: 86% –Majority required surgical removal of involved bone * Ruggiero SL, et al. J Oral Maxillofac Surg; 2004; 62 (5):527 - 534.

32. CP-32 Literature Report of ONJ: Durie et al. 2004* Web-based patient survey Key issues –Data reliability/quality Anonymous responders Unable to assure data quality Potential bias & analyses considerations –Patients with an event, more motivated to respond –Patients with more recent event, may be more likely to respond Kaplan-Meier & logistic regression must be interpreted with caution –Not adjusted for time as confounding factor –Impact of approval / launch / usage time Aredia ® approved since 1991 & Zometa ® since 2001 * Durie et al. Blood 2004;104:Abstract 756.

33. CP-33 Review of Available Data on ONJ Clinical trials Spontaneous reports to Novartis Literature MD Anderson Cancer Center study

34. CP-34 MD Anderson Cancer Center Study Objectives and Methods Principal Investigator: Ana Hoff, MD Objectives † –Identify ONJ cases in cancer patients treated with IV BPs to estimate frequency –Identify risk factors associated with ONJ Methods –Retrospective chart review in past 10 yr All IV BP users (N = 4032) Identify patients with ONJ and ON of other sites 963 charts reviewed by Jan 12, 2005 Issue: Non random chart review –Charts sorted by pharmacy records based on number of BP infusions (highest to lowest) –7 charts reviewed out of sequence because ONJ was suspected Principal Investigator: Ana Hoff, MD Objectives † –Identify ONJ cases in cancer patients treated with IV BPs to estimate frequency –Identify risk factors associated with ONJ Methods –Retrospective chart review in past 10 yr All IV BP users (N = 4032) Identify patients with ONJ and ON of other sites 963 charts reviewed by Jan 12, 2005 Issue: Non random chart review –Charts sorted by pharmacy records based on number of BP infusions (highest to lowest) –7 charts reviewed out of sequence because ONJ was suspected † Amendment to expand the review to non-bisphosphonate users being considered. (NS10-11) Zometa Core presentation ONJ (CO).ppt

35. CP-35 MD Anderson Cancer Center Study Interim Data: ONJ Cases by Tumor Type (NS4-16) Zometa Briefing Document January 2005.doc Table 4-7 Tumor typePatients (N)ONJ cases (n) Breast cancer63111 Multiple myeloma1486 Renal cell carcinoma32– Prostate cancer18– Lung cancer17– Lymphoma13– Others891* Noncancer15– Total96318 * Thyroid cancer

36. CP-36 (NS4-18) Zometa Briefing Document January 2005.doc Table 4-8 Time from first BP to ONJ, mo Median (range)30 (4 – 57)* Bisphosphonate received, n Aredia ® only4 Zometa ® only3 Alendronate then Zometa1 Aredia then Zometa10 MD Anderson Cancer Center Interim Data: 18 Cases * 4 months on Aredia. 57 months on Aredia followed by Zometa.

37. CP-37 ONJ in Cancer Patients Treated With BPs Frequency Estimates DatabaseFrequency estimateAssessment Spontaneous reports875 of 2.9 million (0.03%) Likely under-estimate Controlled clinical trials6 of 4056 pts (0.15%)Follow-up needs to be updated MDACC18 cases of 963 charts (1.9%) Review not complete Web-based survey (Durie) 75 of 1203 (6.2%) of respondents reported ONJ Likely over-estimate

38. CP-38 ONJ in Cancer Patients Treated With BPs: Open Questions –Natural history –Clear case definition Diagnostic criteria Staging system Severity measures –Time to onset –Risk factors –Prevention measures –Treatment algorithm –Causality –Natural history –Clear case definition Diagnostic criteria Staging system Severity measures –Time to onset –Risk factors –Prevention measures –Treatment algorithm –Causality (NS3-19) July15,2004FDAONImeetingslides.doc

39. CP-39 Novartis Initiatives

40. CP-40 2002 2003 2004 2005 Novartis Initiatives—Completed Activities 12/02 First ONJ report to Novartis 9/03 – 11/03 Zometa ® PI update/ Aredia ® PI update (NS21-5) 12/03 Ad. board #1 (understand ONJ) 3/04 Ad. board #2 (generate guidelines; “white paper”) 1/03 Initiate f/u & data collection on cases 2Q-3Q Oncologist & dental surgeon visited to collect data 6/04 Distribution of the “white paper” at ASCO 9/04 Distribution of “Dear Doctor” letter 2/05 ASCO burst (FDA) 5/04 Patient initiative/Generation of education materials 4/04 initiate MDACC study 8/04 Zometa and Aredia labels revised 3/04 Updated PIs with additional ONJ info 4/04 IC changes made

41. CP-41 Recommended Management of ONJ Advisory Panel – March 24, 2004 (1) Diagnosis –Typical symptoms: pain, soft-tissue swelling and infection, loose teeth, and exposed bone –Imaging (eg, panoramic and tomographic), biopsy, and cultures may be helpful Treatment –Nonsurgical approach preferred: minimal debridement, cover exposed bone, protective stint –Antibiotics, antifungal and antiviral agents, oral rinses –Close follow-up, and cessation of BP therapy may be considered. Risk of SRE needs to be considered when stopping BP therapy Diagnosis –Typical symptoms: pain, soft-tissue swelling and infection, loose teeth, and exposed bone –Imaging (eg, panoramic and tomographic), biopsy, and cultures may be helpful Treatment –Nonsurgical approach preferred: minimal debridement, cover exposed bone, protective stint –Antibiotics, antifungal and antiviral agents, oral rinses –Close follow-up, and cessation of BP therapy may be considered. Risk of SRE needs to be considered when stopping BP therapy

42. CP-42 Recommended Management of ONJ Advisory Panel – March 24, 2004 (2) Prevention –Avoid elective jaw procedures –Routine dental exams including panoramic radiograph –Tooth extraction prior to BP therapy if possible –Preventive dentistry prior to chemotherapy –Patient education regarding importance of good hygiene –Oncologist to perform visual inspection of oral cavity prior to BP therapy and at each follow-up visit –Cessation of BP therapy may be considered if oral surgery required, risk of SRE needs to be considered when stopping BP therapy Prevention –Avoid elective jaw procedures –Routine dental exams including panoramic radiograph –Tooth extraction prior to BP therapy if possible –Preventive dentistry prior to chemotherapy –Patient education regarding importance of good hygiene –Oncologist to perform visual inspection of oral cavity prior to BP therapy and at each follow-up visit –Cessation of BP therapy may be considered if oral surgery required, risk of SRE needs to be considered when stopping BP therapy

43. CP-43 Patient Outreach With Advocacy Groups Meeting held May 2004 –9 patient advocacy groups attended representing multiple tumor types (breast, myeloma, prostate, lung, and kidney) Additional follow-up with 14 groups (Dec 2004/early 2005) Planned activity: post ODAC briefing teleconference with patient advocacy groups Meeting held May 2004 –9 patient advocacy groups attended representing multiple tumor types (breast, myeloma, prostate, lung, and kidney) Additional follow-up with 14 groups (Dec 2004/early 2005) Planned activity: post ODAC briefing teleconference with patient advocacy groups (NS22-17) Patient Advocacy ONJ.ppt slide 1

44. CP-44 Patient Brochure Definition, signs, and symptoms of ONJ Routine dental hygiene for patients with cancer Dental care recommendations to patients with cancer Urge patients to communicate with physicians and dentists regarding adverse events (NS21-1) “Taking Care of Yourself While Living With Cancer: Dental Health and Osteonecrosis of the Jaw” Novartis Patient Information Brochure. 2004. Taking Care of Yourself While Living With Cancer Dental Health and Osteonecrosis of the Jaw

45. CP-45 Clinical Investigations – Actions Planned Develop case definition and severity scale with expert panel Obtain follow up data on patients from pivotal trials for ONJ Develop CRF to capture data regarding ONJ in ongoing studies Implement new studies that include prospective monitoring for ONJ Develop case definition and severity scale with expert panel Obtain follow up data on patients from pivotal trials for ONJ Develop CRF to capture data regarding ONJ in ongoing studies Implement new studies that include prospective monitoring for ONJ

46. CP-46 Clinical Investigation – New Studies Retrospective chart review for ONJ in MM patients (initiate 2Q 2005) Prospective studies to include ONJ assessment –Study 2352: MBC and MM (initiate 4Q 2005) –SWOG 0307: Adjuvant BC (under discussion) Prospective registry for ONJ or ONJ natural history study (2H 2005) Retrospective chart review for ONJ in MM patients (initiate 2Q 2005) Prospective studies to include ONJ assessment –Study 2352: MBC and MM (initiate 4Q 2005) –SWOG 0307: Adjuvant BC (under discussion) Prospective registry for ONJ or ONJ natural history study (2H 2005)

47. CP-47 Phase III Randomized Trial With Zometa ® Study 2352 Design Breast cancer/myeloma + bone metastasis Zometa pretreated: 12 mo N = 3513 Arm 1, n = 1,405 Zometa 4 mg q 3-4 wk Arm 2, n = 1,405 Zometa 4 mg q 3 mo Arm 3, n = 703 Placebo q 4 wk 13-month analysis for efficacy and safety* 0 * Primary efficacy endpoint: Time to first SRE Randomization 2:2:1 + Rescue: Zometa 4 mg q wk after first SRE

48. CP-48 SWOG 0307: Study Design Randomized phase III trial; NSABP 34 replacement trial Stage I, II, and III breast cancer on standard adjuvant therapy (n = 6000) Randomized phase III trial; NSABP 34 replacement trial Stage I, II, and III breast cancer on standard adjuvant therapy (n = 6000) RANDOMIZERANDOMIZE Zometa ® * 4 mg IV q mo x 6 mos, q 3 mos x 2.5 yrs Clodronate* 1600 mg PO daily x 3 yrs Ibandronate* 50 mg PO daily x 3 yrs *Daily supplemental calcium (1000 to 1500 mg) and vitamin D (400 to 800 IU) (NS22-2) Leo’s SWOG slides.ppt slide 2

49. CP-49 SWOG 0307: Osteonecrosis of the Jaw Surveillance Plan Objective:Evaluation of risk factors for osteonecrosis of the jaw Schedule:- Dental exams at baseline and end of study (completed by a dental health professional) - Standard dental exams and care while on study Required Exam:- Visual dental inspection and periodontal probing - X-rays only to assess degree of periodontal involvement and endodontic problems Documentation:- Completion of S0307 Dental Examination Form, Osteonecrotic Jaw Lesion Form, Treatment Summary Form, & Supplementary Follow-up Form - Consultation with S0307 Jaw/Dental Health Coordinator for any patient diagnosed with osteonecrosis of the jaw (Dr. Mark Shubert, DDS, MDS) Patient Information: - Patients are requested to avoid dental procedures while on myelosuppressive chemotherapy - Patients are expected to undergo standard dental exam and care while on study - Osteonecrosis of the jaw was listed as one of the possible side effects of zoledronic acid in the S0307 Inform Consent Form (NS22-3) Leo’s SWOG slides.ppt slide 3

50. CP-50 ONJ Monitoring in Clinical Trials: Proposal Physical examination of head & neck and oral cavity to –Rule out metastatic involvement –Detect Breach of the oral mucosa Exposed bone Imaging –Panoramic radiograph Assessment frequency based on tumor type and stage of disease (minimum: baseline, q6 months) Develop specific case report forms –Dental exam –ONJ assessment Physical examination of head & neck and oral cavity to –Rule out metastatic involvement –Detect Breach of the oral mucosa Exposed bone Imaging –Panoramic radiograph Assessment frequency based on tumor type and stage of disease (minimum: baseline, q6 months) Develop specific case report forms –Dental exam –ONJ assessment

51. CP-51 Conclusions

52. CP-52 Conclusions (1) Zometa ® and Aredia ® are important medications that reduce complications of bone metastases in patients with solid tumors and multiple myeloma Novartis has actively examined issue of ONJ since first spontaneous reports received in Dec 2002 –ONJ remains poorly understood –Frequency estimates variable; however, ONJ appears to be an infrequent occurrence –Insufficient evidence to support difference between Zometa and Aredia Zometa ® and Aredia ® are important medications that reduce complications of bone metastases in patients with solid tumors and multiple myeloma Novartis has actively examined issue of ONJ since first spontaneous reports received in Dec 2002 –ONJ remains poorly understood –Frequency estimates variable; however, ONJ appears to be an infrequent occurrence –Insufficient evidence to support difference between Zometa and Aredia

53. CP-53 Conclusions (2) Novartis is committed to –Ensuring patient safety –Enhancing understanding of ONJ through additional clinical investigation –Continuing dissemination of evolving information and guidance to health-care providers and patients Balance of benefit-risk for Zometa ® and Aredia ® remains favorable Novartis is committed to –Ensuring patient safety –Enhancing understanding of ONJ through additional clinical investigation –Continuing dissemination of evolving information and guidance to health-care providers and patients Balance of benefit-risk for Zometa ® and Aredia ® remains favorable