(case Document 320-3 Filed 03/02/12 Page 470 of 550 23110 From? LEFKOWITH, JAMES B. Sent: Friday, September 08, 2000 8:56 Toi ARBE. EMILIO Subject: RE: CLASS Data . Emilio- I think that it might be a good Idea for you to' discuss your concerns with me directly before matting any more statements regarding the issues that concern you, I believe that you do not fully understand the data andthe analysis. Jim Lelltowlth - --"Original lVloss ge_ Fromt AREIE, EMILIO 30] Sent: Friday, September DB, 2000 6:57 AM To: SHIELD, MICHAEL JADEREERG, MAGNUS FORREST, DAVID Co: LEFKOWITH, JAMES El. HAMELIN, PAUL R. 8201. Sublect: RE: GIASS Data The results I quote are lifted from the study report. double-chectt that alt the figures are correct and I havent made any gross rnlsinterpretatlons. Emilio original Mes'-age From: SHIELD, Sent: Thursday, September 07, 2000 0:23 AM- EXHIBIT To: JADERBERG, FORREST, DAVID Co: LEFKDWITH, JAMES El- HANIELIN, PAUL R. |!1820]; ARBE, EMILJD - Subtest: RE: CLASS Data - 6? Magnus, I haven*t seen these data presented In this way before so cannot judge properly the validity of what Emilio ls stating. I would agree that the analyses reported ln JAMA are not exactly as stated-In the original protocol. Tl-ioro are though I understand from the 'group good reasons for what has been done. ln my-notes from the presentation made here last week by Jim Lefkowith I see that he used the term "refined" as applied to the subsequent dats analyses. The six months issue, as explained by Jim was to set a polnt which all patients had completed (taking into account earlier withdrawals up to that time). don't know whether you were at the EULAR conferencetdune 2000) but it you were and attended the Searle/Phzor symposium then you would have heard the considerable debate there was re 'intent-to-treat". In a trfuo "lntent~to-treat" there is actually a need to follow-up ALL patients for the ENTIRE treatmentperlod (whatever period is defined) whether or_ not they have withdrawn from the original test medications. In practice this israrety done and these cliehates aldout largely semantic ones. ln-'thc real-world one know, rroyons whether or not a treatment produces'a desired effect and whether or not there' are undesirable effects of any consequence. Emitio's statements that there are no dltlerences between Celebrex and re spiioustsl events I find and as Indicated above I havent seen the- data- before. From what have' seen I am satisfied thatln the non-aspirin group (which of the patients treated and which ls comparable to the VISOR study ln the sense thatpatlents lit the Merck- not use aspirin, except by protocol violation) that we have a statistically stgnihcantoutcome for Celebrex versus Ibuprofen' and-`Diclofensc. When combining the results for both NSAIDs one does not see statistically significant differences for'Celebrex vs NSAIDII1 the opsirin taking population. My only comments about that are twofotd. First, that ls what one would expect ln that Celebrex doesn't have any protective ellect against aspirin (unlike _say the rnlsoprostol component in Arlhrotec) so I would expect to see exactly the earns sort_of result In takers of a drug titre psracetarnol which as lar as we know is non-GI damaging. The second point is that I believe our rlata le actually better than we have currently fiubjeot To Protective Order 00| lSt1t'?5 Case Document 323-3 Filed 03/02/12 Page 477 ol 550 Pagelljt B111 presented in the public domain in that when one looks at the separate NSAIDs there is a greater GI-event rate on than on celcbrext- aspirin. This, believe, is readily ln terms of tlte differing pharrnacodyna mic effects of celebrex and diclofenac on platelet function (beneficial towards Celebrex). This. though,l atn happy to set to one side as the folks have done to save unduly complicating the massage, tltough ln doing so we do lose to some extent a potential advantageous ppolr|t_ Consequently ln summary re the Gt event rates everything I have seen demonstrates, to me at least, that we have clear separation of celebrex from dlclo and ibuprofen. The Kaplan-lvlaier plots which take into account differential exposure times show that very elegantly. Re the tolerability profile think lt has to be stressed, from the outset, that the CLASS study was never intended to be other than a study to focus on whether or not the drug retained specificity CLINIGALLY end to demonstrate thatlt was decided (ln fact demanded bythe FDA) that twice the maximum therapeutic dose should be used. Consequently if one does obtain reasonable tolerability at this dose that ln itself would be remarkable glventhat no NSAID can be used at twice its maximum therapeutic dose without causing SEVERE intolerance (e.g what tolerability prohle would you expect to see at 300mgfday of diclofenac). Consequently an overall GI profile for Celebrex B00mgfday which was unquestionably better (statistically so) than diclofenac at i50mgfday and which was virtually the same seen with ibuprofen has think to' be regarded as_a good result. Additionally re both dlclo and ibuprofen Celebrex demonstrated, at this dose, a better- prohle re biochemistry and renalland on EP and on potential to cause anaemia as detected by Hb changes. point re rash really singles out one item that is very readily take the incidence ol rash tn the CLASS study as an indicator of tolerability appears to me to be erroneous for the following reasons, As pointed out in the original Integrated Safety Summary (ISS) prepared for registration submissions by Rti.D (page 332, document as is reflected ln the' "Skin" adverse events section _(p24 BM) oi the "_Celecoxib Clinlcal_Summary" which wrote for the EU submission, celecoxib demonstrates a"dos-Je-related increase in rash, This ls the LACK of dosefresponse seen. with celecoxlb, as far as I am aware, for any other adverse event. The ISS on page 332 states: 'There was an lndrease ln incidence of rash at higher celecoxlb doses, with the maximal incidence of 3.4% associated with the 400mg BID dose, thus suggesting a doe-response relationship". Emilio certainly has access to, and thought had seen, both o_f these documents. tl _the mechanism. which as yet is unknown, is exposure-duration related than obviously in longer studies at high dose (above the therapeutic dose currently recommended) the incidence increase. As pointed out above, the study was not there to examine the overall side effect profile of celec'oxil_t_ That was very satisfactorily done in the registration studies. The findings re rash in the CLASS study merely confirm what we already know about the product._l have no hesitation- in that on this basis we can focus on the-Gt-event rates from GLASS without having to focus on the other findings for the reasons stated. The TGLEFQABILITY PRGFILE and other ADE profile from the extensive database we have at theraputto doses is perfectly satisfactory, _and In fact isbetter than the GLASS. data, for our medical tit marketing colleagues to use to demonstrate our superiority over NSAIDs. (l made the latter point at lastwoek's UK marketing rneetlng with Jim Lefkowith) am a great believer' ln such discussion points belrtg_out'ln the open and also in encouraging people to raise their issues sothat they can be is only fair that Jim Left-cowith should have the opportunity torsee arf|d=respond to ErniliQ's points-since Jitn has lived with and-breathed the CLASS data over the past several tnontl-is and has seen the detain much greater depth than me - hence- I have copied on this reply to you. Magnus. _ln that way hopefully we can focus on the facts and see exactly where the truth Iles. would hope that in this process discussion can be held without any parties the discusslont A lack of objectivity ls always dangerous". Regards Michael Message- Frornt JADERBERG, MAGNUS Sent: D7 September 2000 05:01 Tel SHIELD, MICHAEI. FORREST, DAVID Subject CLASS Data nl Subject To Protective FS 00| 13.175 Case Document 328-3 Filed 03/02/1? Pagc -1178 ni 5:50 Pac]e|D ella Please see Emtllo's comments below any comments from Michael who has followed this study from the beginning? - The rest of us have a lot to catch up on and so not that easy to advice Emilio although lt ls clearly ot concern to hear someone on 'the Inside' express these views. 1 Magnus Fonrrard Header Subject: CLASS Data Author: El'vl|LlO ARBE at Exchange Date: 04fO9r'2000 10:19 Dear Magnus, . Since you brought up the subject this morning, here is what think about CLASS. The study was set out to demonstrate lhathased on a withdrawal rate of up to 35%, patients would experience clinically significant UGI adverse evans at a rate of 0.3% per year with and 1.2% per year with as a group The protocol did not specify that the endpoint would be assessed at 6 months only. An Interim analysis was planned, but this was only to make sure that- enough events had occurred so that the dltlerenccs would be statistically significant by the end of the study, which was 12 months. There are sever.al flaws In the waythat we present the data. We claim that wo cannot compare the groupe at 12 months because the' drop out rate was so much higher in tho diclofenac group. In fact at 23.5 %`it was lower than expected and not that different from celecoxlb with 22.4% and lbuproten`23%. The fetal number of events required, which was 37,1/vas actually met as there were 35 in total, 17 with celcoxib, 10 with diclofenac and 11 with ibuprofen. Considering that twice as many patients had been treated with celecoxlb, this equated toannual rates of 0-50% and 0.55% percent, None ot the differences were statistically significant. ll oneloolts at the subset of patients who did not take aspirin, which we so much publicise, the rates were 0.26%, 0.26% and again with no statistically significant differences. Wltha bit of_ data rnassage,.what Steve Gels and his team-l1ave_done ls to focus rrtonth data, forfrio .sitter reason-'that it and this time -tlteyconcentrate on the non aspirin treated patients, the fact- that-at no time-Interval didwa sees 'statistically difference with diclofenac, wltethei' one loolts at riot, aid 'dr at 12 months. Unfortunately, UK doctors' would only bc interested ln looking at- the rate of GI events with diclofenac since such a high dose of ibuprofen ls rarely used. ln terms 'of tolerability-the results are also disappointed, in that the rates of withdrawal due to dyspepela were 4.4% and 3.9% for celebrex, diclofenac and ibuprofen6.2% of rash, which was statistically' significantly. greater to that seen for the-diclofenac _and ibuprofen groups. So much for our delivering lastingcontrol ln arthritis claim based on Improved safety profiles. - In my opinion though, th_ese results do not say much about Celebrex used at therapeutic doses, and hence our interest ln collecting some more meaningful data' through a SAMM study. Probably then. the annual complication rate is 0.3% Subject To Protective Dr-der 131] 3 13417 Case Document 328-3 Filed Page 479- of 550 i 8113 i ee expected and there is prolfielnly tolerability advantage ee seen in the Emery study, celebrex 200 mg bid vs diclofenac 75 mg bid over 6 months in RA. The point I em trying to melee though is that i:lon't see what is so greet about CLASS- Personnelly it bizarre tlretwe would wont to roll out the data to opinion leaders who ererft necessarily dupe and I woulcln't feel too comfortable presenting fuclged version of the facts. Any guidance from your side is ol course welcome. Kind regards, Emilio Ollfideltiinl - Protective DEFS OO Case Document 328-3 Filed 03/02/12 Page /481 of 550 8115 From: Wahoo, Mona Sent: Tueedey, May 22, 2001 5:17 PM To: Cristo, Stephen Subject: CLASS manuscripts for review: Urgent attention required Hnponanee: Iinh I Follow Up Flag: Followup Due By: 'Mend-ey, May 21, 2001 12:00 PM Flag Status: Ftagged smanusmpt; 1 "ee--Original From: Wahba, Mone Bent: Monday, May 21, 2001 2:03 PM To; Denton, James; Harrie, Andrew; Silber, Beth Ann; Pettitt, Dan; Sirote, Eric; Eahrt, Kenneth; Shefner, Lori 3; Fletcher, Merk Cary, Meg; Gavigan, McElwee, Newell Subject: FW: CLASS manuscripts for review; Urgent attention required Importance: High . Deer All, Please see my comments attached, i'd recommend to refer to the conclusions of the eecond attachment in the CVS ms. In my opinion, the GI me ie apologetic, weak and not convincing, since ex did not show etatiatical difference from Diclo oven using the combined endpoint. We'ere oloo cherry picking the data u5ing.6 HE study duration). There is a need tc sharpen the story around the effect of GI withdrawals in the diclo group and the effect of ASA ae a confounding factor on the expended endpoint if we decide to publish this me. . - Do we have the newly created tablee eupporting these 2 me to QA the Me? Mona M. Wahha, M.D. Pfizer Global Research and Development Office; B50 441 B950 Mobile: B50 625 9356 . Fax; neo 715 aftea 0 ~~"~~Originel Denton, Jaime; 2 /rg' `0 Sent: Sunday, Mey 20, 2001 5:36 PM TDI Sedoeky, Aleoia; Dyer, Alicia; Harris, Andrew; Silber, Beth Ann; Prostel, Hetine; Pettitt, Den; Nickerson, David Alemayehu, Domisei@;. Shapiro, Elyoe Sitota, Eric;'Lee, Fleur; Ancono, Frank; Cawkwell, Geili Jeffrey: Plofohan, Jenrnifer Goldman, .iionotzhany DiCker, Joy; Dohrt, Kenneth; Levy, Lisa; Shefner, Lori 5; Fletcher, Mark Horn, Mark; Cary, Meg; Govig-un, Michael; Gancielrnan, Mitchell; wanna, None McElwoe, Newell; Sobel, Rachel; Reynolds, Robert; Nelsqn, I tnfidential - Subject To Protective Qrdur 1313125 00500595 Case Document 320-3 FiIed 03/02/12 Page 482 of 550 Page|D: 8116 Rooney; Miller, Tina: Quinn, Tricia; Leishman, Valerie Subject: FW: CLASS manuscripts for review: Urgent attention required Please forward comments to Both and me by Wednesday May 23. - Jim Driginal Message From: Corniek,'David Sent: Thursday, May 17, 2001 4:01 AM To: Fort, John; Denton, James: 'Tim Walbert' Cc: Markind, Jan 'Jim Lefkowith'; Donovan, Dan . Subject: CLASS manuscripts for review: Urgent attention required Importance: High Dear All, - Please find attached two draft CLASS manuscripts (Gi and CV) from Jim Lefkowith's group. I would appreciate it if you could review the attached I documents and return your comments to Jan Markind and I by Thursday 24th May at the latest. Jim, I would very much appreciate it if you could consolidate all the Pfizer comments into one e-mall prior to returning them to Jan and I. Many thanks for your help. Look forward to hearing from you all in due course Regards Dave corniek Editorial Leader PPS International Communications Phone +44 (0)1903 238131 Fax +44 (0)1903 282707 E~mai1: dcornick@hbase.eom From: MARKIND, JAN 1 Sent: 17 May 2001 02:20 To: 'Cornick, David' Subject: FW: Importance: High Dave, Please send out for review to Jim Denton, John Fort, and Tim Walbert. Please ask Efizer to consolidate all comments for each manuscript into 1 e-mail. Please use the abstracts from these as we discussed; alter as needed. Thanks, Jan 2 onfidtntinl - Sxlbicct To Protective Order DEFS 00500596 Case Document 328~3 Filed Page 483 of 550 F'age|D: - B117 - JAMES B. Sent: Wednesday, May 16, 2001 9:56 AM *rm JAN Subject: Jan- Please distribute these draft copies to the Publidahibn Team- I would like to 1in?t the review process to 7 business days. JL 1- 3 Confidcntihl - To Protective Ol`dCl' DEFS 00500597 Case Dotiumerit 328-Ei Filed Page 135 oi J..-49 8507 Subject: Updated: CLASS Steering Committee Location: ll-3213 Start: Mon 8:30 All/1 End: l\/Ion 10:00 Required Attendees: RICH JANE GEIS, GEORGE S, ISAKSON. PETER MARKING, JAN [Ftl-lRl1B2U]; CAROLYN F. KUNDEL, SUSAN Weekly Call in number for these meetings is as follows: Access code B112-fl" Attending: Noshay. C. Wilson, R. ll/iontwill. lvl. Fleming, J. 53. Walker Llpoorning Deadlines: - April 15 ADA April 1? AACJE3: Will this need an orthopotl to author? to oonlilrn it this will on required. April 5; Abstract from data to be available. E. Noshsy to J. Woeltly Meeting: What updates are needed for lol'norroW's AH Celebrex Weekly - Council? Priorities Ensuring all are clear on strategy going forward and contingencies. Prepare slides and pass lo Loo Simon, el.el. Strategies contingency plans are a for tornorrow mornings meeting. ailr:-hfagy layout M. Ctption 1: Deolsii,>n is that we are going out first, going out quloltly to provide rnotivatton for reps. Do not want Merck to start with the story. Ret`stJ|l3flr5srJeS Recognize that we are dependent on three critical results: primary endpoints ol' serious AE 1 Corilingenoy: primary endpoints do not deliver i-fl. it Contingency: Prirririry deliver but the other two/three do not. R. Diagnostio events - oi tolerability HTN tit edema rruironl; on trial. Ours is US theirs is |nle|'rial'l'? Ours is B000 theirs is lerger 7? Rtroll than latte to il. if hlumlver' of events? greater value or not QU |'or.iuotlon, how do we speak to the trial design? lvley need to depend on haoltground rates. Worse ease; we have to attack the trial design lfwe do not see the reextillswe want. Boat case: Data is want and we go lorward; will noocl to justify our trial - design. If other endpoints do not deliver, we will also need to slraleglze on how we provide the data. Delinitiorisrissues All that Iievo been used historically need to he docurrienled so that tliore is a good eduoritlonal pieoe built on the definitions. For etc. Used in Security Anrilyst release. eto. To oe prep:-:red to defend the standard we are Clorlfidlirlliril - Stliijcot To Protootivo Order DEFS I 5743 I6 Case 328-10 Filed 03/02/12 Page 303 of=f10Q 9041 From: Zwiilioh. Samuel Sent: Tuesday, May 23, 2000 5:59 PM To: Wahba, Mona Subject: RE: Good News on Celebrex Mona: Thanks. They swallowed our story, hook, line and Samuel H. Zwillioh Clinical Research CRAII From: Wahba, Mona Sent: Tuesday, May 23, 2000 1:40 PM To: Forster, Eliot Murphy, Patrioe Meyers, Laraine L: Zwillioh, Samuel Subject: FW: Good News on Celebrex In case you did not see. -~-~~Original Message - From: Leiohmdh, Valerie Sent: Tuesday, May 23, 2000 9:47 AM To: Wahba, Mona Subject: FW: Good NewS Dh Celebrex From; Leishman, Scott (LNG-MBC) Sent: Tuesday, May 23, 2000 8:25 AM To: Val Leiahman (E-mail) Subject: Good News on Celebrex Findings from Ce1ehrsx(R) Safety Study Show Traditional NSAIO Comparators can Cause serious GI Complications Within First Few Days of Treatment No Increased Risk of GI Complications Dbserved for H. Pylori Positive Patients on Celebrex NVIM NVIM May 23, 2000 03:03 AM Eastern Timo 3" SAN DIEGQ, May 23 /PRNewswire/ -- New data from the C&lebroM(R) PUMNUFPS- Aga celeooxlb 7 . capsules) long-term safety study presented during Digestive Disease Week revealed that the risk for serious ga5tIOiRCE5tiHBl FOHWUUEWA -he ee I I the NSAID comparators ibuprofen and diclofenac Goh start within the 1 Con l1ds|'|Linl - Protective Order fJ072375| Case Document 328-lf) Filed Page 30-11 of 409 F'agelD 9042 first few days after treatment begins. Further, study patients who were H- pylori positive had a two times greater risk of developing hoth ulcers and ulcer complications when taking the NSAID comparators than did H. pylori negative patients. No such increase was observed with patients taking Celebrex, regardless of H. pylori status. "This study reinforces what gastrnenterologists have always suspected -- that even short-term therapy carries risks, Many physicians feel that patients requiring short-term administration of traditional NSAIDs are not at risk for a serious gastrointestinal event. These results tell a different story, highlighting that many of the events caused by traditional NSAIDs occurred within the first few weeks," said Jay Goldstein, MD, Associate Professor of Medicine at the university of Illinois at Chicago and Chairman of the GI Events committee of the Celebrex long-term arthritis safety Study, who presented the findings at a satellite symposium sponsored by Searle and Pfizer IHC during DDW. The Celebrex longeterm arthritis safety study, an approximately 13-month, multi~center, randomized, double-blind outcomes trial of about 0,000 arthritis patients -- 5,000 with osteoarthritis (DA) and 2,200 with rheumatoid arthritis (RA) -- was designed to mirror everyday clinical practice by enrolling a broad spectrum of patients, including adult patients of all ages and disease severity, and patients taking low-dose aspirin for cardioprctection, The study, designed to obtain a rigorous assessment of Celebrex safety, compared four times the recommended OA dose of Celebrex (800 mg daily) to typical daily doses of ibuprofen (2400 mg daily) and diclofenac (150 mg daily). The Celebrex study dose is twice the highest recommended RA dose. Impact on Required Medical Care Studied Under the real-world conditions of the study, significant decreases in the use of medical resources were shown in the Celebrex group versus the other NSAIDS studied. On four times the recommended Celebrex OA dose, 12.5 percent of patients required office visits for blood work and evaluation versus 16 percent of patients on usual doses of the NBAID comparators; approximately twenty percent of each group were referred to a specialist, most requiring endoscopy and a complex medical work-up. This amounted to 25 percent fewer office visits and complex work-ups for patients taking Celebrex- "This is an important finding with respect to the increased burden on our medical system and the healthcare resources needed to treat these patients - especially given the finding that serious complications Can occur early in treatment," neted Dr, Goldstein, New Treatment Withdrawal Findings withdrawal from the study one to GI for patients on Celebrex versus traditional NSAIDs was also assessed in the trial. Tolerability data were presented that indicate diclofenac patients had a more difficult time remaining on treatment due to increases in moderate to severe GI Significantly more patients on diclofenac were forced to withdraw from treatment as a result of these side effects, as compared with patients on Celebrat- 2 |5l|h00723752 Case Document 328-10 Filed 03/02/12 Page 305 of 409 Pagelliil 9043 Additionally, significantly more patients on ibuprofen than on Celebrex were forced to withdraw from treatment due to lack of efficacy. These data highlight that arthritis patients need both efficacy and tolerability from their therapy in order to stay with treatment- Blood Loss Data Have Broad Implications As reported at the symposium, study data show that there was an increased incidence of blood loss -- equivalent to two pints or more among patients on the NBAID comparators versus Celebrex, even among those without bleeding ulcers. The rate of blood loco with the NSAID comparators was 5.0 percent, and with Celebrex was 2.4 percent- In the original clinical trials, the rate of blood loss with placebo was 1.6 percent. "Importantly, the lower incidence of GI blood loss has implications for a patient's overall health," Dr. Goldstein noted. Chronic GI blood loss, which often goes undetected, can result in anemia- Less total blood in the body means less oxygen is circulating through the body. To compensate, a patient's heart must work harder and faster to pump more blood through the system. Loft untreated, anemia can exacerbate underlying coronary artery disease and precipitate heart attacks and heart failure- According to Dr. Goldstein, "Blood loss of this kind is often difficult to pinpoint. When discovered, however, patients may be forced to discontinue treatment, thereby preventing them from getting effective relief from their arthritis Obviously we'd prefer to avoid such an outcome." Cardiovascular Findings The long-term safety study also indicated that four times the recommended OA dose of Celebrex, taken with or without aspirin, posed no increased risk of heart attacks or strokes compared with ibuprofen and diclofenac. Approximately 70 percent of the aspirin group and 50 percent of non-aspirin users had cardiovascular risk factors such as hypertension, high cholesterol, tobacco use and a history of heart ottockc- Among study participants not taking aspirin, incidence of heart attack for Celebrex was 0.2 percent, and 0.1 percent for the NSAID comparators. For the same group of patients, the incidence of stroke was less than 0.1 percent for Celebrex, and 0.3 percent for the NSAID comparators. Among study participants taking aspirin, the incidence of heart attack for Celebrex was 0.5 percent, and 0.4 percent for the NSAID comparators. For the some group of patients, the incidence of stroke was 0.2 percent for Celebrex and 0.5 percent for the NSAID comparators. None of the differences were statistically significant. Celebrex is not a substitute for low-dose aspirin used for cardioprotection. Aspirin: An Independent Risk Factor for Ulcers Among non-aspirin users, patients on Celebrex taking four times the recommended dose for OA experienced significantly fewer Ulcer complications compared with ancl who needed we-EE allowed to participate in this study since a large number of patients 3 - 5i11llgECl'I`U Ui' FS 00723751 Case Doeument32B-10 Filed 03/02/12 Page 3O6rJf-409 Page|D: 9044 with arthritis take 1cw~dcee aspirin for cardioprotection, as did one-in-five patients in this study. Excluding aspirin patients from the analysis, however, cffere a clearer picture of the impact of Celebrex on GI safety since aspirin is an independent risk factor for GI complications. These patients experienced three-fold fewer [64 percent) ulcer complications, a statistically significant difference from the NSAID comparators. When patients taking aspirin for cardioprotection were added to the analysis, those on Celebrex experienced two~fnld fewer ulcer complications versus the traditional NSAID comparators, narrowly missinq statistical significance. Patients who have a known allergic reaction to celecoxib, certain snlfe drugs called sulfcnamides, aspirin or NSAIDs, or who are in their third trimester of pregnancy should not use Celebrex. As with all NSAIDE, GI tract ulcerations can occur without warning Physicians and patients should remain alert to the signs and of GI bleeding- As with all NSAIDs, Celebrex should be used with caution in patients with fluid retention, hypertension, or heart failure. The most common side effects of Celebrex were dyspepsia, diarrhea and abdominal pain, which were generally mild to moderate. Celebrex is oo-promoted by Searle, now part of Pharmacia Corporation, and Pfizer Inc. Pharmacia Corporaticn PHA is a leading global pharmaceutical company created through the merger of Pharmacia Upjohn with Monsanto Company and its G.D. Searle Unit- Eharmacia has broad portfolio, a robust pipeline of new medicines, and BH annual investment of more than $2 billion in pharmaceutical research and development. Pfixer Inc BFE is a research-based, global pharmaceutical company that discovers, develops, manufactures and markets innovative medicines for humans and animals. The company reported revenues of more than $15 billion in 1999 and expects to spend about $3.2 billion on research and development this year. For more information on Pfizer, access 3 For complete prescribing information on Celebrex, access or call tollefree B88-735-3214. SDURCE Pharmacia Corporation and Pfizer Inc fl Coniidential - Subject To Prnlualiva 00723754