5, DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service i is '*< .,. :5 Food and Drug Administration _ Rockville, MD 20857 TRANSMITTED VIA FACSIMILE February 2, 2001 James McMillen, MD Central Pemasylvania Clinical Research 3335 Market Street ` _ Camp Hill, PA 12011 RE: NDA 20-998 Celebrex (celecoxib) capsules MACMIS ID #9684 Dear Dr. McMillen: As part of its routine monitoring and surveillance program, the Division of Dmg Marketing, Advertising, and Communications (DDMAG), has become aware of promotional audio conferences presented by you, on behalf of Pharmacia Corporation (Pharmacia)l, that are in violation of the Federal Food, Drug, and Cosmetic Act (Act) and its implementing regulations. We refer specifically, to five promotional audio conferences held on March 7, 2000, March 23, 2000, May 2, 2000, May?4, 2000, and May 16, 2000, entitled, "COX--2 Technology in Clinical Practice: One Year Later," in which your promotion of Celebrex is false or misleading. Based on information received from Pharmacia (at the time Searle), it is our understanding that you were retained by Pharmacia to conduct promotional audio conferences on their behalf and you were trained by Pharmacia prior to making these presentations. It is our understanding that you were specifically trained to adhere to content outlined in a Pharmacia approved slide kit, to not discuss unapproved uses, and to adhere to the regulations governing the content of prescription drug promotion. It is also our understanding that, at some point, Pharmacia became aware that you were not adhering to all of their instructions and brought you to their corporate headquarters for retraining on certain issues. Despite this training, these presentations are false or misleading in that you minimize the ` potentially serious risk of using Celebrex and Coumadin (warfarin) concomitantly. Your minimization of this risk raises significant public health and safety concerns because it minimizes the risk of significant bleeding. Additionally, these presentations are false or misleading in that you omit important risk information, minimize Celebrex's contraindication in . patients who have demonstrated allergic-type reactions to sulfonamides, make unsubstantiated comparative claims, and promote an unapproved new use and dosing regimen for Celebrex. Our specific objections follow. I Pharmacia & Upjohn merged with Monsanto Company (parent company of G.D. Searle & Co.) on April 3, 2000 . K James McMillen, MD * page 2 NDA #20998 Minimizing Celebrex / Coumadin Interaction Statements made by you during promotional audio conferences identified above minimized the risk of Celebrex therapy in patients who are also taking Coumadin. For example, in your March 23, 2000, audio conference you stated that there is no drug interaction between Celebrex and Coumadin. Speciiically, you claimed that: Yes, Celebrex and Vioxx are different compounds. They have different reactions in the body. They are not interchangeable. Celebrex has shown drug interactions with lithium and Diilucan. Vioxx has not shown any drug interactions with lithium and Ditlucan. Vioxx has shown drug interactions with Rifampin, Coumadin, and methotrexate. Celebrex, no drug interactions with those drugs. Your direct statement that Celebrex does not interact with Coumadin directly contradicts the PI that clearly states, ". . .in post--marketing experience, bleeding events have been reported, predominately in the elderly, in association with increases in prothrombin time in patients receiving CELEBREX concurrently with warfarin." As previously stated, the PI for Celebrex was purposefully changed in response to these post-marketing bleeding events that have resulted from the concomitant use of Celebrex and Coumadin in order to warn of the very interaction that your promotion denied. q ,, . ., Your message that Celebrex does not interact with Coumadin is reinforced in the audio- conferences by your selective presentation of Vioxx's (rofecoxib) labeling change regarding its risks in patients taking Coumadin. Your selective presentation of Vioxx's labeling change about its use with Coumadin, and failure to state that Celebrex's PI was also changed for the same reason, further implies that Celebrex and Coumadin can be used safely together with no risks. ln addition, your failure to present Celebrex's labeling change suggests Celebrex is safer than Vioxx in patients taking Coumadin when such has not been demonstrated by substantial evidence. This misleading suggestion is further reinforced by your claim during the March 23, 2000, audio conference that, "Celebrex is the non-steroidal of choice if one is needed when a patient is on Coumadin." 'V We note that earlier in your promotional audio conferences before the discussion of Celebrex's drug interactions, you state, "Now after 16 million prescriptions were out there for Celebrex there has been a very rare increase in prothrombin time and bleed in the elderly. So prothrombin should be monitored .... " However, your disclosure that "prothrombin should be monitored" does not adequately convey the extent to which anticoagulation monitoring is required after initiating or changing Celebrex therapy in patients who are taking Coumadin. Additionally, this disclosure does not correct your misleading message that Celebrex and Coumadin have no drug interaction. Minimizing Contraindication Your promotional audio conferences minimize Celebrex's contraindication in patients who have demonstrated allergic-type reactions to sulfonamides. For example, you state that, ". . .many other drugs such as Diuril, Hydrodiuril, Hyzaar, Vasoretic are contraindicated in those allergic to su1fonarnides," and ". . .if you have used these drugs without worrying about a sulfonamide ~ Q James McMillen, MD page 3 NDA #20-998 reaction, then Celebrex can be no different." Your suggestion that Celebrex can be safely used in patients who are allergic to sulfonamides if they have not had allergic reactions to other drugs that are contraindicated in those allergic to sulfonamides is inconsistent with Celebrex's labeled contraindication that states, "CELEBREX should not be given to patients who have demonstrated allergic--type reactions to sulfonamides." Therefore, your promotional audio conferences are misleading because they undermine the risks of Celebrex therapy in patients who have demonstrated allergic-type reactions to sulfonamides and are inconsistent with the PI for Celebrex, Omission of Important Risk Information Your promotional audio conferences fail to present other serious and important risks associated with Celebrex therapy. For example, your promotional audio conferences fail to present Celebrex's contraindication in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. You also fail to present the gastrointestinal (GI) warning for Celebrex about the possibility of serious GI toxicity such as bleeding, ulceration, or perforation. Moreover, you fail to present Celebrex's precautions in patients who have liver and kidney disease, patient populations in which Celebrex's, use is not recommended such as late pregnancy, as well as Ce1ebrex's most c0mmQ? adverse events. Unsubstantiated Comparative Claims ..? ' A You make several unsubstantiated comparative claims throughout your presentations. For example, you claim that Celebrex is safer, or has fewer side effects, than all available NSAIDs when used in patients that are on Coumadin. Specifically, in your March 23, 2000 audio conference, you claim that, ". . .Celebrex is the non-steroidal of choice if one is needed when a _ patient is on Coumadin." However, Celebrex has not been studied in head-to--head trials ? prospectively designed to assess its safety compared to other NSAIDs in patients who are taking Coumadin. Therefore, your superiority claim that Celebrex is " the non-steroidal of choicc" when compared to the entire class of NSAIDs is misleading because such has not been demonstrated by substantial evidence. ' In your audio conferences, you claim that, ", . . going from a dose of 100 mg of Celebrex a day to an increase of 8 times that dose to 800 mg a day, there was no increase in endoscopic ulcers, no increase in edema, no increase in blood pressure. This information becomes extremely important to all of us if you compare this to the Vioxx research data." Your suggestion that Celebrex is ? safer, or has fewer side effects than Vioxx is false or misleading because such conclusions have- not been demonstrated by substantial evidence. Celebrex has not been compared to Vioxx in trials prospectively designed to assess these endpoints. Another example of your unsubstantiated comparative claims, is your claim that, ". . .in rheumatoid arthritic patients taking Celebrex at 200 mg twice a day, this was more efficacious than 1000 mg of Naprosyn in rheumatoid arthritics." The study that you cited to support this superiority claim actually concludes that Celebrex produced improvement in the signs and symptoms of RA comparable to the improvements produced by Naprosyn. Therefore, your claim of Celebrex's superior efficacy to Naprosyn is false or misleading. _ i James McMil1eu, MD page 4 NDA #20-998 Promotion of Unapproved New Use and Dosing Regimen Your audio conferences are misleading because they suggest that Celebrex is safe and effective in the treatment of acute pain. For example, you discuss a 400 patient, 5 day post-orthopedic surgical pain study comparing Celebrex to hydrocodone plus acetaminophen. You state that the results of the surgical pain study were that, ". . .over the first eight hours 200 mg of Celebrex had a similar onset of action and efficacy to l0 mg of hydrocodone plus 1000 mg of acetaminophen single dose. Now over the next five days, the Celebrex was as effective as the narcotic with less drop-offs for lack of efficacy and less drop--offs for adverse events." Celebrex was not approved for an acute pain indication after review of six studies that were submitted to the Agency prior to Celebrex's approval. Therefore, your audio conferences promote an unapproved new use for Celebrex. You also promote an unapproved dosing regimen for Celebrex. For example, you state, " In this [RA] study the dose of Celebrex could go up to 800 mg ia day and this accomplished with no increase in adverse events. Yes, this was one of our hopes for COX-2 technology that you could double the dose a few times without increasing toxicity." The approved dosing regimen for Celebrex for RA however, is 100 to 200 mg twice daily. Therefore, your suggestion that Celebrex can be safely dosed at 800 mg per day (double the approved dose) promotes an unapproved dosing regimen and is misleading. 3 . . ` Conclusions and Requested Actions We are seriously concemed that your promotional activities described above raise significant health and safety concerns because they minimize crucial risk infonnation and promote Celebrex for unapproved new uses. You should immediately discontinue any promotionalactivities for Celebrex that contain the same or similar claims or presentations described above. Sincerely, Thomas w. Ab}aHRTh., MBA Director Division of Drug Marketing, Advertising and Communications A A Q: 4 DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service BEM;} Q _ Food and Drug Administration Rockville, MD 20857 TRANSMITTED VIA FACSIMILE A February 1, 2001 Fred Hassan - President and CEO Pharmacia Corporation 100 Route 206 North Peapack, New Jersey 07977 RE: NDA 20-998 Celebrex (celecoxib) capsules - I MACMIS ID # 8432 A , ig _ Dear Mr. Hassan: This Warning Letter concems Pharmacia Corporation's (Phannacia) promotional activities and materials for the marketing of Celebrex (celecoxib) capsules., Specifically, werefer to promotional audio conferences given on behalf of Pharmacia} by James McMillen, MD, and certain materials used to promote Celebrex, As part of its routine monitoring and surveillance ? program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed your promotional activities and materials and has concluded that they are false, lacking in fair balance, or otherwise misleading in violation of the Federal Food, Drug, and Cosmetic Act (the Act) and applicable regulations. g 21 U.S.C. ?? 33l(a) and (b), 352(a), (f), and (n). You have engaged in repeated promotional activities that minimize the potentially serious risk of using Celebrex and Coumadin (warfarin) concomitantly. Your minimization of this risk raises significant public health and safety concerns because it minimizes the risk of significant bleeding. Your promotional activities that minimize this risk are particularly troublesome because we have previously objected in two untitled letters to your promotional materials for Celebrex that, among other violations, minimized the Celebrex / Coumadin drug interaction. Based upon your assurances that corrective steps had been taken in order to prevent future violative promotional activities of this type, we considered these matters closed. Despite your - assurances, however, your violative promotion of Celebrex has continued. I Pharrnacia & Upjohn merged with Monsanto Company (parent company of GD. Searle & Co.) on April 3, 2000 I W Fred Hassan page 2 ? Pharmacia Corporation NDA 20-998 Background Since Celebrex's approval on December 31, 1998, post-marketing bleeding events have occurred in patients receiving Celebrex concurrently with warfarin, In fact, these post-marketing bleeding events ultimately led to the June 10, 1999, "Special Supplement--Changes Being Effected" labeling supplement. This supplement included a change in the Precautions Section ofthe approved product labeling (PI) for Celebrex to inform healthcare professionals about the need to monitor anticoagulant therapy closely when Celebrex and warfarin are used in combination. Specifically, the Precautions section of the Pl for Celebrex includes risk information that states: [a]nticoagulant activity should be monitored, particularly in the first few days, after initiating or changing CELEBREX therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications ..., in post-marketing experience, bleeding events have been reported, predominately in the elderly, in association with increases in prothrombin time in patients receiving CELEBREX concurrently with warfarin. As a result of this important new risk infor1nation_being~-added to the PI, we requested that you revise your promotional materials for Celebrex to include this new risk information. Specifically, our letter dated June 24, 1999, requested'that promotional materials for Celebrex that include presentations about the use of Celebrex with warfarin, or drug interaction information in general, be revised to include prominent disclosure of the new risk information related to post-marketing bleeding events. We also informed you that your revised materials should alert healthcare providers about the need to monitor anticoagulant activity, particularly in - the first few days, after initiating or changing Celebrex therapy in patients receiving warfarin. We requested that these revisions be completed no later than thirty days from the date of our letter. ` In your letter dated July 23, 1999, you stated that revisions were made to your promotional materials for Celebrex, including the master sales aid. Furthermore, you stated that future professional journal advertisements for Celebrex would include the new risk infonnation regarding the interaction between Celebrex and warfarin. ' Promotional Audio Conferences ` We have become aware of five promotional audio conferences presented on behalf of Pharmacia by Dr. James McMillen that are in violation of the Act and its implementing regulations. These l audio conferences were held on March 7, 2000, March 23, 2000, May 2, 2000, May 4, 2000, and May 16, 2000. On May 5, 2000, we sent you a written inquiry concerning your involvement with and influence on the initiation, preparation, development, and publication of audio conferences given by Dr. . McMillen. We also asked you to describe the nature of the relationship between you and Dr. ' McMillen. ln your response dated May 19, 2000, you stated: [o]ur company policy and operational basis is to require that our speakers follow _ the content of our approved slide kit, to not discuss off-label uses in their _ ` Fred Hassan page 3 . Pharmacia Corporation NDA 20-998 presentations, to adhere to the promotional regulations, and to provide disclosure of the funding ofthe program. We did have a report that Dr. McMillen was not adhering to all of our instructions, and in fact, brought him in to corporate headquarters in November, 1999, for retraining on these issues. Subsequent to our meeting with Dr. McMillen, we monitored his speeches and were reassured that hc understood his obligations and was following our company policy. Despite your assurances about retraining and monitoring of Dr. McMillen, subsequent programs by him on your behalf are false or misleading. Our specific objections follow. Minimizing Celebrex / Coumadin Interaction The statements made during promotional audio conferences identified above minimized the risk of Celebrex therapy in patients who are also taking Coumadin (warfarin). For example, in your March 23, 2000, audio conference you stated that there is no drug interaction between Celebrex and Coumadin. Specifically, you claimed that: _ Yes, Celebrex and Vioxx are different compounds. They have different reactions in the body. They are not interchangeable; Celebrex hasshovvn drug interactions with lithium and Diflucan. Vioxx has not shown any drug interactions with lithium and Diflucan. Vioxx has shown drug interactions with Rifampin, Coumadin, and methotrexate. Celebrex, no drug interactions with those drugs. Your direct statement that Celebrex does not interact with Coumadin directly contradicts the Pl that clearly states, ". . .in post-marketing experience, bleeding events have been reported, predominately in the elderly, in association with increases in`prothrombin time in patients receiving CELEBREX concurrently with warfarin." As previously stated, the PI for Celebrex _ was purposefully changed in response to these post--marketing bleeding events that have resulted from the concomitant use of Celebrex and Coumadin in order to warn of the very interaction that your promotion denied. , - ? Your message that Celebrex does not interact with Coumadin isireinforcedin the audio conferences by your selective presentation of Vioxx's (rofecoxib) labeling change regarding its risks in patients taking Coumadin. Your selective presentation of Vioxx's labeling change about its use with Coumadin, and failure to state that Celebrex's Pl was also changed for the same reason, further implies that Celebrex and Coumadin can be used safely together with no risks. In addition, your failure to present Celebrex's labeling change suggests Celebrex is safer than Vioxx in patients taking Coumadin when such has not been demonstrated by substantial evidence. This misleading suggestion is further reinforced by your claim during the March 23, 2000, audio conference that, "Celebrex is the non-steroidal of choice if one is needed when a ` patient is on Coumadin." We note that earlier in your promotional audio conferences before the discussion of Celebrex's drug interactions, you state, "Now after 16 million prescriptions were out there for Celebrex there has been a very rare increase in prothrombin time and bleed in the elderly. So prothrombin should be monitored .... " However, your disclosure that "prothrombin should be monitored" does not adequately convey the extent to which anticoagulation monitoring is required after _ i Fred Hassan page 4 Phamiacia Corporation NDA 20-998 V initiating or changing Celebrex therapy in patients who are taking Coumadin. Additionally, this disclosure does not correct your misleading message that Celebrex and Coumadin have no drug interaction. Minimizing Contraindication Your promotional audio conferences minimize Celebrex's contraindication in patients who have demonstrated allergic-type reactions to sulfonarnides. For example, you state that, ". . .many other drugs such as Diuril, Hydrodiuril, Hyzaar, Vasoretic are contraindicated in those allergic to sulfonamides," and ". . .if you have used these drugs without worrying about a sulfonamide -- reaction, then Celebrex can be no different." Your suggestion that Celebrex can be safely used in patients who are allergic to sulfonamides if they have not had allergic reactions to other drugs that are contraindicated in those allergic to sulfonamides is inconsistent with Celebrex's labeled contraindication that states, "CELEBREX should not be given to patients who have demonstrated allergic-type reactions to sulfonamides." Therefore,_your promotional audio conferences are misleading because they undermine the risks of Celebrex therapy in patients who have demonstrated allergic-type reactions to sulfonamides and are inconsistent with the PI for Celebrex. p i . \__-- ' ? " Omission of Important Risk Information ?' i I Your promotional audio conferences fail to present other serious and important risks associated with Celebrex therapy. For example, your promotional audio conferences fail to present Celebrex's contraindication in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. You also fail to present the gastrointestinal (GI) waming for Celebrex about the possibility of serious GI toxicity such as bleeding, ulceration, or perforation. Moreover, you fail to present Celebrex's precautions in patients who have liver and kidney disease, patient populations in which Celebrex's use is not recommended such as late pregnancy, as well as Celebrex's most common adverse events. U Unsubstantiated Comparative Claims _ You make several unsubstantiated comparative claims throughout your presentations. For example, you claim that Celebrex is safer, or has fewer side effects, than all available NSAIDs when used in patients that are on Coumadin. Specifically, in your March 23, 2000 audio conference, you claim that, ". ..Celebrex is the non-steroidal of choice if one is needed when a patient is on Coumadin." However, Celebrex has not been studied in head--to-head trials prospectively designed to assess its safety compared to other NSAIDs in patients who are taking Coumadin. Therefore, your superiority claim that Celebrex is " the non--steroidal of choice" ` when compared to the entire class of NSAIDs is misleading because such has not been demonstrated by substantial evidence, In your audio conferences, you claim that, ". ..going from a dose of 100 mg of Celebrex a day to an increase of 8 times that dose to 800 mg a day, there was no increase in endoscopic ulcers, no increase in edema, no increase in blood pressure. This information becomes extremely important to all of us if you compare this to the Vioxx research data." Your suggestion that Celebrex is safer, or has fewer side effects than Vioxx is false or misleading because such conclusions have . Fred Hassan page 5 ? Pharmacia Corporation NDA 20-998 not been demonstrated by substantial evidence. Celebrex has not been compared to Vioxx in trials prospectively designed to assess these endpoints. ? . _ Another example of your unsubstantiated comparative claims, is your claim that, ". . .in rheumatoid arthritic patients taking Celebrex at 200 mg twice a day, this was more efficacious than 1000 mg of Naprosyn in rheumatoid arthritics." The study that you cited to support this superiority claim actually concludes that Celebrex produced improvement in the signs and symptoms of RA comparable to the improvements produced by Naprosyn. Therefore, your claim of Celebrex's superior efficacy to Naprosyn is false or misleading. Promotion of Unapproved New Use and Dosing Regimen Your audio conferences are misleading because they suggest that Celebrex is safe and effective in the treatment of acute pain. For example, you discuss a 400 patient, 5 day post--orthopedic surgical pain study comparing Celebrex to hydrocodone plus acetaminophen. You state that the results of the surgical pain study were that, ". . .over the first eight hours 200 mg of Celebrex had a similar onset of action and efficacy to l0 mg of hydrocodone plus 1000 mg of acetaminophen single dose. Now over the next five days,_the Celebrex was as effective as the narcotic with less drop-offs for lack of efficacy and less drop-offs for adverse events." Celebrex was not approved for an acute pain indication after review of six studies that were submitted to the Agency prior to _ Celebrex's a roval. Additionally,l; ,____?____ _ _ r_ 52nd were also deemed insufficient to support Celebrex's effectiveness for the treatment of acute pain. Therefore, your audio conferences promote an unapproved new use for Celebrex. You also promote an unapproved dosing regimen for Celebrex. For example, you state, " In this [RA] study the dose of Celebrex could go up to 800 mg a day and this accomplished with no increase in adverse events. Yes, this was one of our hopes for COX-2 technology that you could double the dose a few times without increasing toxicity." The approved dosing regimen for Celebrex for RA however, is 100 to 200 mg twice daily. Therefore, your suggestion that Celebrex can be safely dosed at 800 mg per day (double the approved dose) promotes an unapproved dosing regimen and is misleading. ' Violative Celebrex Promotional Labeling Pieces We have identified a sales aid (CEl8586Q), a four-sided card (CEI 8528W ' YCEl 8528W), and a wall chart entitled, "Commonly Available Sulfur--Containing Drugs" (YCEl859l W) that are false or misleading in violation of the Act for similar reasons as stated above. Specifically, these materials minimize the importance of Celebrex's contraindication in patients who have demonstrated allergic-type reactions to sulfonamides. For example, they indicate that sulfonamides can generally be grouped into two categories, "antimicrobials" and "others." They further state that the antimicrobial sulfonamides have metabolites that may be more likely to cause primary allergic reactions than the metabolites of the "other" sulfonamide classes, thereby suggesting Celebrex is less likely to cause primary allergic reactions. However, your claims and representations that Celebrex is less likely to cause allergic reactions than other sulfur--containing compounds is inconsistent with Celebrex's labeled contraindications. Specifically, the PI states, . I Fred Hassan page 6 ? Pharmacia Corporation NDA 20--998 "Celebrex should not be given to patients who have demonstrated allergic-type reactions to sulfonamides." Therefore, your promotional materials are false or misleading because they suggest that Celebrex may be used safely in patients who have demonstrated allergic--type reactions to sulfonamides when, in fact, such is not the case. Conclusions and Requested Actions Your promotional activities described above raise significant health and safety concerns in that they minimize crucial risk information and promote Celebrex for nnapproved new uses. In two previous untitled letters dated October 6, 1999, and April 6, 2000, we objected to your dissemination of promotional materials for Celebrex that misrepresented Celebrex's safety profile by minimizing the updated Celebrex / warfarin risk information and other risks, contained unsubstantiated comparative claims, and lacked fair balance. Based upon your written assurances that this violative promotion of Celebrex had been stopped, we considered these matters closed. Despite our prior written notification, and notwithstanding your assurances, Pharmacia has continued to engage in false or misleading promotion of Celebrex. It is our understanding that you have decided to terminate this audio conference series with Dr. McMillen. Due to the seriousness of your violations and the fact. that this behavior has continued despite your written assurances to the contrary, we request that you provide a detailed response to the issues raised in this Warning Letter on or before February 15, 2001. This response should contain an action plan that includes a comprehensive plan to disseminate corrective messages about the issues discussed in this letter to the audiences that received these misleading messages. This corrective action plan should also include: -- 1. Immediately ceasing the dissemination of all promotional activities and materials for Celebrex that contain violations like those outlined in this letter. 2. Issuing a "Dear Healthcare provider" letter to correct false or misleading impressions and information. This proposed letter should be submitted to us for review. After agreement is reached on the content and audience, the letter should be disseminated by direct mail to all healthcare providers who were, or may have been exposed to the violative promotion. 3. A written statement of your intent to comply with "1" and "2" above. I Your written response should be received no later than February 15, 2001. If you have any questions or corrrrrrents, please contact the undersigned, Spencer Salis, Pharm. D., or Mark Askine R.Ph., by facsimile at (301) 594-6771, or at the Food and Drug Administration, Division of Drug Marketing, Advertising and Communications, HPD-42, Rm. 17B-20, 5600 Fishers Lane, Rockville, MD 20857. We remind you that only written cormrrunications are considered official. In all future correspondence regarding this particular matter, please refer to MACMIS ID #8432 in addition to the NDA number. The violations discussed in this letter do not necessarily constitute an exhaustive list. We are continuing to evaluate other aspects of your promotional campaign for Celebrex, and may .. V Fred Hassan page 7 ' Pharmacia Corporation NDA 20-998 determine that additional remedial messages will be necessary to iiilly correct the false or misleading messages resulting Hom your violative conduct. Failure to respond to this letter may result in regulatory action, including seizure or injunction, without further notice. A Sincerely, Thomas W. Abrams, R.Ph., MBA Director ' Division ofDn1g Marketing, . Advertising and Communications _- . ,V>>`>> 7* ' _ ,7 7 , V . : . . 7 _ 7 ? ~ ` 7 __ Sulfcnamides g o Sulfonamides can generally be grouped into 2 categories,antimicrobials and "others," ` ?A based on metabolic pathways. "' .-.7 o The antimicrobial sulfonamides such as Bactrimm, Septra? and Gantrisin(R) have metabolites thatmay be more likely to cause primary allergic reactions than the T _ _ ,metabolites of the"other" sulfonamide classes such as diuretics, sulfonylureas, etc."" ? o "Su|fa" is a 0 ular term that is broadl used to refer to sulfuncontainin . _ P P Y . _ antibiotics and is associated with antimicrobial sulfonamides."?" - o CELEBREX is not an antimicrobial; it falls into the"other" group of sulfonamides. , ? Many commonly prescribed medications are sulfonamides, including Lasix"', ` Hyzaar(R), Ziac", Imitrex? and Glynase'? PresTab(R)." ? Clinical Implications X o CELEBREX is contraindicated in patients who have demonstrated allergic-type " reactions to sulfonamides. o This contraindication is based on chemical structure." o Due to the presence ofa sulfonamide moiety on the CELEBREX molecule, patients who had demonstrated allergic-type reactions to sulfonamides were proactively excluded from the CELEBREX clinical trials." . ' o The overall rate of hypersensitivity to all sulfonamide-containing agents in the _ general population is low, estimated at approximately 3%.'?'?'""? ` 1 ? 97% of the general popu|ation--the vast maiority--are not allergic to 7 sulfonamides."?'?'?'*? - ? Patients who have not demonstrated allergic--type reactions to sulfonamides are ' 7 potential candidates for CELEBREX. V C0ntraindications--CELEBREX is contraindicated in patients with known . hypersensitivity to celecoxib; in patients who have demonstrated allergic--type reactions to sulfonamides; and in patients who have experienced asthma, urticaria, or allergic--type reactions after taking aspirin or other NSAIDs. Serious Gl toxicity can occur with or without warning symptoms with NSAIDs. , In clinical trials, most common side effects of CELEBREX were dyspepsia, diarrhea, V - and abdominal pain, and were generally mild to moderate. l References: I. Mandell GL, Petri WA }r.An?microbia| agents (continued): sulfonamides. trimedioprim-sulfamethoxazole, quinnlones, and agents lor ' urinary tract infections. ln. Gilman AG, consulting ed, Hardman ]G, Limbird LE edsrin-chief; Vlolinofl PB, Roddon RW, eds. Goodman & Gilmuns The . Plvanrmcalngical Basis afTI1erapeunc 9th ed. New York. NY: |"lcGi?aw>>HiII Book Co: |996;|OS7--|062. 2. |"lontanaioA. Sullcnamide allergy lnimunullillergy Clin Nanh Am l998.l8;B43rBSO 3. Cribb AE, Lee BLTrepanler LA, Spielberg SR Adverse reactions to sulphonainide and sulphonamide-trimetlioprim 7 antimicrobials: clinical syndromes and pathogenesis./idversc Drug Reac1T0xic0I Rev. I996;lS:9-50.4. Duncan C. Sullanamidc cross-aIlergenicity~answcrs to common questions. Has]: Pharm. W89,24.666-66B. S. Sullivan Tj.Cr?ss-reactions among furosemidc, hydrochIor?t}1iazidc,and sulfonamides.]AMA r _Q |99|;l6S*l2D--l 2 I. 6. Rieder M], Ueurecht l,Shmr NH, Cannon M, Miller Mjpielberg SE Diagnosis ol sulfonamide hypcrsensltivity reactions by in?vitr? "recha||enge" with hydroxylamine metab?|ites.Ann lntern Med. l989; I Hl:286-289. 7.Weinszein L Madolf MA, Samet CM The sulfonamides. N Engl] Med. . ? ' , V i%<>.z6sn6;.m.??? (eununieaan im; A C E L E B R E . x 100 mg . (CFLECOXIB CAPSULESJQOO Please see full prescribing information inside. "o "I?o I o`."l' |' .": d'Ij A _ _? . V * ? _V.; Many commonly prescribed .medications.aresulfonamidesnncluding Lasix, Hyzaai; `V _ V>>__ ___V_ ? _ ? . >> . __ Zlag. _|np_treg<, Glynase PresTab,_Bactr1m,rSeptra, and Gantrlsln, _ ._ __ . _ -- _ i a " V 1 ~ ? '' . ` '? ? [ NZ P . fr > QQ" . ?V N0he&htI|]1ICf0bI?lS Vwlth sullfonamlde-related contraindications i ? Brand <`. ?D_ri.lg(s) Q V --- gi ?sDrug class cnf- Company l Sulfonamide-related _ . V _ .. `. { 7. . Q >> Vagerit containing . ' contraindicatiqnw __ V `r`' T V _ _} " [ sulfonalwtide group ? ? ? - . Ca 0zide" ca to riI/ An iotensin-I inhibitor/ Brist0l--l"I ers S uibb reviousl demonstrated >>_ { P P P 2 Y Q P >'_ _ ' hydr0ch|or0thiazide* diuretic Company hypersensitivity to...other .. sulfonamide derived drugs" - ? -- i-- ti if is .- -- ? - .? -iri . tt a ` ? e ` F-;---'-' ?' -' ` liElHIriilEi7Iii`:1GlE?= im? i?? V 1.?.y ;T?.Y,s1 lo??? El-3!.ol?'=iiE:?IT1lfEUR>3"?--"i"i-{ i Diurils chlorodiiazide Diuretic _ Menck & C0., lnc. Hypersensitivity to. Mother sulfonamide-derived drugs" ; . - - E r''i? , lr . Ff@?>7??--?. '?`>>* V. . Hydr0Diuril"' hydrochlorothiazide Diuretic Merck & C0., Inc. Hypersensitivity t0...0ther sulfonamide-derived drugs" . t?--;'-- ' Tis . . . r ,-?.-esa,. rt. - _>>. . .-,. , -- as V -. ?_-t,,_st,? .? ?~ .5 ss...s ~r_ ,.>>,.-,?--, l . V >>'?v aL '?>? . '.'- ' ?'"'?''r' -2 Y { . ','i ? - 1.;. . ` ? Lozol? indapamide Antihypertensivel Rh6ne--Poulenc Rorer mhypersensitivity. ..to other diuretic Pharmaceuticals Inc. sulfonamide-derived drugs" I L ?. ; '>> ,: e.i:.r 2 -. ? I-tic: f = e V ***2* Tenoretics atencloll ` Bem-b|ocker/ Zeneca .. .hypersensitivity t0... ch|ord?ialidone* diuretic Pharmaceuticals sulfonamide-derived drugs"* . ;= ?V -?? ' . - --.sZ:e:.>>am_ =?1'>3>??$!'~EURl?--t . ;if>> VV --t>>= ;--?r- A ' Zest0retic(R) Iisinoprill Angiotensin-I inhibitor! Zeneca mhypersensitivity to other dr0chl0r0thia1icle* diuretic Pharmaceuticals sulfonamide-derived dru " . ES =.?>> er.:-s.?t;,;,~>>s,a- ? *>?'r*?*?'it'i?' :;*?>???*???"= _s>`?1$f'*?i*i'P1P!&;?>>',?. ' eek _is?p?x>l@_s?Y;~ _4i:?i,>Ll?chet? ~ Vi:. =r?@?`EUR[?%,i..? tonesents...hypel;serisi?vil;y,?;:9,.>>:?s;tl?el;Vea??; --? a:=.:t?_ ..,. .' .:?:>>ca?:& ". ? " . .>> =t Fi-ie ?. " --- . ` =?'1=-==eT:r.ea?s.o;:--%e ?~ .;,."1?";"? i?i'*--i ii?:--EUR?>>-- +*?':??= {-IAQ? ?"?';'??}EUR*1*'?",;>>i?! 5! _ l9 l&Z' & evil e. X2? `??i"Y..$l?!lfOD?1r!]lElETdEUR[lY EURl ~Fll}lZ$%1fi;iE?[s `-`.`ae,a'.Q?.;s;Zw:;;- :$< " . U i= * 7 i "="=f f Y ~ "i " ?' W 2` "'-* ' !r' . ;i????}";"' * Strllonamiae-containing component laslit is a ietisterea trademarlt olrloeoltst rlarion lxousselcactnrri is a tradernsrlt ana Gantrisin is a registerea rraaeniarlt otitoclse iaboratonetseptra is a registered toaernartt cl Monarch rltannaceuutals.?itiril,lalydrot>iuriLantl vaseretic are all registered tiadernarlts oiriertlt n co.lnc.<;apotide is a registerea aaaernartt nf sriatolriyen sqinbls company nyaarae is a regasterea ?1demark?lSmizhK|ine seecliarn rlannaceirneals. Lozol is a registered trader-rare ?fRh6rw.~Pou|en< rtorer Phamiaceutiuls ine.i~1asoiae is a registerea tiaaeniarlt or senrelt Pltannaceuucals int. Tenoreuc aria zettoretit are registered trsdernarits oizeneca l>ltannaceiitstals.ziac is a registered oaaemartt orlederle iaboratones Hy-taar is a registerea trademark olelau Pant de Nernouta ana company lmioet is a rt-gisterea tradernsrlt ol clasowellcarne lncciyntase ana rresrab are registered traaernancr orrlrannacia at upioltn company (rnysicians? Desk rtelerence, awe) References, continued: 8.V\/einstein L, Mzdoli MA, Samet CM.1 he sullonanildes (continued). N Engl] Med l%0;26$(l 7) 84241-19. 9.vl/einstein L, Madnfl MA, Sarnet CM. The sulfonamides (concluded). N Engl j Med l%0;7.s5(l9).9$1-957. I0. Mont HE Baron j, Kawakuboi Hen] M.]ugert E Metaboiites and allergic reactions, nin Exp Allergy. ? l998;2B(siippl 4):2l-24, l I. Shear Nl-l, Spielberg SR Grant DM,Tan; BK, Kaloww Diflerences in metabolism cl sulionamtdes predisposing to itliosynci-atic toxicity. Ann Intern Med. was; l0S:l 79-IB4. l1. Nakamura H, uetrethtl. Cribls Ali, et al. In vitro Iorrnation, disposition and toxicity ufN--accm>>I IO4. lxvveisbeclter CA,Fr1unfe|der FE Golem Naidoll M,Tippermann Pced consultants and contributors. Plrysitionybesk Reference for 0plrtholrnelogy.13*? ed. Nontvale, N]. Meaical Economics Co. l995, I4. Silverman HM, edeirechiel me Pill Aoolt, oth ed. New York, NY; Bantam Books; 1994. IS. Sonnedecker G.Kr:m?rs ond Uraongs History ?f`Pi1?mI?cy.4!h ed (reprint) Maaison,wis;Anieritan institute of the History ol Pharmacy: wss, I6. Arky R, med consultant; Greenberg sB,VP Directory Services.Physicians'l>esk Reprenceszrd ed, |"|ontva|e,N]:l'1edi<2| Economics Co; I999. I7, Data on me, GD Searle at Co (Patterson R, ' Lacorrilae M. Bello Atelltovvith j). Safety prolilc ol celecoxib in sulionamide-hypersensitive patientssubmittetl tu Farr: Med. la. Gruchalla RS, Pesenlto RD, Doli sltlest Dj Sullonarnide-induced reactions in desensitized patients with AlD$--(he role ol covalent protein haptenauon by su|fametht>><.uoIe.] Allergy Clin Immunol. l998; l0l :37I -178 ' lv. Kutera CM, Greenberger PAAdverse drug r~eacuons? treatment and prevention. Hosp Moa. I996 (Dec):l l~24 10. WaI|ey`|Z Coleman lwlxllergic drug reactions incidence ? and avoidance.Clin lrninunotlrer. I994;|:l0|-109.2I. IMS America, National Proscri tion Audit. anua l99s4une ww Z2, Dennittori PL nea. l994 Ph ician: Gcnli P 1 nr 1 y= , Srnithtown, NY. Physicians Genllx; l994;ll-324-Il-37.5, ll>>l 7.00, Il-l1Dl. , P C E L E B R E 100 mg - CELECOXIB CAPSULES) an 9 -- Please see full prescribing infomation inside. ' ` _." ?-'. @2000 Searle SEARLE @ ll/99 ceisszavv ? YCEl85Z8W Printed in usrx _ ? manu A prrarrnrmtruerre array tr. are tran: ? -- , ? ?? ' '-'? rtuuumcns mo usitoz ,?,Q;'>> ~_?Y;I??; ? SEARLE has our mrnt r>>r;lrcta? tt rrra rrrrramra tcrrna7 trrrsanra. ar o.am4?r?4orr.t nears rnrrrr erraqwrwze cstsanzx is lmimea- ` ._ ' `? ? Pugh Class II) hepatic mtpeimtent has shown that st?adyV Studs: In DA and RA Patients ll For relief of the signs and symptoms of V lc? EUREUR?'*' ?aP$?lEUR>i Therelnre. 7st.zs?sx capsules sharrta no rrrtmuucert ar arthritis in adults a reduced dose in pauanuwrth moderate hepatic impair- ?'?' i l Um Vaml nsscntmou rrrarrr vrrrrrrrr wm. were rr.,r?rr?rr..,..r.r.r...r rm .r..r c?????-~ s? me ??? ? 4* > V ??EUR"'W"?"?`?"?"S , csrzrurzx rariwrrahy as atramamiy aessgrnraa as ?7rs7 been srrrarerr. trrr rm rrr crrrrrrrnr arr pararrrrs warn cetrtrrer rm rrrrr urn zixumr; rn-!. omni mf?"? _?= _???l*?????????s? ?? v?l*??tS ??#>????~????? V Mwtitsrl . "" ?, "? .mr.. rr ra, rr. rarrwrrrg crrmar tr...?r..rr mn, We W., .,,,,.,,,r.,.,,,r,, me rm, r,. ,,,,.rE,..S umrmm rw ??? r??>><<;;???r? ???>> ??v???>>? "?'?Z[?'.??J?,?"?',,Z,'],T,??f.$"$ 'EQTF '?-`"f'L},'""},?" M 0 wr". cr......rc ..,..r r..$..rnr.r.r, torn ran rrrrrrrrrrrr -.'..r.r .... W. .,...m., V7V" ,,,,,,,.,,?,,d.,.,,,,,,,,,,,e,,?L, ,,,,,..,$'?f;f,'{,,e ,,?c,,??? " *l""_"'?( "*" "' {"bl!n$ wml "l?'m*i "?'"' hln?"?"? avter taking aspirin or other NSAIDs, Severe rarelyfntal No srgrrrfiunt relattonshrp was found between GPR and Figure 2 and Table 3 summarixe data tram two l1Vweel< a"avhyuc"c like mania"; [0 NSAIDS 'hlve be"; Jy celecoxib clearance. Patients with severe renal irtsutfrV studies that enrolled patients in whom baseline endoV R d ? h V WARNING _A"_ h _ X k>.c,, amy rave not tra". .r..rrr.rr selves rsmrar rrzrrrezi part".; ..rr.r.,.oarrr rmmr [??Q;,,f ,,;;'fj,_Sf'Tf?,"'?,,Q?*;?,,,,,T,c,,,S j,_m,S'],,_'g r V' WARNINGS CN General. Significant interactions may occur when cele Figure 2 Glnminksmul (Gu E"tc'$_mSk nl GI Uluumm g"H`,;,N]()154 Mug lh, morxura, wmgm ,5 3gr_38_ P450 ICS. In vrrru studies indreate that oeleooxto ts not on K Serial Entioscoplcs over l2 Weelti Serious gastrointestinal toxrerty such as bleeding, ulcer of celeooxib Clinical studies with oeleooxib have identthed l><>ten7 Y"' or large intestine, can occur at any time, with cr 1?he;,,,?;,q ;,,g,,d,,m; H., CELEBREX capiwcs lmludg tlally significant interactions with fluconexoln and lithium gw V Ago t wrtheut warning syntptorns, in patients treated with C,?,,,,,,,,,,,,,, s,,,,,,,m_ ,,,,,,,, ,,,,s4 CMM. ,m,m Fwarrem vrrrrr rrrrrrsrsrrrarrst rrrraerrilyrrmarury arrrrrs ?=? l-,,_;QQ_,,,,, V VVV VV rrrmsrerarasr snr xrrrorrrrnsrrrry rtrrrgs rwsaiosn. Marmr ,,,?,',_,.,v,;,"?_ mtgnesium steamer Dovidmmr Sudium iNSAIDs2dsugg1e;tEghehmentr?}lforr;rttera$tlor's wit; gi upper gastrointestinal problems, such as dvspepsiaare " ? ? mum ? ... .r._.,..m..a.rr.a, M. ,..rr.a..,r.me rr g ${31737 ".Z.?"",,.r?sL'22J'1;.r:R;"me >> _ "'*KN||GULCK?\' _ _ slyhttrtdo, ilttwonaxole, metftotrcaate. pfterty\l>>rrtrt?1rr?rr ?rcyr:l???yr;onssa721c0x7z1,and nrrrer. m"'Ex' '?'; '"?':"??"'?? '?? I 3;**. ? g :,.3, ??s???. only one in nu patknt: who ??v?t?rr ? we ??r??=??tr??l???? in h?????r?s, cetzerrsx am not muzzzfffgg Mwm mjzpin ;':';xi,__,B,; 5 rr. YY 5 7 7777777e7 ? same uw-r Gl ??~???? mm ??? Msitm tor???r>v is hlhit the --l V ' _ . . . . . { ' :??:? .. ' ?"df'?""'??""" (mx U "?"""'"? una psrrarrn rrr ptrrartrrr- mt aarvrrarrr-rrratrea arrrrur 'V"'?'?"'"""? " ""' '?"" "?"'?"""'?d "'" "l'??' G' Pt???????>>orrrwtr?: urn, or U, I., rz ,,,,,,r, .4,.....;,,. r,. ,,.r;...r, warn rm s 77 7 ----VV-- -- ---- --- "'?"'? "'?" ?'?""'"? '" "?"?""?"? """? by Absorpuon A nnxmem wm ammzx mn mg, mn M Rm mu DD ' NSl\IDs, appeiai toziccur ix uplpjoximetely 1% og not plasma tmir or ratarmrn wrrr aparrrrarrrartry z rurrrraa rrr arrrrrrrrvarrrsrrr rrr wooac rvvuorrr orrrarra rr7 ii-??= ?";?"" """? fg '"?"' si: '" 'fyl **7* ? rrr: mer arr ant rims. eater perk plasma rmt; rc.,..,,y are mamsasr urri?o?araor)r>>srorrsrrtrrirar arrrsrrrr. a ?>>rrr7 ? *? ? ? ? $"::'}" "?s"fW? mg |f;;_h*:;;??f :::2;;,; :;:2;;; Ind lria under the curve (AUDI are rouqrtry dose pro posite of oain, stiffness, end furwtional menurexin DA 'v>??\ vs rtrvvcrwrt "v> eeeeeee Y eeeeee -- ??---- -- ---->> d Th ` ' lea T lt' - , , , _ grtrliurvt reduction rn romt tenderrnes/pan-i end taint Nnvronn l9.0% li.2% 9.9% $4.a% I K- ? { l- { lh N , I D urn; $**9***1** jaw ?;=; l2?? T?:;v???*;?=?? mrrrro compared rr. ,.r.?.r.?rr;nmor va. ....>>...r..r sm rn ?? umm rzrrror rrurrrr rmsrr ?,f,,fZ,;,f,,f$?[,';T,;',,Z, Z,f,,,'?,,, ,;,,}};,f,f, ,,2,,;,,, ff, K""?':e-H NST; P:'m"*-'|m.u', `ZIxsIo?? {gr tro.|urr:'vr gag: jen. and Lymptomsrzi Re in $W'v?m=m?J _ ineldenoe ot serious, clinically significant upper Gl hm r..>>. >>?>>.sV.rV.r. vsrr r arrrrr. wvrmttea arrrrar me or rr, rr. gr me r.. .r....rr?..Y ?;;','?_; ,,,, ,,;;'$,, ,;;,, ,g,g`g';,, gg), ,.,,,,,, ,rS,r,,, ,,,,,,,"',m,'? me ,Q,,,?m,, ,,E,,,,,,`{,'E,,'T?'" ros ml za rm ru on rrr arr m rw ?EURLE?l*E? *9* ?*??rM? ?? ?= =???=r??r ?? o?l=?=?? ?? ?l*???>?= ------- ----- >>->>->>------- 7- >>>>~~~e?eeeeeeeeeeeeeeee usuos more be prescribed with mrerm urrrorr rrr Hvdres, ustpg the ACRZ0 Responder Index, A composite Dlelofenon 5.1% 33% 2.9% $.7% vuyguqs wm., I FHM hgswry ?,{ uic, disease 0, ga,"?Y Sol ' E ?"?'" "'51 V"] ul clinical. laboratory, and Iunettonal measures ln RA. 75 ntellli (\!f.\50l lt0IJ?6| t?IZ7B| (36/3111 gmnmnal hlwdingr Mon svumanews Nouns or {mal ;:,,?d gyda, QL????>< dossier of IDD mg BID and 200 mg BID were `'````` ; ;E'2""`%`;?"";g,;' rrrr { SBQWV GI evutts are an eldehy or debilrtaled patients and tlterr wtrerr csrsersx esparies Mr. rarer wm. . mah rar ;""o' *" ;g;?'"?;f;* W ??"* '"*'* ??"'??*'??'= '? ma., no nmol rrsmrr rzrmrrr ouest) *??r =r>?=i?l_=?t?_=????ld ?= ??l3?? [? lr??*??e ""5 ??P?V me-sl. peak plasma levels were aerayaa rrrr alrrrrrr 1 ra "'""'" "'U - lntmn. Ta mlnrmtzs tlrn ??to?tool risk for an ndvuse Gl 2 r.,,.,,s wm. ..r r...Vm.r rr. r..r..r .?m.?r?rr?? num rr ,_Q;?'?$',,f?"f,";"',f??,]",?,"'" """ ""' '"? E"? ?'Q" ??T$i$`Z??"?"' "' "'?"'"" ""?" "" '"'?"" """ '"'"""'"' ?'o"*"o* '?"*' ?"??"" "??? *'*???'?' '*o "*~' '?" *** 10% to 20%. Coaerrrrrrtsrrariorr arcrtrenrx wrrrr rrrr sur ,, " " ' " "'?"'"? ""'? W '?" ' r arms crosnrr vs rar arm sr. rm arr .....r rr r.,mr....- $'*?*"?** P?'*"'l* **"'*'i?"- F?' **9** 'l**' ??'l?"'*? ?l*"V rrrrrrrrrrr ana ,M,,..Esr,,,,r,,,,,.r,;,,;,,g ,,,,,.c,d ,,s,,r,,? ,,., ???*=? *????l???=' ?????*il l??>??? th- 2**0 nje Bl? ??=e Errrrym ?' ? ? ` I ? i i rrsre trrerapaes mar arr rrar rrrvoive resales sorrrrrrri are . r.rr..a.?rr rr. Wm armor. m..?.?.r.r.r,r, an A ??=?? 0* *?? M Bm ?*?????*?=?* ??? ??*?*?*??*?=* *?-~?*?? _ w?>>~??????. ,1,,,e,s, or 3% In cmu and mag, in AUG CELEBREX ?b?*/B K"l?\ $??l'l with WUYZUU my BID- One randomized and doubleblinded 67month study Studies have shown that patrents with a prror history Capsules can bc admmdmmn wmmm ,,93,,1 in me sped,. smdks in lat) RA patients was ounducted in which an en?to7 of peptic ulcer disease and/or gastrointestinal bleeding ummg cr marx Glmnymeginalr Scheduwd upper GI endasccpm EVIL scope: examination was performed at 6 months The and who use NSAIDs. have a greater than ltlVf0ld higher Dismbminn luna", vm,. unarmed in We .4500 anhrms vulenu results are shown in Figure 3 gxszdeflmgg aIGLt:;:dtl1an patlintts ruth zetaher | he my ' , ? ? i mm wl\? were enrolled tn five controlled randomizeq \z71? . _ rl! I rv. tt ir?rt'? ? vas. ts ury ul u cer ri Z iyhtetits. mlccexb ts highly orote n lr _ d week mils ming miw Cum Mawr; Mu of wmch aysu Ftlllre 9. drsease, yrlrarrruoneprdemrologrnel studies have identi- l 97%} wtlhtn the clinical dose ran e. in vrno studres P . . . M, hs , 9 V Included placebo mmm: Twulvvwuk mduwwc Po?v?lo??c? vi Enetwwptnally Ghservm had several artrar eryrhrrrapre; or ersrrrrrrlrrri urrrrrtrrrrrrrs more t t celecoxto binds prtrnariry to allzumrn and, , ` . . Gastruduodenal U|?on litre Si! Months ?VYre??toeo\t that ma increase the risk for Gl hleedin such as. treatV rrr . ram arrrrrr. mart .r,,m,.?r..r. na ..,..mr ??*==*??*? ??=?~??*??*o ?=?? ????????????-lv '?*?? ??*?-??l= r.. r?.rr...a war rr........r.r.r rrrtarr. >> Wrrms .,r.rr.rrrr...rr.... .ra.a,,Sr.a rvssrrr rs s,r..V?.. Mg =1_~??o?g;3;g$ _;???==??*??? ;?= ?,_;?**?g;--,?g,; ??? ;",;'g',,,?',?$ {gf;,$'{,'},';i?$,','?;",jg,???",??",$?,?,*Q?f,',,;',}QV tmatetvwc L. srrgqrsrrw extensive ersrrtmzarr zrrrrr me *'" '?" ?" . ?'" ""? "? '" ' '"" " ? .r??rarr;rrr` naar s e arra r eneral rr>>.riror statusi using; Cahcmdh is Wl wevutmiallv hmmd m md BID. In allrthree studies that Included naproxen RX} mg f ? V ? V?? V ? _ TID. CELEERSX was axoclated wtth a statistcally sigV ; A, wm, NSA") V | yy hcwd y gj;?c:?!?;??? b ,_ _ I rtiliuntlylovrortrtciderrce artrrrrrmrrrr rrraa mr me g U V V V V ------- V >>---------- .,,,.,, r,. ,,,,,,,,f,",),?,f,',?$,?"k,,2;,";j,',,Z,.,,,,L,,,??f,$Q'}Q?'Q',jQf onmm;'P,5"$";E5?;_':'_;'ml;';Q";j:`:S";??'?'?? "T *$?l?*r ??t???- l'?~? Studies ??????r=? CH-E??=?? _o~ltr? { W i_,___ _____ __ ___,_,_ _ __ V max. rrr paa7rrrar-mir.; rrrrprrrsem, my rare cam rrr h _ ? ? |'_""'*'Y ' 'i? _? 4 djditllnlv 75 rtw BID: line Rtldy revllltd I S??tl5tt??||y 5 nnaphylectie reactions end anqioedema have been ' '_EUR?"?'P""'d'"9 ??fb?*Yl_l? #**7 and lli lil??ll'?'"d? ?t?ftlf>?=??lly itltiher P??o/Hlellve of enltcsccvlc lllkfs lrt 3 at .Y, Y Y Y Y rrrr rerlttftld itt tlltilttli rl??iVi?9 CFNBFEX CHEURB*'EX comugate. have identified tn human plasrvtariltese the diclofenac group at the study endpoint {E months E should not be given to patient: with the aspirin triad metabolites are irraotrve as EUX t or COXV2 inhibitors on treatmentl, and one study revealed no statistically 5 5 Y 7 7 7 ..7 V V - 7 This symptom complex typically oecurs in asthmatic Patients who are known or suspected tu `be Pl5? 203 srgnrticant difference between eumulative endoscoplc `i patrenrs who experience rhinitis with or withrrot nasa: gordmelatjoltxzrs teased on a previous history should uleer rnerdenee rates in tlre didoferrae and CELEBREx E 4? ? -- ?- ~ - V -- - - V polyps, or who exhibrt severe, potentially fatal br?nt:huV matter.; r,m.,.rt?.ra.r me wr rr, ar. rr Cetzenex ,r,.rmr E.".,g.m its .r.,rr.r ... 5;.,..;,,, the range studiet1Y D c_,;"r ?,_,,,_,__ S, where an anaoltylactoid reaction uocurs ara". arrrr rrrrr. ra-hr ..r.Cr....ge.r rr...g rem.V.rr rrr rrr. ?r???$????< Msn ?? ?-? l2V~?=? ~????l=? ????? ????r?>???? '?"f'"?"' "'"" "'"*" umu wd has Fouuwmg 2 smgm mal dun M udiug Dann", ,,, wywm baselma Endumwies availed N., 'Sron?t~o:ar?royerr1ore?rirarrr catatsmq peanut No tniormation is available regardrng the use of CHL7 I , V use _ l _ V _ ' fore, treatment with CHEBREX is not recommended tn $if?.?3T;,";ZZ11Z?3.?'?r?Z'i?i'JZ???2;';;"" ??~?? ? 1?S;'"?T".'1?"; Z22?Z2,'$?rLZ?2;i$??"f?l'r??Z;Zi M ??" ?"** " ?**'?"" *"V???* M M ??a* ??*V arrmvrm sm r...r,r,.,.... nsw; Q. rmi wr., ..... *"?*?*?=*,*;f,?;?'?*??'?**?*_,,_, ,, ,[jy_;'; _, ;j_$,;_i;,;"'*??" ' prrms. or mr err r????r ?m???s???? Serwvs rim ?.?'3?tEURi?L'$ 3?E'&rLrr0'l5?Y$renZr"r5L,Lr ?' ? ' lt appear; that me row sqtghrtny ug me dwg um|u,,gs NV V- in patients receiving CKLLBRKX in controlled and npen7 P"?9'""'iV the ??S?r?!i?rt process making terminal lraIfVlrfe {tw] g ?_I,_____?__`__"~ labeled trials, albeit infrequently (see WARNlNG$? l'l WY! F'??"?'\?Y EURElE?"El< $"??l?7 M |V?ld?? Z`?>EUR??$? determinations more variable, The etteqrioe halniie is E ts ,,_,__,,__"____ ererrrr- - ? Gastrointestinal IGII eltects). Prospective, long-term '* ""?'V???5?P'EUR"'?W'? ?l?5?'? ?ll*'? ??'~7t?$a'\?"?$?5? ittvrmtimxtely l1 hours under lasted conditions The g V V itttdies required no compare the ineidenoe of serious, PRECAUHDNS snpsrrar plum crwsm rem .s aw sun mom"., s ,.,7 7. V..V .. . .... . 7 rrrr 7 7 7 ?l*??i?"r >>e????~=??? ?r???r?l =?~???= ?=~?=~?= *?? ??**????? rt 1-crtznrrrxu ar ra or swan raarrrsrrm 5 :_?";"*l ?"'?']"' V; ??'"??"'?' NSA") ???????'* hm earramrrraaar rrr ra rrur rarraamrrrrarr rrarrrrawy Geriorrrcs At steady state, elderiy Srrnrarqrs (qw; 55 rg *5 V V V I _ W Yvneh _ ' Abrupt diseorrtinuation of corticoneroids may lead in AUC wmpuw ,0 me Wang "m_C,S_ In emwy i H, , ,,,, e YYYYYY ceeee ,Y.Y *??9?l ??*9l_le4 tn 4 ?l tY?? 5 =???=????? studies were Patients an ?r?|?n??d ??rt????t?=t?l? th???r>r`=h??l? {Em,4"_ nleccxih cmlx and AUC In mghu man mow E talttrtg :s?>corn>> hmau [heavy al me hwln Iewmmlnded dose- `t ??*.`:_ ', uaayniar Da.lt?r groups, wtth or without asonvn. plrcatrons ot presumed nonmfeo:ttou?s,psmfu| oondlttons ptdinfk. CELEBREX ( ham N U o4n.>>ar par. Pfafeleb: In clinical trial:. CKLEBPEX at srnqle doses up Ihperie Effoets: Borderline elevations ol one or more an in . ?"?"?' " ?' ?$'[ ""'?"' ?s.rrrr.?..r>>,, am.r.VVr nm .>>r ana. rV.srrV.mrr, Perris te stm mr; and rrrrrlripie eras; rrrsnu rag em tar up ra 1 raver rear; rrrsy rmur an up to 15% at patients takirrq k.'r Men In N _ ur phumncck wa c sud-ES M Carman tw me MD and ztw me ??, BD arr lvm rewrrwnutded xyz pagina tzigher man ncommended rherapeutie NSAADs, and notable elevations ot ALT or AST l:trrvr??'V . V n xix- r t - . as ? V I vac m ( N ' ' am u su no e ect on platelet aggregation and k>leed>> rmetely three or more times the uoper limit ol twrmall "l?%????':| 2; ?D?r?>> zax BUD mg TID, diclofenac 75 ma BID) significantly reducod clirtiul trials with NSAID1 Those laboratory abnormal t: rntca sign rcanoe n t ix Ending ts unknown, strrevz otaxhrr utorr my ? zine platelet aggregation and prolonged bleeding time ities may progress, may remain unchanged, or may be Wi ? . ? . ; l .--l.~lla??>>. ? s~s,_???-e>>?--?r -?-g?_';;?;oFnEUR;?g4??.;1;?P?VlF?!v.?l ' , , . j ` _ `.->> . V, * >> r >>_ _. . `_e";'~ ?2_llf;;*;{;'{3:3jt;_ _: 1-@.'????'i??--:? "@a.;,;?`?j'?%J *6* ???||?\?i?q therapy. Rnra usa; ql avery Aguila: CEAZBREX cart he used wlth I?w dose lualdn. ` ADVERSE ' ' _ ` Dbl llhrn lint! uttlat coun rarely ?;_;_ A ? reatrlltmx. including jaundica and fatal Iulmirum ltuwevar, cnncorrulant adminlstratinn cl asplrln with Ol the CELEBREX tmatod pntrenta in mrtlrulled rnals. av (>surgrt:oI`parn. More lnan 8,500 Clanfavascaiar: Svncnna, congestive heart {allure, vena I mrdullne ?'??vatlons 01 lrvtrr test: was 67.1ar CeL????>t (;.srrl-lrrttastlnall Because od its lack cl platelet effects, patierm have rncawed a total datlv dma ul CEURLEBRE1t ol tncular Iibrlllattun, pulmonary emhnlntm, rerebrovascu and 5% for placebo, and ap?mxlmat?0y02% ul patients CKLEBREX ts nut a substitute Iur aspirin tar cardiuv 200 mg (10tl mq BID nr 200 mq ODI ar mare. mcludtng lar accident. pertpnerul gnngrerte, thmmbuphlebrtls raking CELEBREX and 0.3% ol ualienls takinq placebo vascular prophylaxis. more than IW treated MMO mq (*00 mn BUOY. Al?pr??? Gastrwrttosthul. Intestinal uhstnrztiqn, intestinal pertu- *??--* ???>*?*='= El-?/?????? ?o MT =??* *5* rr.,..l..?.lr. lallllallllllalll lalllllllellllllln anlllcllllml. ??????e?v uw l?=?????= l???? ????~?? c=?s?r> ??????? ,ll,,.,.,,, ,,,,1,,.., ,ll..l, ?". ??"?'?"'""" ?' ' "'?'? """"' "'?""? '"?"?" lllle lm vnallllmlllnlllaps-Me?a?aolslll>. cnaansx am., ....ll? rnllll aalltrllnaa uianl mln. o use an q.,.,r, am. Mal l.ll.,.. '"?"'" '"' """'Y' "l"' ?f"{"'""d." ?""';" ':?"" '"'} snallla ae allllaallnea nl lll! umm lllallnnlenalla aase ..a,,?,,, ..,..l?_ laamlae ar lalrsatlly, lmanlnl; all Genmk Sens;. ,_",L,,,_ dem wei! ';'":;;i":;:|:?:? ?',; ln panama lmivlllg llumnazala. sax at pataenls leealvzng cnsanex tram I1 eanirullaa OVERDDSAGE ' ?'" ? 7 - . ? >> a all llnllanla wllrl cut lll RA tllat dt:.) CELEEIEX xhuuld be dlsersntrrtuel-1 lnhrum. In a study conducted rn healthy sunrqzts, mean eludtes canducte ` _ AID ' ' uu r xi. luded ulacehn and/ura posrtive snntml group Symptoms Iollowmg acute NS uverdoses are sulun mm- ulllamlln ??ll????l?uall?ll vi ~s>>???= Ms ""?""?'? """""T """"'" 'T " '"?'?'"" """ ? "`? " llnnll llllllua la lalnllllly, alllwllllals, llnlm, rlmll. mater wut. ln surrlem rlllzslllng lltnllrrn Asn lng anu V . . '?'""'" i" '""" ?'"""" "??""" ?"" ?"'?' '"""' ann ?slstrlex zoo lng ain as (anllwaa la allbyms tamu lng. alla cplgasnlc llalll. wlllnn are generally lwmlsl, injury. Renal lnxlcity has aIs? been seen an patients in I, I . I P U ms U rmium Hamm"! Ad,,e,S? E,H,,_' 0,,,,,,,qng in 22* qg t;,|,;,,,K page"', witn supportive care. Gnstrumtestlnal blending car wnanl renal pmnaanallallls nav- a ??m?ensax?lv rare (?""'"'" " ""'" *'?"? A ? " ' . r V -- -- rr) cm,. Hy,,,,w,,.?,,4 ,,me ,...,l rallum, ,,e,.,,,,.,,, lll llle lll-llllsllalllullmllln peltlulllll. ill nlm alllanls. >"?""' "" ?':"'V "'?""'"*? "*'?" ?""'""' " "" ? ....?":::i.l""'*' '""....":" ?"....."l%" """*""...... acplllssallll .llll llllns my lmll, lllll all me am a?on?o?istr????? ?????????s?er?i?t?lanti-i??=m?=???rv?ruu ?"'?" "' """ "'""' _ V d I M ??j?;?'gy? "kmy Mm mam Wim pnylaaaza lllacllalls naw aaan lapllnaa llvltn lllalar alll rarnllallall rlll manaargdan renal maaa naw, annrllls pallenls raking rllelrlatrexatl.-. cslesnrx dla not G,mu;,m,,,_;,__, an mmaw which may urecipruta overt renal decmnpensatmn. have a slgrlilinarlt affect on the pharmacokinetics nl nbdnmlmwm I K 2,,% ygm gw Hm Patient; gnqlald be managed ny svmntnntsxlc and Patients at greatest risk ul this reaction are those with methotrexate Dwmm S W um 52% 93% 5 nh suppanive {are Inlivwing an hlSA|D overdose. are are rrnpatved renal functiun, heart {allure, Iwer dystunctlcn, wld. : I wh h Id b m -' ,d_ ` rm spesml; antldates. Nu rnlormatron ls nvnjlable ????=? Mw ??~?=>? ???? M ?????i=~?-?>?? ?~? ??~= ...lllnZlZllC"l$1?EURRi"??2 $$1. J.L}' `Lll.lEUR...l3l?l'Z{ ll. **~?=?? W M lm M lm regsrdingthervmtwalof?loc?xrhl1yhemadlalvsl?,l>u1 elderly. Discorrtinuztian ul NSAID therapy is usually Idle uhmglnq CEL-EGREX memw in pawn.; mmlving wlnb llanrlarnaa 22% IVA 15% ui 15% based 0,, gu ,,,.1;, dqme gy dum, yawn hlmgmg xwgr ggggx ;joo*??;*;y we jing; lll. lll llllllln mllls alla. Ms. lallslla .l. .l .ll ~??-=? M 12* W- M W ;>??j; frggtgvxzzkzm M *:sg=;*jlxy--v?:=;::'j;? ""' increased risk ol bleeding euvrtplications. The efleel of gag, lanyqwt, _ ' V _ . ' . W mow ??"N?d wm mmmrnm NSA"]; nelecmnta on the anticoagulant affect of warlarin was sad. ;,, I". jx 22% ,6* nm W I WW I" *'?*'f'd'?"} ?"?V?f ?$m?'*? umimf "'?Y_bEUR Carman should be used when tnmatlrtg treatment d d cl Mmm wmeds IWBM daw V ?? tndrsarted ln patients nan wtthin 4 hours of mgestrun wth ???*?*** *?? ??**=?*? *?*?'? ?=~=??*??=?'= ?*E"*"*?? ZW `??E'? T??"" lllllnllallll lll ne. ...l.l.?2 C,.} *'???*??*?*??*??~ 1** ??** W M 35* ull. lylllplm lll l..ll.,l.ll.,, , al,. l.....lm nlm tion, It is ndldsnhla to renydrete potvanls lust and than xesdu 1:9 th `. `ulam mum u' w?runn lnilrryaeddntnl Z1! 23% 3.0% 16% 32% diuresis, alkalmtzatinn ulunrre, hemddlalysts, nr hamst- aan therapy vralrl aztaawl. cnlrulln la also laaaln- ::':mm_;_';;'bY' ?hf_;";";j:""me ( in ms`, E __, wm palrlltaall lllay nal all llsatllt alla la man prawn {"""'vjfu:;"?;;"" ';""' ?"R*"'f'$l"f_:':;"' "'""' nlaltlnlallq llllperlenalr, siaaazna warns nays seen alarms an me wr me ust ?*"'~""?-- ??? . ?, ` , ?=??no?. vr?>:~l?.l . . . I m up tu IDD rnglkq for males and 10 rnglkg lar Iernnlnx ?*V?7 - ? day admtrustered As a sing ? ae or as mg ice mf;} lZ"l.h" ?T,';f?"c2.'?..?E'i"Z.,Z; Z,Y,T'?;'.,i..T; ln.-lll?ln.ll??rz. lll lelllu ln. lam l..m..ls .$ .n... llnllll. I la ln lla ml. ll., ,,, ,,, zlfeq glatelet ?mrrlvs_ orothrnmbirt time (PT] ur partial ""'d bY "'* AUQY-ii a' No "'*9.?'m ?' K" "'i?" via-; $oro?-ilu $*7% *3* UW 5** 5-W Rheumatoid antlritie Fur relied uf me signs and rympe - ' r f?r MMS ???? 50 mu/*9 - 1 nl lllnatala mnlnlt ma leaalnlrlellaaa alan tnrombunlasun nme (PTT}, and mes not anpear to ? " ??"$ W '?_25 '"9""J uapal rssalmtaly tamu]; e _ ? MM! pmalm anon lr |"g;?`,d gunna, (5., 'om?*?5 (?P????lm?l?'V WWI W YWm?" nlmx'"' " trm infqnuan u li 6.1% SPSS 9.9% 51% dose rs 100 to 200 my twice per day. EJNICAL 5TuD7EURgr;?5",c|,| g"_,d;"-p|,"ms)_ measured hy the AUQ144 at Zlwrmg BID) for rwu years. skin Naw SUPP.-ED M4 **??-?*???? ????* ??=???-= '*??? *=?=??*??? =??? ?????? ll.ZEURl.?l." L`L"?$`l.C"Kl.'L`lZ';?Tl'?'ZlLI`J'L?'.'L'Y8?T?`l'l?.`il$" M ua M M M ?-?< cslslllnl lmullll ?>>sll?>> ?l? ~?o-lla l?~?ls? >>r??>>?e? *""? ??"' ?*""'*?? '" '""" ?"'?'"' '*"'"? ?""""' nar naslllganac lll ll anlolllasanlll nzlanallan may ln i ' ' mlm an mu. tuna ar amy alla cap wml lllal-unas or g_?jll:':;'5Q_ffv'?`i*?"i';';*?_'? *;j_:'j?; nfJ?_;?';f'jf cna can alla lll lll lrlvll lnlcnlnllnela lan lll ral sm ,,, ,,w,,_,_ _, ?,_,,?,,,m,,,d mm, ,,,a,,_ me ms. new all the can alla too all uu mv, lllnpllla as: un: hvoemmium or hun him VWVWW- _ _ __ _ continuation rate due to adverse events was `I.l1o lar LDC Number ilg ' _ _ _ _ ' Celecoxib dvd not lmpair male and female llemllty ln Ding"`, Nmivgng OELEBREX ,,,,1 571% gm nammts g?;5,t5;?.31 ham; qt tm *"*??*"*"? ,?'!"'?"'** *""?"" "o"* *'"'!'1' }"*Y FM ms at ml ??=?= vv ?? 600 msfts/???v l=??r??????l=*r lelxrllang .,o.a.al,_>>nlana ala lllaalaanlnlall lltssansral wzsnszn-st allure arsoc o'P""""'*""? """"*? 1*** "" "' "P""' 'f' P""?']'s l1?l?|? hnmnn etvoswe ?\ im? mn Fm ??5?l50 TM i?"?Wl?9 ?\?'*EUR'$EUR ?"*\l$ ??EUR?"o? ?? ? ? V 0 n02?e\5z5e;ll tmttla at 100 in patients with praexisnng astnmrr rng/kgfday lauurnximately 2--lold human exposure at patients regardless of ecuselrxy mygrtgzgegt hum, of 5qq mn ind uml more Qrious side anus mm as dence ol letal alterations. such as ribs (used. K\?YM?f?? two-IN mg ID ?r2?? mn UD) _ stare at 25'C UPF); excursions permitted to 15-3l7'C ?asll?.llnlLslan.lyilleealnq wllznl lllay lesllll ..2 nlnlllllal. '????? and ???*?*?**??? m?$????=?? -?= ?'?=?~?? A ??S?= asn...r.ll?l:...rl ellnalnallllll, anlllllnlllllle llyspnsgla, tssewn. rsllll usp cllnllallea naolll relnpmlllle: nation and evan Valar airtlmlner. Altnalrgn seranlls Gl "*l'?""?"_' l"?'?':' "' ?'"?"?9'":'? *'I?Q"'" Wg; enrcratlan, uapnaglns, gastrlns, gaslrnentenvs, gasrrue Hx only -10,45/gg t t I ri n d bl din oc with t ??'?"'? '" ""' " 'W? '"' sm '" ' '"" ?'"' * esophageal rellux, nurmrrhcids, hiatal hernia, melena, vzilllnlacgilllglllillsnaslleliss nilllizns. gill la. il; rr-?l'*?/?*?v <=???*????*?*?*# ?s'?'?* *???*?=*? =???=???? alylllalllll,slalnalllls,lalll.slllll?,llllll+lalsllllll.l,vanlallllg ? ` ? based on the A\JCq.;a at 200 mg BID) There are na V Mia l>vSe.-lm Lld ;;"_;*.?;Q.jj'g;;*;s"'___ ?;{_;*j;g_jf;,'a'p_g;;';';g';id*g; .l.,,..., ....9..,M, lll., ll lla ,l,l.lll,l llllenl .lel.n... ml ?=_???:~ --?~?~ ?*?=?=;=lIy?v?_=?*?j_V*?'?l? sn, M,A,,,,,,,, ?""" ? ' ? """?"'"?? ? ' " ? ?K" "? '?" _ algal llalneystuus, eallllla aemllllllleu, me eaalna, CMA Mmm USA WARNINGS-Risk ul Gastrntntestlnal Uloeratmn, Bleed N?r?rre?royenr??(le?1s:CeIec0xlh vrvduwd we-lfn?|??s {align! {E"' HN nushes ;""u?ma,Hk,: Sympmmx H] i" ing and Federation). tatrcn and pnsteimplantation losses and reduced in 'N had Dain ' N'""Y':NY 'WUUSA P?1i=?? rlnwld nwrnnlly rov?r\ siqrls or symclnms el-naryorreml survival ln rats at oral dosages ssa rllgr ?' j "? ? 7 _ _ _ ?"' ? at gastrointestinal ulceration ar aleedlng, skin rasn, tg/aaytappraxarrlataly Mala nllnlan ellpaxlrre based an "*"""'?' "{"""{""" "'EUR':'f':? "'?'i?$ "pl':?'? a4.;r.s,,.l,.1,?.r,...,lrr,l..r,~,- unetnlained weight dam, ur edema tv their physicians me Auc,?l.;l at znn rl-lg uml. Than srlarlges are *}?'F"' *???* "'*EUR"'?"_b""EUR'" ? "' '?"?", ""?' ? "P "?' an. s-aria al ca. Patrents should be intamlelt ul me warning signs and avpaqw wml anlllbltlqll at plqstaglarldin syntnesis and '*?""':":":?'"?? `;;??"?" ""' ? ""?" '" 4 ? mmcazhruy?gn So~>>?es -\'VW\?!??\5 ?' h???i?!0?|?ilY ll Q-. Muse;. fltiyvc. are not me result ral permanent nltnretmn ul Iemale l7?" al E me 52000 rm: *??o??r?vl ?r?ri??=v i????i??. r??o?? aww ????r???? tan- leplaatlnave tllnrnllll, nar an; may allpllataa at srlnzcal r:?lrr?rparu>>?arn?~?uaay?e.rll? Lea nlalnps, rlypale srlulll it wm dernnss. and '||u-like' Symulnmxl. I! these uccur. gylyqslare; No guqigs naw bun aandtrned tu evalu-- tunia. hypoesthesia, migraine. neuraldia. nnurupxthy. mgm GD Sung kcm ???ior??? sl??>?????=?=- *?v??=*=?*????=? NPN ?r??*??==l =*????????? WC "?"' ??"'V"' ""' ?"'?'"$ ?"??" "? *' h -|k d 0, the Wnllal yo, Serum: increased. alkaline phosphatase increased, weight laaaramly alanlmnalltles that nlxurrea mam lleauently :"'?" '"' df" _ fa":?'??m CELEBREX 2 incr"! ? ?,,?['?,,{Zj"?fd ,f???,?'f,?,{?,'ZT?T,?',Q"$L'{,'T,'i'?,_,;",,'f,,.`;i llmllan xnllllla ll. nlm wnalllel la almllllllllll rlrl.se..r.ll.lel.l alll.l.l?.., nlllllllns, ann. .l.m.ll.., m,|;l;,, ,1,,,, atm wen In pam"`, ,,,,;,0 ,2:4.,,,:6 mm. nurslng ur tu dnscunrlnuc the drug, raking rnta account fracture accidental, myalgra, neck sutlness, svrlnvrtls_ niutor NSAIDs in thase studies. Tha gllnrgal slgrlitl. lltn lrnvcrtnnce otthe drug I0 the rvwlher '???"'*?*$ d - / E h V I nm, t..l..,?.?,.s Salary and effectiveness ln plmiatlia patlants below me *h???????rt*o?m?? _ V A General. Calemxin metabaliant is predt~rn.il?rlt|y mam age nf IE {vars have nut been evaluated Psychiemr Anurexla. anxiety, nppettle lncreased, lied vu rrytuchrurne P450 ZC9 rrr me llver, Cmalimrnlse Guhuic use delwessmn. nervousness, Sornntrlence ;?;?o;_?'|j1?:;j1???M';:;?j,*o??*??= *>.n.e well mn ,...,c..l?,......l.l, Stn. lllellazl, an lla, Mall., ? A95-ir?hi?i????r= ?e??~'\= wqqesl that N5?l?= nlav ansel-vaa between mcse suuyects and younger sub lrlclaasemlrrtrqrla ?*????i??=t? me =???*?v???=?$i~e -**?=? ?*_ ?'?7?i???q=?? gm ctw reputed ?li???c?? =??=?=??? o?= ??? ??????- a,,,rc.lr.... al, a>>,ll.a..,? calllllalas, lnlnlalllls cllnlacl, Converting Enzyme (ACE) llnhrpltnts. Thls vll?>g , long-held belief that cross-allergenicity is common among various h, U sulfonamides may be open to question _ _? .4 V o There is, in fact, very little literature describing clinical cross-reactivity between sulfonamide ?. ` __ _ drugs of any class.' l V _ _ ? Several patients have been reported to be sensitive to one sulfonamide but not to other - L sulfonamide-containing drugs} A . " V ". . .metabolic susceptibility factors for sulphonamide antimicrobials would not be shared _ l? by non-arylamine containing sulphonamides. A differing set of metabolic factors would be expected to influence the occun?ence of toxicities associated with those compounds and there is no apparent metabolic basis for a shared rislc"' ` A Sulfonamides can generally be grouped into 2 categories: ? o Antimicrobial, arylamine sulfonamides ' --Bactrim'" (trimethoprin1/sulfametlwoxazole),Septra(R) (trimethoprim/sulfamethoxazole), . l '_ and Gantrisin(R) (sultisoxazole) >> ? Other, non-arylamine sulfonamides A 1- -- Diuretics such as HydroDlURlL(R) (hydrochlorothiazide) and Lasix(R) (furosemide) --Antihypertensives/diuretics such as Hyzaar(R) (losartan/hydrochlorotl1iazide) and Ziac(R) >> (bisoprolol/hydrochIorothiazide) --Su|fony|ureas such as G|ucotrol? (glipizide), Orinase(R) (tolbutamide), Amaryl(R) `_ (glimepiride), and G|ynase(R) PresTab"' (micronized glyburide) l --Additional medications such as Benemid(R) (probenecid),Trusopt(R) (dorzolamide hydrochloride), |mitrex? (sumatriptan), and Flomax(R) (tamsulosin) ` The antimicrobial metabolites may be more likely to cause primary ' allergic reactions than the metabolites of the "other" sulfonamides '.t`: V BLl'r?panler LA.$pidber; Sllldveme ruuionsm lhlwumideand ?4lp*??nm1ide~?'im?d\?prim lndmcrubials dlnicl iyndmmemd pado?geneskAdv?m Drug l'le?cxTnni??l > ` hcirim kabadeuv?rkandGan?ish1aregis1?edvzidum:kdRado? $qxr1isAr?gi?u?d ?1d?1?l'l0lU|\|LzndTnisopt2re rqimmi - ?1dunarl??fMmd?&C?Z?ciur?gismmd?1dumrkdL:d?1?lah?nmrl?s,AnuryhndlzsixamrzgkzzmdvwunulodHoedmHanonR?nul.hcHm?xkar?gis:e1zd??d?im:1??fB?eliri\gu ,_ Z |ng2heim.Orir\?seGlyn?s>>e,?i\d PruTah are rqiunrzdhadunarlcs ?fPl?m?c.h& Uphln Cnnpuiyelmitzu is 1 mdsmred ?1d=m:A>,, Z 2 E l _ E 4 Lg ? E P %'..[ E i g is ' Z ? m * l Z >> sg -a ? O 2;-g ?w! *1 U E3 ii! 3 l ? gi ; y, ggasg ? z'!,>>| %-;.? D 3 go] Ts; $.*61 C o? Q; u. Q 4 ??r qi L; Q LJ gg Ei --=A wa ns ag A;3 E ?;g%_ A >> m Lg., 1 lg.; :5% < ,.~? A ?ggg . , _ aw 41 E '? J ? 9 ] ! {Ec"? E T *5 E E. E ? Eg.; A 5,; ` >_. 2 >> is; gg?g JJ E 2 :-5; 2 =g A ?g% Zi ' Z i -??; L A ? 5 .*-? ii.} E i? I '~-_1 zi`.! iign? ?? ?9;??t2?? 3 ? V Q; ?% Eg? Z " -- . AE ? ? k E A- ,_ >> 1 l Egg 0V $,;?? gi ' Egg EEA -3EgE ` E 5 QE IE ` >> g ; U! 5 (2NIE 1 q USE ? sig R g ; '???2i 5%%-; wz ? g=;? 1 ` chai om5?5j.--= E `E E ?"?! '*???????*; ggg _ gg Egg, Z gig? EUR?@ .3;%;,, gi ; . V -- ,?9.?? ? E Q 5 _. E ?g? Y , 9 @@2 ?ig?z gis`? >> 2%; V 5*2 _ E . *-~-? >> NSE 1, gg . _ A5