Product Monograph INDICATIONS AND USAGE IMPORTANT RISK INFORMATION WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY

Transcription

1 Product Monogrph INDICATIONS AND USAGE OFIRMEV (cetminophen) injection is indicted for the mngement of mild to moderte pin, mngement of moderte to severe pin with djunctive opioid nlgesics, nd reduction of fever. WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY Tke cre when prescribing, prepring, nd dministering OFIRMEV Injection to void dosing errors which could result in ccidentl overdose nd deth. In prticulr, be creful to ensure tht: the dose in milligrms (mg) nd milliliters (ml) is not confused; the dosing is bsed on weight for ptients under 5 kg; infusion pumps re properly progrmmed; nd the totl dily dose of cetminophen from ll sources does not exceed mximum dily limits. OFIRMEV contins cetminophen. Acetminophen hs been ssocited with cses of cute liver filure, t times resulting in liver trnsplnt nd deth. Most of the cses of liver injury re ssocited with the use of cetminophen t doses tht exceed the recommended mximum dily limits, nd often involve more thn one cetminophencontining product. Plese see dditionl Importnt Risk Informtion, including complete boxed wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion. To report SUSPECTED ADVERSE REACTIONS, contct Mllinckrodt Hospitl Products, Inc. t or the FDA t 1-8-FDA-188 or

2 TABLE OF CONTENTS 1. EXECUTIVE SUMMARY...4 Pin mngement in tody s helth cre environment... 4 Overview of unmet need in pin mngement... 5 Multimodl nlgesi in pin mngement... 6 Multimodl nlgesi: Efficcy of OFIRMEV (cetminophen) injection... 8 Overview of the tretment of fever nd current medicl needs in dults... 8 Pin, fever, nd current medicl needs in children... 9 IV cetminophen development PRODUCT DESCRIPTION INDICATIONS AND USAGE CLINICAL PHARMACOLOGY Phrmcology overview...11 Distribution...11 Peditric PK...12 Metbolism...13 Clernce...14 Mechnism of ction...14 Phrmcokinetic prmeters of IV, orl, nd rectl cetminophen...14 Phrmcodynmics...16 Clinicl considertions regrding route of dministrtion CLINICAL SAFETY...38 Mximum dily dose (4 mg) Heptotoxicity in clinicl trils Heptotoxicity in clinicl use... 4 Contrindictions Wrnings nd precutions Adverse rections Use in specific popultions Drug interctions DOSING...46 Adults nd dolescents ( 13 yers of ge) Children 2 yers of ge ADMINISTRATION...47 Instructions for IV dministrtion Storge nd hndling CONCLUSIONS ABBREVIATIONS REFERENCES CLINICAL EFFICACY...19 Anlgesic efficcy...19 Antipyretic efficcy Plese see Importnt Risk Informtion, including complete boxed wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion. 2 3

3 1. EXECUTIVE SUMMARY OFIRMEV (cetminophen) injection is indicted for the 1 Mngement of mild to moderte pin Mngement of moderte to severe pin with djunctive opioid nlgesics Reduction of fever OFIRMEV is the first nd only intrvenous (IV) formultion of cetminophen to be pproved nd mrketed in the United Sttes. The pprovl of OFIRMEV is supported by the results of 2 clinicl trils involving 1375 ptients. 1,2 Three re pivotl studies. Two of these demonstrted the nlgesic efficcy nd sfety of OFIRMEV in orthopedic nd generl surgeries. 3,4 One demonstrted ntipyretic efficcy nd sfety in dult ptients. 5 In ddition, there exists considerble body of evidence supporting the efficcy of IV cetminophen. 3,4,6-13 In rndomized, controlled clinicl trils, IV cetminophen hs demonstrted effective pin relief in wide vriety of surgicl procedures. In severl of these studies, the inclusion of IV cetminophen resulted in sttisticlly significnt reduction in opioid consumption compred with plcebo. 3,6,8-11 OFIRMEV hs n estblished sfety profile in dult nd peditric ptients 2 yers of ge nd ws well tolerted in clinicl trils. Since the introduction of IV cetminophen in Europe in 22, more thn 4 million doses hve been distributed in more thn 6 countries worldwide. 2 Over 14 million ptients hve been treted with OFIRMEV since its US pprovl in Administrtion of cetminophen in doses higher thn recommended my result in heptic injury, including the risk of liver filure nd deth. 1 Acetminophen is contrindicted in ptients with known hypersensitivity to cetminophen or to ny of the excipients in the IV formultion, or with severe heptic impirment or severe ctive liver disese. 1 The IV form of cetminophen my be prticulrly useful where rpid nlgesi or fever reduction is cliniclly indicted, or where other routes of dministrtion re imprcticl or undesirble. Pin mngement in tody s helth cre environment Over the pst 2 decdes, effective pin mngement hs become priority for helth cre orgniztions, prctitioners, nd policy mkers. In 21, The Joint Commission instituted pin mngement stndrds for the ssessment nd mngement of cute pin. 14 A pin mngement section is lso included in the Hospitl Consumer Assessment of Helthcre Providers nd Systems (HCAHPS or CAHPS) survey, stndrdized method of mesuring ptient experiences in the hospitl. Results of this survey re publicly reported, which llows ptients to mke comprisons of hospitls cross the country, nd re used to crete incentives to improve qulity of cre nd enhnce public ccountbility. 15 Qulity of cre nd ptient stisfction hve become importnt mrkers of overll hospitl performnce. Thus, HCAHPS ptient stisfction nd pin scores re centrl when considering periopertive nlgesic regimens. In mny hospitls, ptient stisfction, or the Ptient Experience of Cre Domin, is 3% of the totl performnce score for vlue-bsed incentive pyment (1.5% for fiscl yer 215). 16 By lw, the vlue-bsed incentive pyments re required to be bsed on hospitls performnce scores, nd ech hospitl s vlue-bsed incentive pyment mount for fiscl yer will depend hevily on the hospitl s totl performnce score nd the mount of the hospitl s bse operting dignosis-relted group (DRG) pyment mounts. 16 As result, hospitls re plcing incresing vlue on improving pin mngement, reducing overll opioid consumption, nd improving ptient stisfction. Overview of unmet need in pin mngement Acute pin is common nd suboptimlly mnged occurrence, specificlly in the postopertive setting. 17,18 Trditionlly, s well s currently, in the United Sttes, monotherpy with opioids is used s the minsty to tret postopertive pin. In 214 study nlyzing dt from 2,853,632 hospitl inptients, 73% of ptients treted with IV pin mediction received IV nrcotic monotherpy. 19 Additionl nlysis of 873,96 nonsurgicl inptients reveled tht 85% of ptients treted with IV pin mediction received IV nrcotic monotherpy. 19 Despite the vilbility of effective nlgesics, the incidence of postopertive pin remins high. 2 In 212 survey, pproximtely 85% of ptients reported postopertive pin, with totl of 65% reporting pin s moderte to extreme. 21 These dt re similr to those from survey conducted in 1995 (62% of ptients reported moderte to extreme postopertive pin). 17 Furthermore, postopertive pin is ssocited with vrious complictions nd poor outcomes. 6 Postopertive pin is lso one of the most common resons for hospitl redmission following dischrge. 2 These fctors mke pin mngement chllenging in postopertive ptients. In 212, The Joint Commission published Sentinel Event Alert tht underscored the need for judicious nd sfe use of opioids in hospitls. Included in The Joint Commission s recommendtions were mesures imed t reducing the overll use of opioids nd recommendtions employing multimodl nlgesi s one method in the pursuit of these gols. 14 WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY Tke cre when prescribing, prepring, nd dministering OFIRMEV Injection to void dosing errors which could result in ccidentl overdose nd deth. In prticulr, be creful to ensure tht: the dose in milligrms (mg) nd milliliters (ml) is not confused; the dosing is bsed on weight for ptients under 5 kg; infusion pumps re properly progrmmed; nd the totl dily dose of cetminophen from ll sources does not exceed mximum dily limits. OFIRMEV contins cetminophen. Acetminophen hs been ssocited with cses of cute liver filure, t times resulting in liver trnsplnt nd deth. Most of the cses of liver injury re ssocited with the use of cetminophen t doses tht exceed the recommended mximum dily limits, nd often involve more thn one cetminophen-contining product. ADVERSE REACTIONS Serious dverse rections my include heptic injury, serious skin rections, hypersensitivity, nd nphylxis Common dverse rections in dults include nuse, vomiting, hedche, nd insomni. Common dverse rections in peditric ptients include nuse, vomiting, constiption, pruritus, gittion, nd telectsis wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion. 4 5

4 Multimodl nlgesi in pin mngement Figure 1B. Multimodl nlgesi pproch for mnging different levels of pin 26 Acute pin, prticulrly postopertive pin, my be complex nd multifctoril nd my be treted optimlly vi multimodl nlgesic pproch. In this form of therpy, 2 or more nlgesics cting by different mechnisms re dministered with the gol of providing nlgesic efficcy superior to single nlgesic. 22 Using different clsses of nlgesics, ech with different pthwys nd receptors, multimodl nlgesi cn optimize nlgesic efficcy by using lower doses of ech respective gent nd my lso reduce the risk for dose-relted dverse effects. 23 Figure 1A. Multimodl nlgesi combines 2 or more nlgesics cting by different mechnisms 1,23-25 Opioids α 2 -gonists Acetminophen NMDA ntgonists Step 2: Moderte pin Step 3: Severe pin Step 1 + step 2 + higher doses of opioids Step 1 + low doses of opioids Locl nesthetics NSAIDs COXIBs Step 1: Mild pin Acetminophen, NSAIDs, or COXIBs + locl or regionl nesthesi COXIB, cyclooxygense-2 specific inhibitor. COXIB, cyclooxygense-2 specific inhibitor; NMDA, N-methyl-D-sprtte. Locl nesthetics Opioids α 2 -gonists NMDA ntgonists In prctice, multimodl nlgesi my be implemented vi stepwise pproch with non-opioids serving s the foundtionl gents given preopertively for the mngement of pin nd djunctive opioids dded s needed for moderte to severe pin (Figure 1A). Tretment begins t step 1, nd medictions or interventions with different modes of ction re dded in subsequent steps in response to incresed pin intensity. 22,23,26 Over the pst decde, multimodl nlgesi hs gined recognition s n effective strtegy for the mngement of cute pin in the periopertive setting, nd the concept is supported by numerous professionl orgniztions. The Americn Society of Anesthesiologists (ASA), 22 the Americn Society of PeriAnesthesi Nurses (ASPAN), 27 the Americn Geritrics Society (AGS), 28 the Society of Criticl Cre Medicine (SCCM), 29 the Americn Society for Pin Mngement Nursing (ASPMN), 3 the Agency for Helthcre Reserch nd Qulity (AHRQ), 31 nd The Joint Commission 14 encourge use of multimodl pproch to periopertive nlgesi. The ASA Tsk Force on Acute Pin Mngement recommends tht ll surgicl ptients receive n round-the-clock regimen of cetminophen, NSAIDs, or cyclooxygense-2 specific inhibitors (COXIBs) unless contrindicted nd tht dosing regimens should be dministered to optimize efficcy while minimizing the risk of dverse events. 22 Acetminophen is contrindicted in ptients with: known hypersensitivity to cetminophen or to ny of the excipients in the intrvenous (IV) formultion severe heptic impirment or severe ctive liver disese Do not exceed the mximum recommended dily dose of cetminophen by ll routes The mximum totl dily dose of OFIRMEV (cetminophen) injection for dults 5 kg is 4 mg wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion. 6 7

5 Multimodl nlgesi: Efficcy of OFIRMEV (cetminophen) injection Use of non-opioid nlgesics such s OFIRMEV s the foundtionl gent within multimodl regimen hs been proven to chieve cliniclly significnt pin relief while reducing the consumption of opioids. 3,6,8-11,22,23 The clinicl benefit of reduced opioid consumption with OFIRMEV hs not been evluted or demonstrted. As the only IV formultion of cetminophen vilble in the United Sttes, OFIRMEV provides the only option to use IV cetminophen non-opioid, non-nsaid IV gent s prt of multimodl nlgesic regimen. OFIRMEV my fill medicl need for well-tolerted nd effective nlgesic regimen in the periopertive setting. With limited IV nlgesic options to mnge cute pin in multimodl fshion, n gent tht hs demonstrted sfety nd efficcy in the tretment of pin is highly desirble. Overview of the tretment of fever nd current medicl needs in dults Fever is n elevtion in body temperture nd is commonly defined s body temperture greter thn 1.4 F (38 C) Fever cn hve both infectious (eg, bcteril, virl) nd noninfectious (eg, inflmmtion, drug hypersensitivity) etiologies. 35 High fever my result in ltertions of mentl sttus, confusion, irritbility, or convulsions. 36 Surgery is lso common source of fever in the hospitl setting, with published fever incidence rtes rnging from 14% to 91% of postopertive ptients. 37 Surgicl trum leds to the relese of pyrogenic cytokines, which ct directly on the hypothlmus, cusing the relese of prostglndins the more trumtic the surgery, the higher the risk of postopertive fever. However, in such ptients, infection rtes re less thn 1%. 37 The vilbility of n IV formultion my ddress significnt nd long-stnding unmet medicl need for rpid nd relible delivery of cetminophen for fever reduction when other routes of dministrtion re imprcticl. Pin, fever, nd current medicl needs in children At the recommended therpeutic dosing, cetminophen hs demonstrted nd well-estblished sfety profile nd hs been n effective nlgesic nd ntipyretic for over 5 yers in children. Despite the widespred use of cetminophen, orl or rectl delivery is not lwys idel for hospitlized children. Orl dministrtion my not be prcticl in ptients who re nesthetized or nil per os (NPO) following surgery nd my be n imprcticl route in some peditric ptients. Rectlly dministered cetminophen cn be difficult to dminister for the helth cre professionl nd unplesnt for the ptient. For children 2 to 12 yers of ge, the recommended dosge of OFIRMEV is 15 mg/kg every 6 hours (q6h) or 12.5 mg/kg every 4 hours (q4h), with mximum single dose of OFIRMEV of 15 mg/kg, minimum dosing intervl of 4 hours, nd mximum dily dose of cetminophen of 75 mg/kg per dy. Fever is one of the most common resons prents bring their children to the emergency room for evlution nd tretment. 38 Up to 4% of children experience fever-induced seizures, or febrile seizures, nd up to 17% of children who were born premturely suffer febrile seizures. 39,4 IV NSAIDs such s ibuprofen nd ketorolc re not pproved for fever reduction in children. 41,42 Common dverse rections in peditric ptients include nuse, vomiting, constiption, pruritus, gittion, nd telectsis IV cetminophen development An IV formultion of cetminophen ws first pproved in 21 for use in Frnce nd hs been mrketed in mny countries s Perflgn by Bristol-Myers Squibb (BMS) since 22. Currently, IV cetminophen is pproved in more thn 6 countries. 2 The sfety of IV cetminophen hs been monitored through postmrketing surveillnce progrm, with more thn 4 million units distributed since its Europen pprovl. 2 Additionlly, the results of mny rndomized controlled trils (RCTs) evluting IV cetminophen for the mngement of pin or fever hve been published in peer-reviewed literture. 2 In 26, Cdence Phrmceuticls, Inc. licensed North Americn development nd commerciliztion rights to IV cetminophen from BMS nd undertook its US development. The clinicl development progrm ws completed in 28 nd included 2 trils involving 1375 ptients. 1,2 OFIRMEV ws pproved by the Food nd Drug Administrtion on November 2, 21 for the mngement of mild to moderte pin, the mngement of moderte to severe pin with djunctive opioid nlgesics, nd the reduction of fever. 1 In 214, Mllinckrodt cquired Cdence Phrmceuticls. Acetminophen is contrindicted in ptients with: known hypersensitivity to cetminophen or to ny of the excipients in the intrvenous (IV) formultion severe heptic impirment or severe ctive liver disese Use cution when dministering cetminophen in ptients with the following conditions: heptic impirment or ctive heptic disese, lcoholism, chronic mlnutrition, severe hypovolemi (e.g., due to dehydrtion or blood loss), or severe renl impirment (cretinine clernce 3 ml/min) Serious dverse rections my include heptic injury, serious skin rections, hypersensitivity, nd nphylxis Common dverse rections in dults include nuse, vomiting, hedche, nd insomni. Common dverse rections in peditric ptients include nuse, vomiting, constiption, pruritus, gittion, nd telectsis wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion. 8 9

6 2. PRODUCT DESCRIPTION 4. CLINICAL PHARMACOLOGY OFIRMEV (cetminophen) injection is nonslicylte ntipyretic nd non-opioid nlgesic gent. 1 It is distinct from other commonly used drugs for reducing fever nd pin, such s NSAIDs, s it is not significnt direct cyclooxygense inhibitor; therefore, OFIRMEV is in different drug clss with different mechnism of ction. 43 Acetminophen is the US-dopted nme for the compound, which is known by its nonproprietry nme of prcetmol outside the United Sttes. 43 Acetminophen hs moleculr weight of Its structurl formul is 1 Phrmcology overview Acetminophen exerts nlgesic nd ntipyretic effects following systemic dministrtion. Onset of nlgesi occurs within the first 15 minutes of dministrtion of OFIRMEV. Pek nlgesic effect occurs within 1 hour, nd the durtion of nlgesic effect is through 6 hours. 1,3 Fever is reduced within 3 minutes fter the strt of the infusion, nd the durtion of ntipyretic effect is through 6 hours. 5 Phrmcokinetics (PK) of OFIRMEV hs been studied in ptients nd helthy subjects, from premture neontes up to dults 6 yers of ge. 1 The mximum concentrtion (C mx ) occurs t the end of the 15-minute infusion of OFIRMEV. 1 The phrmcokinetic profile of OFIRMEV hs been demonstrted to be dose proportionl in dults following dministrtion of single doses of 5, 65, nd 1 mg. 1 OFIRMEV is sterile, cler, colorless, nonpyrogenic, isotonic formultion of cetminophen intended for IV infusion. It hs ph of pproximtely 5.5 nd n osmollity of pproximtely 29 mosm/kg. Ech 1 ml contins 1 mg of cetminophen, United Sttes Phrmcopei (USP); 385 mg of mnnitol, USP; 25 mg of cysteine hydrochloride, monohydrte, USP; nd 1.4 mg of dibsic sodium phosphte, USP. The ph is djusted with hydrochloric cid nd/or sodium hydroxide. 1 In generl, cetminophen is poorly soluble in solution. In ddition, cetminophen is highly rective with oxygen nd rpidly polymerizes in the presence of oxygen. The unique formultion nd mnufcturing process for OFIRMEV hs finlly creted stble liquid solution of cetminophen suitble for direct IV dministrtion. 2 Distribution At therpeutic levels, binding of cetminophen to plsm proteins is low (rnging from 1% to 25%). 1 Acetminophen ppers to be widely distributed throughout most body tissues, except ft, nd rpidly enters the centrl nervous system (CNS) in concentrtion (C mx )-driven process. 1,2 Phrmcokinetic prmeters of OFIRMEV (re under the curve [AUC], C mx, terminl elimintion hlf-life [t 1/2 ], systemic clernce [CL], nd volume of distribution t stedy stte [V ss ]) following dministrtion of single IV dose of 15 mg/kg for the peditric popultion nd 1 mg for dults re summrized in Tble 4A INDICATIONS AND USAGE Tble 4A. Phrmcokinetic prmeters of OFIRMEV 1 Men (SD) OFIRMEV (cetminophen) injection is indicted for the 1 Mngement of mild to moderte pin Mngement of moderte to severe pin with djunctive opioid nlgesics Reduction of fever OFIRMEV is pproved for use in ptients 2 yers of ge nd older. 1 Subpopultions Neontes Infnts Children AUC (µg h/ml) C mx (µg/ml) t 1/2 (h) CL (L/h/kg) V ss (L/kg) 62 (11) 25 (4) 7. (2.7).12 (.4) 1.1 (.2) 57 (54) 29 (24) 4.2 (2.9).29 (.15) 1.1 (.3) 38 (8) 29 (7) 3. (1.5).34 (.1) 1.2 (.3) Acetminophen is contrindicted in ptients with: known hypersensitivity to cetminophen or to ny of the excipients in the intrvenous (IV) formultion severe heptic impirment or severe ctive liver disese Adolescents 41 (7) 31 (9) 2.9 (.7).29 (.8) 1.1 (.3) Adults 43 (11) 28 (21) 2.4 (.6).27 (.8).8 (.2) AUC, re under the curve; C mx, mximum concentrtion; t 1/2, terminl elimintion hlf-life; CL, clernce; V ss, volume of distribution t stedy stte. wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion. 1 11

7 These phrmcokinetic prmeters for dults, dolescents, nd children were chieved by delivering dosges s described in Section 7 of this monogrph. The phrmcokinetic exposure of OFIRMEV (cetminophen) injection observed in children nd dolescents is similr to tht observed in dults, but is higher in neontes nd infnts (Tble 4A). Dosing simultions from phrmcokinetic dt of infnts nd neontes suggest tht dose reductions of 33% in infnts 1 month to less thn 2 yers of ge, nd dose reductions of 5% in neontes up to 28 dys, with minimum dosing intervl of 6 hours, will produce phrmcokinetic exposure similr to tht observed in children 2 yers nd older. 1 Peditric PK A totl of 355 peditric ptients (47 neontes, 64 infnts, 171 children, nd 73 dolescents) hve received OFIRMEV in ctive-controlled (n=25) nd open-lbel (n=225) clinicl trils, including 59.7% (n=212) who received 5 or more doses nd 43.1% (n=153) who received more thn 1 doses. 1 A met-nlysis of peditric phrmcokinetic dt llowed the cretion of mturtionl phrmcokinetic model for cetminophen. 2 A pttern between normlized cetminophen CL, djusted for body weight, nd ge (expressed s postmenstrul ge) ws observed, with rpid increse in CL in neontes nd infnts (Figure 4A). 2 Metbolism Acetminophen metbolism is well chrcterized. In dults nd children, cetminophen is metbolized by the liver vi 3 mjor pthwys: glucuronidtion (5% to 6%), sulftion (25% to 35%), nd oxidtion (<1%). 44,45 In neontes nd infnts, sulftion is the predominnt metbolic pthwy due to delyed mturity in glucuronidtion. 46 Other minor cetminophen metbolic pthwys include hydroxyltion nd decetyltion. 44,47 Unlike orl cetminophen, IV cetminophen does not undergo first-pss heptic metbolism due to its direct systemic dministrtion. 48 Within therpeutic doses of cetminophen, smll mounts of N-cetyl-p-benzoquinone imine (NAPQI), toxic intermedite, re produced primrily by cytochrome P45 enzyme CYP2E1. 49 NAPQI is then conjugted with intrcellulr glutthione to produce nontoxic thiol metbolite nd is excreted in the urine. At very high cetminophen dose levels or in the presence of significnt depletion of glutthione stores, NAPQI is produced in lrger mounts, which cn result in heptotoxicity. 2,5 These mjor metbolic pthwys nd the chemicl structures of the metbolites re shown schemticlly in Figure 4B. 51 Figure 4B. Metbolism of cetminophen in humns 51 O Clernce (L/h/7 kg) Figure 4A. Age vs normlized cetminophen clernce 2 29 dys 6 months 12 months 2 yers 12 yers 18 yers Neontes Infnts Children Adolescents Adults Biliry excretion (1% 2%) Cysteine conjugte: sfe urinry excretion (3%) N-rchidonoylphenolmine (AM44) Excreted unchnged in urine (1% 4%) O Acetminophen NH OH H 2 N OH (In CNS) p-aminophenol Phenolsulfotrnsferse (+ glutthione precursor) (2% 46%) O HN C CH 3 OH Depletion of glutthione/ overdosge of prcetmol HN C CH 3 OC 6 H 8 O 6 O N C CH 3 Cellulr toxicity (covlent binding nd ryltion of criticl cell proteins) Cell mcromolecule O Glucuronic cid conjugte (predominnt in dult life) O HN C CH 3 OSO 3 Sulphuric cid conjugte (predominnt in fetus nd erly life) N-cetyl-pbenzoquinone imine (toxic metbolite) Norml levels of glutthione/ therpeutic doses of prcetmol Nontoxic conjugtes (glutthione, cysteine, mercptte) O HN C CH 3 OH GSH Postmenstrul ge (wk) Acetminophen PK nd exposure levels following single nd multiple doses of OFIRMEV 15 mg/kg q6h in children nd dolescents were comprble to the normlized vlues in dults. 2 Adpted from Bertolini A et l. CNS Drug Rev. 26;12(3-4): Serious dverse rections my include heptic injury, serious skin rections, hypersensitivity, nd nphylxis Common dverse rections in dults include nuse, vomiting, hedche, nd insomni. Common dverse rections in peditric ptients include nuse, vomiting, constiption, pruritus, gittion, nd telectsis wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion

8 Clernce Acetminophen metbolites re minly excreted in the urine. Less thn 5% of the dministered dose is excreted in the urine s unconjugted (free) cetminophen, nd more thn 9% is excreted within 24 hours. 1 Mechnism of ction The precise mechnism of the nlgesic nd ntipyretic properties of cetminophen is not estblished but is thought to primrily involve centrl ctions. 1 Exmples of centrl ctions include prostglndin inhibition (no peripherl effect), nitric oxide pthwy medition, modultion of descending nordrenergic nd serotonergic pin pthwys, modultion of opioidergic systems (dynorphin relese), modultion of the cnnbinoid system, ctivity within the hypothlmic het-regulting center, trnsient receptor potentil nkyrin 1 (TRPA1) ctivtion, nd trnsient receptor potentil vnilloid 1 (TRPV1) ctivtion. 43,47 Phrmcokinetic prmeters of IV, orl, nd rectl cetminophen The PK nd phrmcodynmics of IV cetminophen hve been well chrcterized. 2,52 In n open-lbel, single-center, rndomized, 4-period crossover study conducted by Cdence Phrmceuticls, Inc., Mllinckrodt compny, IV cetminophen ws compred with orl cetminophen in helthy mle volunteers (N=6). 5 Subjects received totl of 8 doses ech of OFIRMEV (cetminophen) injection 1 g q6h, OFIRMEV 1 g q4h, orl cetminophen 1 g q6h, nd orl cetminophen 1 g q4h divided mong 4 tretment periods. OFIRMEV ws dministered s 15-minute infusion. 2 Men plsm concentrtions of OFIRMEV 1 g nd orl cetminophen 1 g for the first 6-hour dosing period re shown in Figure 4C. 2 Compred with 1-g dose of orl cetminophen, 1 g of IV cetminophen resulted in up to 7% higher plsm C mx vlues, with medin time to rech C mx (T mx ) of 15 minutes (end of infusion). 1 Plsm AUC ws very similr for the sme dose of IV cetminophen nd orl cetminophen. 2 The pek effect of 1 g of cetminophen occurred within 1 hour of dministrtion, nd durtion of effect ws 4 to 6 hours. 2 Rrely, cetminophen my cuse serious skin rections such s cute generlized exnthemtous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), nd toxic epiderml necrolysis (TEN), which cn be ftl Hypersensitivity nd nphylxis ssocited with the use of cetminophen hve been reported. Clinicl signs included swelling of the fce, mouth, nd throt, respirtory distress, urticri, rsh, nd pruritus Men plsm concentrtion (µg/ml) Figure 4C. Men plsm concentrtions of OFIRMEV 1 g nd orl cetminophen 1 g 2 Time to rech Cmx (Tmx) 3 minutes fster thn orl cetminophen Time (h) OFIRMEV 1 g (n=38) Orl cetminophen 1 g (n=38) Distribution nd men CL vlues t stedy stte were comprble between delivery methods, nd neither the route of dministrtion nor the dosing intervl hd cliniclly significnt impct on frctionl excretion in urine of free or unconjugted cetminophen. The t 1/2 vlues were lso found to be comprble (2.39 hours for OFIRMEV vs 2.66 hours for orl cetminophen). Adverse rections, drug ccumultion, effects on pltelet ggregtion, nd chnges in electrocrdiogrms were comprble between IV nd orl dosing. 2 In second phrmcokinetic study by Singl et l, both plsm nd cerebrospinl fluid (CSF) PK of IV, orl, nd rectl cetminophen were compred. Six helthy mle subjects were included in 3-wy crossover, single-center, single-dose phrmcokinetic study. 52 The IV route produced 76% higher men plsm C mx (P=.4) thn orl dministrtion nd 256% higher C mx (P<.1) thn rectl dministrtion of cetminophen (Figure 4D). 52 The T mx for the IV route ws erlier (.25 hour) thn tht for the orl route (1 hour, P=.18) or the rectl route (2.5 hours, P=.25) Dt on file. Open-lbel, single-center, rndomized, 4-period crossover phrmcokinetic study involving helthy dult mles (N=76). Subjects received totl of 8 doses ech of OFIRMEV 1 g every 6 hours (q6h), OFIRMEV 1 g every 4 hours (q4h), orl cetminophen 1 g q6h, nd orl cetminophen 1 g q4h divided mong 4 tretment periods (results for the first 6-hour dosing period shown bove). Primry endpoint: comprtive exposure of OFIRMEV nd orl cetminophen (rpid-relese liquid formultion). OFIRMEV ws dministered s 15-minute infusion. wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion

9 Men plsm concentrtion (mg/ml) Figure 4D. Men plsm concentrtions 52 Time (h) OFIRMEV 1 g (n=6) Orl cetminophen 1 g (n=6) Rectl cetminophen 1 g (n=6) Singl et l. Three-wy crossover, single-center, single-dose phrmcokinetic study of 6 helthy dult mles. Ech received 3 singledose tretments of IV, orl, nd rectl cetminophen, seprted by wshout period of 24 hours. Tretment dosge ws 1 g IV nd orl cetminophen, nd 13 mg rectl. IV cetminophen ws dministered over 15 minutes commencing t hours. Cerebrospinl fluid nd blood drws were performed prior to study mediction dministrtion nd t 8 dditionl time points for 6 hours in ech tretment period. Clinicl considertions regrding route of dministrtion Surgery, opioids, nesthesi, preopertive fsting, nd postopertive stress cn ll work together in the period immeditely following surgery to produce gstropresis nd delyed gstric emptying. These fctors re importnt when choosing the pproprite formultion of cetminophen in the periopertive setting s bsorption of orl nlgesics my be compromised in the immedite postopertive setting Figure 4F. Opioids Contributing fctors Compromised gstric function Pyloric nrrowing or closure Significnt dely in gstric emptying Surgery Rectl cetminophen dt reflect stndrdiztion of the 13-mg dose to 1 g (liner kinetics). Phrmcodynmics Acetminophen penetrtes redily through n intct blood-brin brrier nd enters the CNS rpidly in C mx -driven process. 2 Levels re detectble in the CSF within 5 minutes fter OFIRMEV (cetminophen) injection. 53 Given tht the mechnism of ction of cetminophen is thought to be centrlly medited, the erlier pek CSF levels my correlte with the more rpid onset of ction. 2 In the 212 Singl et l study, the men CSF AUC for IV cetminophen over 6 hours ws 75% higher thn the orl AUC (P=.99) nd 142% higher thn the rectl AUC (P=.4) (Figure 4E). 52 The men CSF C mx vlue for IV cetminophen ws 6% higher thn tht for orl (P<.1) nd 87% higher thn tht for rectl dministrtion (P<.1). 52 Figure 4E. Men CSF concentrtions 52 Anesthesi Subsequent intestinl bsorption of nutrients/mediction inhibited Fsting In study by vn der Westhuizen of 16 ptients undergoing orthopedic surgery or er, nose, nd throt (ENT) surgery, 96% of ptients receiving IV cetminophen reched therpeutic levels t ny time during the study period compred with only 67% of ptients receiving orl cetminophen (P<.1). 58 Stress Men CSF concentrtion (μg/ml) Time (h) OFIRMEV 1 g (n=6) Orl cetminophen 1 g (n=6) Rectl cetminophen 1 g (n=6) Singl et l. Three-wy crossover, single-center, single-dose phrmcokinetic study of 6 helthy dult mles. Ech received 3 singledose tretments of IV, orl, nd rectl cetminophen, seprted by wshout period of 24 hours. Tretment dosge ws 1 g IV nd orl cetminophen, nd 13 mg rectl. IV cetminophen ws dministered over 15 minutes commencing t hours. Cerebrospinl fluid nd blood drws were performed prior to study mediction dministrtion nd t 8 dditionl time points for 6 hours in ech tretment period. Rrely, cetminophen my cuse serious skin rections such s cute generlized exnthemtous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), nd toxic epiderml necrolysis (TEN), which cn be ftl Hypersensitivity nd nphylxis ssocited with the use of cetminophen hve been reported. Clinicl signs included swelling of the fce, mouth, nd throt, respirtory distress, urticri, rsh, nd pruritus Rectl cetminophen dt reflect stndrdiztion of the 13-mg dose to 1 g (liner kinetics). wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion

10 Following surgery, compromised gstric function hs been shown to diminish the bsorption of orl cetminophen. In prospective phrmcokinetic study designed to ssess bsorption, Berger nd collegues demonstrted tht opite-relted pyloric nrrowing or closure leds to decresed plsm concentrtions of cetminophen given orlly (Figure 4G). 55 Figure 4G. Pek plsm levels of orl cetminophen on dy CLINICAL EFFICACY The efficcy of OFIRMEV (cetminophen) injection for the mngement of pin nd fever is supported by 3 pivotl, well-controlled clinicl trils. 3-5 Additionl rndomized, controlled trils tht support efficcy for these indictions hve been performed. 4,6-13,59 Pek plsm concentrtions (mg/ml) Additionlly, n orthopedic surgery study by Petring nd collegues confirmed tht significnt delys in gstric emptying occur with the dministrtion of intrmusculr opioid nlgesics (Figure 4H). When used s gstric bsorption mrker, postopertive plsm concentrtions of orlly dministered cetminophen were significntly lower thn preopertive vlues (P<.1) in ptients who received single dose of morphine fter surgery. 54 Men plsm concentrtion (μg/ml) Crdic surgery ptients who received opioids (cetminophen vi nsogstric tube) (n=11) Figure 4H. Men pre-op nd post-op plsm concentrtions 54 2 Pre-op orl cetminophen without morphine (n=8) 18 Post-op orl cetminophen with morphine (n=8) 3 45 Time (min) wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion Helthy volunteers who did not receive opioids (n=6) 9 12 Berger et l. Prospective phrmcokinetic study conducted in ptients who underwent crdic surgery (n=16) nd helthy volunteers who served s controls (n=6) to ssess intestinl bsorption s function of plcement of tube insertion. As mrker to ssess bsorption, 1 g of cetminophen in liquid formultion ws dministered on post-op dys 1 nd 3 through nsogstric (n=11) or postpyloric tube (n=5). Petring et l. Rndomized, double-blind, phrmcokinetic study involving 15 ptients undergoing orthopedic surgery with spinl nesthesi. Upon first complint of post-op pin, ptients were rndomized to receive single dose of intrmusculr morphine 1 mg (n=8) or single dose of intrmusculr ketorolc 3 mg (n=7). Orl cetminophen solution 2 mg/kg ws dministered twice in ech ptient s mrker, t lest 12 hours before scheduled surgery (pre-op) nd 3 minutes fter dministrtion of morphine (post-op) Anlgesic efficcy Two pivotl trils hve demonstrted significnt efficcy for reduction of pin nd improved ptient stisfction. 1,3,4 Sintr et l (pin study 1): A phse 3, rndomized, double-blind, plcebo-controlled, multicenter study tht evluted the nlgesic efficcy nd sfety of single nd repeted doses of OFIRMEV 1 g in comprison with plcebo in 11 ptients experiencing moderte to severe pin following totl hip or knee replcement.* Ptients were llowed rescue mediction with ptient-controlled nlgesi (PCA) morphine. Efficcy ws mesured s 3 : Pin relief on 5-point verbl scle t selected intervls up to 6 hours (primry endpoint) Pin intensity on 1-mm visul nlog scle (VAS) nd 4-point verbl scle t selected intervls over 24 hours Quntity of morphine consumed Time to first use of rescue mediction Ptients globl evlution of stisfction t 24 hours * This study lso included n ctive comprtor, propcetmol. However, since propcetmol is not commercilly vilble in the United Sttes, the dt here reflect only IV cetminophen nd plcebo. Therefore, for discussion purposes, propcetmol is not included. In totl, 49 ptients received IV cetminophen; 52 received plcebo; nd 5 received propcetmol. Since this study ws completed, the preferred primry efficcy endpoints for regultory evlutions of pivotl studies in pin indictions hve shifted to summed difference in pin intensity. An extended nlysis ws performed in order to confirm nd ugment the sttisticlly significnt single- nd repeted-dose efficcy endpoints in fvor of OFIRMEV vs plcebo observed in this tril. Wininger et l (pin study 2): A phse 3, rndomized, double-blind, plcebo-controlled, multicenter, prllel-group, repeted-dose study of the nlgesic efficcy nd sfety of OFIRMEV vs plcebo for the tretment of postopertive pin fter bdominl lproscopic surgery. Ptients (N=244) received OFIRMEV 1 g or plcebo q6h, or OFIRMEV 65 mg or plcebo q4h. Opioid rescue mediction ws vilble to ll ptients. Efficcy mesures included the following 4 : OFIRMEV 1 g q6h vs combined plcebo group: sum of pin intensity differences from to 24 hours (SPID24) from bseline VAS score (primry endpoint) OFIRMEV 65 mg q4h vs the combined plcebo group: SPID24 from bseline VAS score Subjects globl evlutions of study tretment t 24 hours Time to first rescue mediction dministrtion Totl mount of rescue mediction consumption over 24 hours In ddition to Sintr et l nd Wininger et l, severl other trils hve exmined the nlgesic efficcy of IV cetminophen. Procedure types included, but were not limited to, orthopedic surgery (including totl hip or knee replcement, knee rthroscopy, nd hip frcture), gynecologic surgery, generl surgery, ENT surgery, nd crdiothorcic surgery. 2-4,6-13 Use cution when dministering cetminophen in ptients with the following conditions: heptic impirment or ctive heptic disese, lcoholism, chronic mlnutrition, severe hypovolemi (e.g., due to dehydrtion or blood loss), or severe renl impirment (cretinine clernce 3 ml/min) Do not exceed the mximum recommended dily dose of cetminophen by ll routes The mximum totl dily dose of OFIRMEV for dults 5 kg is 4 mg

11 Across this extensive clinicl dt set, IV cetminophen showed significnt nd reproducible benefit in nlgesi s mesured by vriety of endpoints relting to pin relief or reduction in pin intensity. Importntly, severl studies demonstrted tht including IV cetminophen in the nlgesic regimen resulted in significnt reductions in opioid consumption. 3,4,6-13 The clinicl benefit of reduced opioid consumption ws not demonstrted. Pin relief nd pin intensity Numerous studies in multiple clinicl settings hve demonstrted the efficcy of OFIRMEV (cetminophen) injection for pin relief nd reduction in pin intensity. Sintr et l (pin study 1): In 6-hour, single-dose evlution period, OFIRMEV 1 g with PCA morphine demonstrted superior pin relief vs plcebo with PCA morphine (15 minutes through 6 hours, P<.5) (Figure 5A). 3 In repeted-dose evlution period, OFIRMEV showed greter reduction in pin intensity over 24 hours (SPID24) compred with plcebo (P<.1). 6 Pin relief PCA, ptient-controlled nlgesi. Figure 5A. Men pin relief scores, single dose (totl hip or knee replcement surgery) 3 Significnt improvement over plcebo + rescue Time (h) OFIRMEV 1 g +/ rescue (n=49) Plcebo + rescue (n=52) P<.5 t every time point Sintr et l. Rndomized, double-blind, plcebo-controlled, single- nd repeted-dose 24-hour study (n=11). Ptients received OFIRMEV 1 g with PCA morphine or plcebo with PCA morphine the morning following totl hip or knee replcement surgery. Primry endpoint: pin relief mesured on 5-point verbl scle over 6 hours. Morphine rescue ws dministered s needed. P<.5 t every time point. There were no differences between OFIRMEV nd plcebo groups in incidence of dverse rections. No serious heptic events were relted to tretment with OFIRMEV 1 g. 2 Common dverse rections in dults treted with OFIRMEV include nuse, vomiting, hedche, nd insomni. 1 Wininger et l (pin study 2): A significntly greter reduction in SPID24 from bseline ws seen with OFIRMEV 1 g compred with the combined plcebo group over the 24-hour period (Figure 5B, P<.7). 4 Time to meningful pin relief fter the first dose ws significntly shorter in subjects who received OFIRMEV 1 g compred with the mtched plcebo group, with medin vlues of 24.9 minutes nd 53.9 minutes, respectively (P=.28). 4 Men SPID24 (VAS 1 mm) Figure 5B. Men reduction in pin intensity differences from bseline over 24 h (bdominl lproscopy) SPID24, sum of pin intensity differences from to 24 hours; VAS, visul nlog scle. Similrly, there ws significnt difference in SPID24 from bseline seen with OFIRMEV 65 mg compred with the combined plcebo group over 24 hours (P=.183) OFIRMEV 1 g (n=92) Plcebo (n=18) P<.7 Wininger et l (pin study 2). Rndomized, double-blind, plcebo-controlled, multicenter, prllel-group study. The morning following bdominl lproscopic surgery, ptients received OFIRMEV 1 g (n=92) or plcebo (n=42) every 6 hours or OFIRMEV 65 mg (n=41) or plcebo (n=66) every 4 hours. IV or orl rescue mediction ws vilble to ll ptients. Primry endpoint: SPID24 from bseline VAS score. Acetminophen is contrindicted in ptients with: known hypersensitivity to cetminophen or to ny of the excipients in the intrvenous (IV) formultion severe heptic impirment or severe ctive liver disese Serious dverse rections my include heptic injury, serious skin rections, hypersensitivity, nd nphylxis Common dverse rections in dults include nuse, vomiting, hedche, nd insomni. Common dverse rections in peditric ptients include nuse, vomiting, constiption, pruritus, gittion, nd telectsis wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion. 2 21

12 Furthermore, n expnded nlysis of these study dt over 24 hours demonstrted tht the men pin intensity scores were significntly lower for the OFIRMEV (cetminophen) injection group t ech dosing intervl through 18 hours (Figure 5C). 2,4 Primry endpoint results showed significntly higher men PID scores t ll time points through 5 hours (Figure 5D, P<.1). Up to 4% of IV cetminophen ptients chieved pin-free stte (P.2), nd greter number of ptients tking IV cetminophen reported being pin free from 45 minutes through 6 hours (Figure 5E, P.1). 6 Figure 5C. Men pin intensity scores t 6-h intervls 2,4 Figure 5D. Primry endpoint: Men PID s mesured by 4-point ctegoricl scle 6, 6 5 OFIRMEV 1 g q6h + rescue (n=92) Plcebo + rescue (n=42) b b b b b IV cetminophen 1 g (n=35) Plcebo (n=34) Men pin intensity (VAS 1 mm) VAS, visul nlog scle. -6 P< P=.12 Time (h) P= P=NS Wininger et l. Rndomized, double-blind, plcebo-controlled, multicenter, prllel-group study. The morning following bdominl lproscopic surgery, ptients received OFIRMEV 1 g (n=92) or plcebo (n=42) every 6 hours (q6h) or OFIRMEV 65 mg (n=41) or plcebo (n=66) every 4 hours. IV or orl rescue mediction ws vilble to ll ptients. Primry endpoint: sum of pin intensity differences from to 24 hours (SPID24) from bseline VAS score. PID (men score) b Time (h) PID, pin intensity difference. Study ws premturely terminted due to visible prticultes in plcebo vils. b P<.1; opioid rescue mediction ws freely vilble to ll ptients t ll times. b b ns Singl et l. Rndomized, double-blind, plcebo-controlled, single-dose, 6-hour study (n=69). Ptients received OFIRMEV 1 g with ptient-controlled nlgesi (PCA) morphine or plcebo with PCA morphine the morning following totl hip rthroplsty. Primry endpoint: PID mesured over 6 hours. Morphine rescue ws dministered s needed. Additionl supportive studies in pin mngement Including the pivotl efficcy studies discussed bove, number of RCTs evluted the efficcy of IV cetminophen nd support its use in vriety of surgeries nd pin severities. These studies involved outptients nd inptients, from reltively helthy dults undergoing minor surgery to elderly nd mediclly compromised ptients undergoing mjor surgery. Although tril design nd endpoints vried, IV cetminophen, either lone (mild to moderte pin) or s prt of multimodl nlgesic regimen with djunctive opioids (moderte to severe pin), hs consistently demonstrted nlgesic efficcy in mny different pin models. 3,4,6-13 Singl et l (totl hip rthroplsty): In this rndomized, double-blind, plcebo-controlled, multicenter study, 69 dults undergoing totl hip rthroplsty were rndomized to receive single dose of IV cetminophen 1 g with PCA morphine (n=35) or plcebo with PCA morphine (n=34). Primry endpoint ws pin intensity difference (PID) from bseline mesured over 6 hours. Acetminophen is contrindicted in ptients with: known hypersensitivity to cetminophen or to ny of the excipients in the intrvenous (IV) formultion severe heptic impirment or severe ctive liver disese Pin-free ptients (%) Figure 5E. Cumultive percentge of pin-free subjects 6, IV cetminophen 1 g (n=35) Plcebo (n=34) b b b b b b b Time (h) Study ws premturely terminted due to visible prticultes in plcebo vils. b P.1; opioid rescue mediction ws freely vilble to ll ptients t ll times. Singl et l. Rndomized, double-blind, plcebo-controlled, single-dose, 6-hour study (n=69). Ptients received OFIRMEV 1 g with ptient-controlled nlgesi (PCA) morphine or plcebo with PCA morphine the morning following totl hip rthroplsty. Primry endpoint: pin intensity difference mesured over 6 hours. Morphine rescue ws dministered s needed. wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion

13 Arici et l (totl bdominl hysterectomy): In this rndomized, plcebo-controlled, prllel-group, single-site study of 9 ptients undergoing totl bdominl hysterectomy, Arici nd collegues evluted the effect of IV cetminophen 1 g given preopertively (3 minutes before induction), IV cetminophen 1 g given intropertively (t skin closure), or plcebo. All ptients hd PCA morphine freely vilble s rescue. 8 Results showed tht postopertive pin intensity scores were significntly lower preopertively nd intropertively for both IV cetminophen groups compred with plcebo (Figure 5F, P<.5). 8 Men pin intensity (VAS 1 cm) VAS, visul nlog scle. P<.5. Memis et l (mjor surgery in intensive cre unit ptients): This rndomized, plcebo-controlled study ssessed the nlgesic efficcy, side effects, nd time to extubtion of IV cetminophen with IV meperidine vs plcebo with IV meperidine, dministered following mjor surgery in ptients requiring plnned dmission to the intensive cre unit (ICU). After trnsfer to the ICU, ptients were rndomized to receive IV cetminophen 1 g q6h with IV meperidine (n=2) s needed or plcebo q6h with IV meperidine (n=2) s needed for 24 hours. Ptients were ssessed for pin using both behviorl pin scle (BPS) nd VAS. When BPS or VAS vlues were >4, IV meperidine 1 mg/kg ws dministered. 9 Figure 5F. Men pin intensity scores 8 IV cetminophen 1 g given 3 min prior to induction (n=28) IV cetminophen 1 g given prior to skin closure (n=27) Plcebo (n=27) Time (h) Use cution when dministering cetminophen in ptients with the following conditions: heptic impirment or ctive heptic disese, lcoholism, chronic mlnutrition, severe hypovolemi (e.g., due to dehydrtion or blood loss), or severe renl impirment (cretinine clernce 3 ml/min) Do not exceed the mximum recommended dily dose of cetminophen by ll routes The mximum totl dily dose of OFIRMEV (cetminophen) injection for dults 5 kg is 4 mg Arici et l. Rndomized, plcebo-controlled, prllelgroup, single-site study. Ptients scheduled for totl bdominl hysterectomy received IV cetminophen 1 g 3 minutes prior to induction (pre-op), IV cetminophen 1 g prior to skin closure (intr-op), or plcebo. PCA morphine ws vilble to ll ptients. Pin relief, bsed on VAS score, t rest nd with movement, sedtion, nd totl morphine consumption were mesured t 15 nd 3 minutes, nd 1, 2, 4, 8, 12, nd 24 hours. Use of IV cetminophen with IV meperidine ws ssocited with significntly lower pin scores s mesured by BPS nd VAS over 24 hours. 9 Hong et l (endoscopic robot-ssisted thyroidectomy): This ws prospective, rndomized, double-blind, plcebocontrolled study. One hundred twenty-four ptients undergoing robot-ssisted endoscopic thyroidectomy received either IV cetminophen 1 g or plcebo before the induction of nesthesi nd then q6h for the next 24 hours. An 11-point VAS ( to 1) score nd rescue consumption were ssessed. 1 IV cetminophen ws ssocited with significntly lower pin intensity vs plcebo s mesured by men VAS scores t 1, 3, 6, nd 24 hours fter surgery (P<.5). 1 Atef et l (dult tonsillectomy): This ws rndomized, double-blind, plcebo-controlled study with 2 prllel groups of dult ptients undergoing tonsillectomy. Ptients received repeted doses of IV cetminophen 1 g (n=38) or plcebo (n=38) q6h for 24 hours strting t the end of surgery. If ptient reported insufficient pin relief, defined s VAS score >3 mm t rest nd >5 mm on swllowing, intrmusculr meperidine 1 mg/kg s rescue ws dministered. Need for rescue nlgesic nd pin intensity (VAS) scores were ssessed over 24 hours. 11 Over the 24-hour study period, significntly fewer ptients in the IV cetminophen group reported insufficient pin relief s compred with plcebo group (P<.1). Men pin intensity scores were lower t ll time points for the IV cetminophen group vs plcebo group, with significnt differences observed t 2 hours (t rest) nd t 2 nd 3 hours (on swllowing). 11 At dischrge, ptients rted their verge pin nd worst pin. In both cses, the men scores showed tht the IV cetminophen group experienced significntly less pin thn the plcebo group (Figure 5G). 11 Pin on visul nlog scle (VAS, -1 mm) 1 5 Figure 5G. VAS pin scores for verge nd worst pin t rest nd on swllowing 11 P<.1 Averge t rest P<.1 Averge on swllowing P<.5 Worst t rest IV cetminophen (n=38) Plcebo (n=38) P<.1 Worst on swllowing Atef et l. Prospective, rndomized, double-blind, plcebo-controlled study with 2 prllel groups of dult ptients undergoing tonsillectomy. Ptients received repeted doses of IV cetminophen 1 g (n=38) or plcebo (n=38) every 6 hours for 24 hours strting t the end of surgery. If ptient reported insufficient pin relief, defined s VAS score >3 mm t rest nd >5 mm on swllowing, intrmusculr meperidine 1 mg/kg s rescue ws dministered. Pin intensity (VAS) scores nd the need for rescue nlgesic were ssessed over 24 hours. wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion

14 The occurrence of insufficient pin relief ws significntly more common in ptients receiving plcebo thn those receiving IV cetminophen (Figure 5H, P<.1). 11 Ptients (%) Cttbrig et l (crdiothorcic surgery): This study ws rndomized, double blind, plcebo controlled, 72-hour study in 113 dult ptients to evlute post crdic surgery pin. Ptients were rndomized to receive either repeted doses of IV cetminophen 1 g with IV trmdol (n=56) or plcebo with IV trmdol (n=57). All ptients received stndrdized nesthesi regimen. The primry endpoint ws pin intensity by VAS t rest nd fter deep breth. This study found tht ptients with post crdic surgery pin who received IV cetminophen hd significntly less pin t 12, 18, nd 24 hours thn ptients who received plcebo (Figure 5I). 12 VAS score (cm) Figure 5H. Proportion of ptients with insufficient pin relief t rest nd on swllowing 11 P<.1 At rest Figure 5I. Time course of visul nlog scle (VAS) pin scores (medin) t rest h 18 h 24 h Post-op time IV cetminophen (n=38) Plcebo (n=38) P<.1 On swllowing IV cetminophen 1 g q6h (n=56) Plcebo q6h (n=57) P<.5 Atef et l. Prospective, rndomized, double-blind, plcebo-controlled study with 2 prllel groups of dult ptients undergoing tonsillectomy. Ptients received repeted doses of IV cetminophen 1 g (n=38) or plcebo (n=38) every 6 hours for 24 hours strting t the end of surgery. If ptient reported insufficient pin relief, defined s visul nlog scle (VAS) score >3 mm t rest nd >5 mm on swllowing, intrmusculr meperidine 1 mg/kg s rescue ws dministered. Pin intensity (VAS) scores nd the need for rescue nlgesic were ssessed over 24 hours. Cttbrig et l. Rndomized, double-blind, plcebo-controlled, 72-hour study in dult ptients to evlute post crdic surgery pin. Ptients were rndomized to receive either repeted q6h doses of IV cetminophen 1 g with IV trmdol (n=56) or plcebo with IV trmdol (n=57) over 72 hours. All ptients received stndrdized nesthesi regimen. Primry endpoint: pin intensity by VAS t rest nd fter deep breth. Note: IV trmdol is not vilble in the United Sttes. Bekts et l (renl colic): This study ws rndomized, prospective, double-blind, plcebo-controlled, single-center, single-dose tril with 3 prllel groups of ptients presenting to the emergency deprtment with suspected renl colic. Ptients received single dose of IV cetminophen 1 g (n=46), IV morphine.1 mg/kg (n=49), or plcebo (n=51). IV fentnyl ws vilble to ptients with indequte pin relief t 3 minutes. Pin intensity, both by VAS nd 4-point ctegoricl scle, ws ssessed 15 nd 3 minutes fter tretment. 13 Results from this study demonstrte the rpid nlgesic efficcy of IV cetminophen s demonstrted by significnt reductions in pin intensity observed t 15 nd 3 minutes following dministrtion. Sttisticlly significnt men reductions in pin intensity scores compred with those for plcebo were observed for IV cetminophen (odds rtio, 16; 95% confidence intervl, 5-27; P=.5) (Figure 5J). VAS score reductions were not significntly different between IV cetminophen nd morphine rms (P=.74). 13 This study ws not designed s hed-to-hed, noninferiority tril compring the efficcy of OFIRMEV (cetminophen) injection with morphine. Medin pin intensity (VAS 1 mm) VAS, visul nlog scle. Figure 5J. Pin intensity scores, single dose Time (min) OFIRMEV 1 g (n=46) Plcebo (n=51) P=.5 vs plcebo Serious dverse rections my include heptic injury, serious skin rections, hypersensitivity, nd nphylxis Common dverse rections in dults include nuse, vomiting, hedche, nd insomni. Common dverse rections in peditric ptients include nuse, vomiting, constiption, pruritus, gittion, nd telectsis Bekts et l. Rndomized, prospective, double-blind, plcebo-controlled, single-center, single-dose tril with 3 prllel groups. Ptients received single dose of IV cetminophen 1 g (n=46), IV morphine.1 mg/kg (n=49), or plcebo (n=51) upon presenting to the emergency deprtment with suspected renl colic. IV fentnyl ws vilble to ptients with indequte pin relief t 3 minutes. Primry endpoint: chnge in pin intensity, bsed on VAS score, from bseline, t 15 nd 3 minutes. q6h, every 6 hours. wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion

15 Morphine consumption Sintr et l (pin study 1): OFIRMEV (cetminophen) injection 1 g with PCA morphine significntly reduced morphine consumption vs plcebo with PCA morphine ( 46% fter first dose, P<.1; 33% over 24 hours, P<.1) (Figure 5K). Medin time to first rescue mediction ws significntly longer with OFIRMEV 1 g compred with plcebo (3 hours vs.8 hour, P<.1). 3 The clinicl benefit of reduced opioid consumption with OFIRMEV hs not been evluted or demonstrted. Figure 5L. Longer time to first rescue mediction 6, 1.4 Plcebo (n=34) IV cetminophen (n=35) P.5 MORE THAN 3 Morphine (mg) PCA, ptient-controlled nlgesi. Figure 5K. Reduction in morphine consumption (totl hip or knee replcement surgery) 2,3 OFIRMEV 1 g + PCA morphine (n=49) Plcebo + PCA morphine (n=52) 17.8 mg Over 6 h P<.1 46 % 9.7 mg 57.4 mg Over 24 h P<.1 33 % 38.3 mg Sintr et l. Rndomized, double-blind, plcebo-controlled, single- nd repeted-dose 24-hour study (n=11). Ptients received OFIRMEV 1 g with PCA morphine or plcebo with PCA morphine the morning following totl hip or knee replcement surgery. Primry endpoint: pin relief mesured on 5-point verbl scle over 6 hours. Morphine rescue ws dministered s needed. P<.5 t every time point Time (h) Study ws premturely terminted due to visible prticultes in plcebo vils. Arici et l (totl bdominl hysterectomy): In this study, preemptive nlgesi with IV cetminophen nd PCA morphine lso demonstrted significntly less morphine consumption over 24 hours when compred with plcebo nd PCA morphine (Figure 5M, P<.5). 8 These dt lso suggest tht when dministered preopertively, IV cetminophen 1 g demonstrted significntly greter reduction in morphine consumption compred with the sme dose dministered intropertively (P<.5) Singl et l. Rndomized, double-blind, plcebo-controlled, single-dose, 6-hour study (n=69). Ptients received OFIRMEV 1 g with ptient-controlled nlgesi (PCA) morphine or plcebo with PCA morphine pproximtely 16 hours fter totl hip rthroplsty. Primry endpoint: pin intensity difference mesured over 6 hours. Morphine rescue ws dministered s needed. The clinicl benefit of reduced opioid consumption with OFIRMEV hs not been evluted or demonstrted. Wininger et l (pin study 2): No sttisticl differences were found between OFIRMEV 1 g or 65 mg nd the combined plcebo groups in totl rescue mediction consumption or in the first time to rescue mediction. 2 Figure 5M. Morphine consumption over 24 h 8 As prt of the numerous RCTs within this clinicl dt set, IV cetminophen lso demonstrted significnt reductions in opioid consumption cross vriety of surgicl models. Singl et l (totl hip rthroplsty): Following surgery, 43% of ptients receiving IV cetminophen did not require opioid rescue during the first 6 hours of the study compred with 15% in the plcebo group (P=.15). 61 For ptients receiving IV cetminophen, the time to first use of rescue mediction ws incresed compred with ptients receiving plcebo (4.7 hours vs 1.4 hours, P.1). Additionlly, totl rescue mediction ws significntly reduced compred with the plcebo group in both study 1 (4.5 mg vs 9.6 mg, P=.17) nd study 2 (1.9 mg vs 5.1 mg, P=.6) (Figure 5L). 6 Acetminophen is contrindicted in ptients with: known hypersensitivity to cetminophen or to ny of the excipients in the intrvenous (IV) formultion severe heptic impirment or severe ctive liver disese Morphine (mg) IV cetminophen prior to induction (n=28) P<.5 P<.5 IV cetminophen prior to closure (n=27) Type of dministrtion Plcebo (n=27) Arici et l. Rndomized, plcebocontrolled, prllel-group, single-site study. Ptients scheduled for totl bdominl hysterectomy received IV cetminophen 1 g 3 minutes prior to induction (pre-op), IV cetminophen 1 g prior to skin closure (intr-op), or plcebo. Ptient-controlled nlgesi morphine ws vilble to ll ptients. Pin relief, bsed on visul nlog scle score, t rest nd with movement, sedtion, nd totl morphine consumption were mesured t 15 nd 3 minutes, nd 1, 2, 4, 8, 12, nd 24 hours. wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion

16 Memis et l (mjor bdominl nd pelvic surgery): Following surgery, opioid consumption ws significntly less in the IV cetminophen nd IV meperidine group compred with the plcebo nd IV meperidine group (77 mg vs 198 mg, P<.5). 9 Figure 5O. Reduction in opioid consumption (post-op britric surgery) 62 Hong et l (thyroidectomy): Among ptients undergoing thyroidectomy, consumption of rescue opioids ws significntly lower in the IV cetminophen group (6/63 vs 4/61, respectively; P<.1). 1 Time to first rescue in the IV cetminophen group ws more thn twice s long s in the plcebo group (113.5 minutes vs 53.5 minutes); however, the difference did not rech sttisticl significnce. 1 Atef et l (dult tonsillectomy): Following tonsillectomy, significntly more ptients receiving cetminophen 1 g did not require ny opioids vs ptients receiving plcebo. In fct, rescue nlgesic ws required in only 29% of ptients who received IV cetminophen, wheres 1% of ptients in the plcebo group received rescue nlgesic. Furthermore, ptients in the plcebo group requested n verge of 2.2 doses of rescue mediction compred with n verge of.47 doses for the IV cetminophen group 78% reduction in opioid consumption (Figure 5N). 11 The clinicl benefit of reduced opioid consumption with OFIRMEV (cetminophen) injection hs not been evluted or demonstrted. Morphine (mg) Without IV cetminophen With IV cetminophen 5.5 mg Sleeve P<.1 42 % 29.5 mg 68.2 mg Roux-en-Y P<.1 48 % 35.6 mg 6.7 mg Combined P<.1 46 % 33 mg Song et l. A retrospective review of medicl records of britric surgery performed t Memoril University Medicl Center from My 211 to November 212. Inclusion criteri were met by 14 ptients. Of the 44 ptients who underwent lproscopic sleeve gstrectomy, 22 received 1 g IV cetminophen (IV APAP) nd 22 did not. Of the 6 ptients who underwent lproscopic Roux-en-Y gstric bypss, 3 received 1 g IV APAP nd 3 did not. The combined group represented the dt from both surgicl types. The primry outcome mesure ws the mount of opioids used, wheres secondry outcome mesures included men pin scores, men hospitl length of sty, intensive cre unit dmissions within 24 hours fter surgery, nd post-op dy return of bowel sounds nd fltus. Figure 5N. Reduction in opioid consumption fter tonsillectomy 11 Opioid doses were converted into the equivlent IV morphine doses IV cetminophen (n=38) Plcebo (n=38) P< % Tsng et l (hip frcture): In prospective, consecutive cohort study, 1 g IV cetminophen q6h with opioids s needed significntly reduced opioid consumption vs orl cetminophen nd orl opioids with IV opioids s needed (Figure 5P). 63 The clinicl benefit of reduced opioid consumption with OFIRMEV hs not been evluted or demonstrted. Pethidine (mg) Cttbrig et l (crdiothorcic surgery): Among ptients with post crdic surgery pin, the cumultive morphine consumption over 72 hours ws 5% lower (not sttisticlly significnt) in the IV cetminophen group compred with plcebo. 12 Song et l (lproscopic britric surgery): In this retrospective study, nlysis of 2 types of gstric surgery, lproscopic sleeve gstrectomy (LSG, n=44) nd lproscopic Roux-en-Y gstric bypss (LRYGB, n=6) reveled significnt opioid reduction with postopertive use of 1 g IV cetminophen q6h (Figure 5O). 62 The clinicl benefit of reduced opioid consumption with OFIRMEV hs not been evluted or demonstrted. wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion. Atef et l. Prospective, rndomized, double-blind, plcebo-controlled study with 2 prllel groups of dult ptients undergoing tonsillectomy. Ptients received repeted doses of IV cetminophen 1 g (n=38) or plcebo (n=38) every 6 hours for 24 hours strting t the end of surgery. If ptient reported insufficient pin relief, defined s visul nlog scle (VAS) score >3 mm t rest nd >5 mm on swllowing, intrmusculr meperidine 1 mg/kg s rescue ws dministered. Need for rescue nlgesic nd pin intensity (VAS) scores were ssessed over 24 hours Morphine (mg) PRN, s needed. Figure 5P. Reduction in pre-op opioid consumption (hip frcture) 63 Orl cetminophen nd orl opioids + IV morphine PRN (n=28) IV cetminophen + orl nd IV opioids PRN (n=47) 9. mg 58% 3.8 mg Combined IV morphine per dy P<.5 Opioid doses were converted into equivlent morphine doses. Conversion rtes were dopted from the UK Deprtment of Helth, with 1 mg of IV morphine considered equivlent to 2 mg of orl morphine, 2 mg of codeine, or 1 mg of trmdol mg 7% 6.5 mg Overll IV morphine P<.5 Rrely, cetminophen my cuse serious skin rections such s cute generlized exnthemtous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), nd toxic epiderml necrolysis (TEN), which cn be ftl Hypersensitivity nd nphylxis ssocited with the use of cetminophen hve been reported. Clinicl signs included swelling of the fce, mouth, nd throt, respirtory distress, urticri, rsh, nd pruritus Tsng et l. A prospective, consecutive cohort study t one hospitl in the United Kingdom. In the first cohort (n=28), ptients with hip frctures received pre-op pin mngement bsed on World Helth Orgniztion pin ldder guidelines. These ptients received orl cetminophen nd codeine or trmdol. IV morphine ws utilized for brekthrough pin. The second cohort of ptients (n=47) hd demogrphics similr to the first but were provided with IV cetminophen (1 g every 6 hours) with orl nd IV opioids s needed. Endpoints included totl pre-op opioid dosge nd men pre-op pin score, s ssessed by visul nlog scle.

17 Ptient stisfction Ptient reports of globl stisfction in number of trils cross vriety of surgeries hve been shown to fvor IV cetminophen over plcebo. The gretest differences between IV cetminophen nd plcebo groups, s mesured by the percentge of ptients reporting good or excellent stisfction, hve been demonstrted in orthopedic nd generl surgeries. 3,4 Sintr et l (pin study 1): Ptients globl evlution of study tretment ( excellent plus good scores) significntly fvored OFIRMEV (cetminophen) injection with PCA morphine over plcebo with PCA morphine (Figure 5Q, 4.8% vs 23.1%, P=.4). 2,3 Figure 5Q. Ptient-reported stisfction with study tretment t 24 h (totl hip or knee replcement) 2,3, Wininger et l (pin study 2): Ptient globl evlution of study tretment ( excellent plus good scores) significntly fvored OFIRMEV 1 g over the control (Figure 5R, P=.4). 4 Figure 5R. Ptient-reported stisfction with study tretment t 24 h (bdominl lproscopy) OFIRMEV 1 g (n=92) Plcebo (n=18) P< % 7.3 % Ptients (%) OFIRMEV 1 g (n=49) Plcebo (n=52) P=.4 b 4.8 % 23.1 % Excellent plus good Subjects were sked to evlute the study tretments, overll, using 4-point ctegoricl scle. b Overll P vlue derived from sttisticl nlysis of 4-point ctegoricl scle. Sintr et l. Rndomized, doubleblind, plcebo-controlled, single- nd repeted-dose 24-hour study (n=11). Ptients received OFIRMEV 1 g with ptient-controlled nlgesi (PCA) morphine or plcebo with PCA morphine the morning following totl hip or knee replcement surgery. Primry endpoint: pin relief mesured on 5-point verbl scle over 6 hours. Morphine rescue ws dministered s needed. P<.5 t every time point. Ptients (%) Excellent plus good Overll P vlue derived from sttisticl nlysis of 4-point globl ctegoricl scle. Wininger et l. Rndomized, double-blind, plcebo-controlled, multicenter, prllel-group study. The morning following bdominl lproscopic surgery, ptients received OFIRMEV 1 g (n=92) or plcebo (n=42) every 6 hours or OFIRMEV 65 mg (n=41) or plcebo (n=66) every 4 hours. IV or orl rescue mediction ws vilble to ll ptients. Primry endpoint: sum of pin intensity differences from to 24 hours, bsed on visul nlog scle score, from bseline. Apfel et l: A 213 publiction of pooled nlysis of ptient stisfction scores evluted IV cetminophen in the cute postopertive setting. The nlysis included ptient-level dt from 5 RCTs (2 pivotl trils nd 3 FDA registrtionl studies). In ech of these studies, ptient stisfction ws mesured using 4-point ctegoricl rting scle. The endpoints were excellent stisfction (primry endpoint) nd good or excellent stisfction t 24 hours fter first dministrtion of study drug. 64 Administrtion of cetminophen in doses higher thn recommended my result in heptic injury, including the risk of liver filure nd deth Acetminophen is contrindicted in ptients with: known hypersensitivity to cetminophen or to ny of the excipients in the intrvenous (IV) formultion severe heptic impirment or severe ctive liver disese wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion

18 The nlysis concluded tht implementing multimodl nlgesic regimen tht includes IV cetminophen results in significntly greter ptient stisfction. Ptients who received IV cetminophen were more thn twice s likely s those who received plcebo to report excellent stisfction with study tretment (32.3% vs 15.9%, respectively; P<.1) nd significntly more likely to report good or excellent stisfction overll (Figure 5S). 64 Dt on file: Additionlly, in n orthopedic surgery study, 85.7% of ptients receiving OFIRMEV (cetminophen) injection reported good or excellent stisfction with their pin mngement vs 39.3% of ptients receiving opioid stndrd of cre (Figure 5T) Figure 5S. Ptient-reported stisfction with study tretment t 24 h (cute post-op setting) 64 IV cetminophen (n=356) Plcebo (n=37) P< % Figure 5T. Percentge of ptients, fter totl hip replcement, rting stisfction s good or excellent t bedtime improved 2, % OFIRMEV + rescue (n=3) Plcebo + rescue (n=31) P=.18 Ptients (%) % Excellent plus good Apfel et l. Pooled nlysis of ptient-level dt from 5 rndomized, plcebo-controlled studies in dults undergoing elective surgery in which ptient stisfction ws mesured using 4-point ctegoricl rting scle. Primry endpoint ws excellent stisfction, nd secondry endpoint ws good or excellent stisfction t 24 hours fter first study drug dministrtion. Ptients (%) % Excellent plus good This study ws terminted erly due to the detection of prticultes in some plcebo vils. Dt on file. Rndomized, double-blind, plcebo-controlled, multicenter, multiple-dose study in ptients undergoing hip rthroplsty (n=61). Ptients received 4 doses of OFIRMEV 1 g or plcebo over the dy following totl hip rthroplsty. The study ws suspended nd subsequently terminted due to reports of prticultes in plcebo vils. Primry endpoint for multiple doses: ptient evlution of efficcy on dy 1 t bedtime (4-point ctegoricl scle). Opioid rescue ws dministered s needed. When these dt were further ssessed s prt of multivrible nlysis of other fctors tht my ffect stisfction (eg, surgery type, durtion of nesthesi, lst pin rting, nd opioid consumption), IV cetminophen ws identified s Antipyretic efficcy the strongest modifible fctor for excellent ptient stisfction, with n odds rtio of 2.76 (95% confidence intervl, ). 64 Kett et l: A phse 3, rndomized, double-blind, plcebo-controlled, single-center study evluting the ntipyretic efficcy nd sfety of single dose of OFIRMEV 1 g compred with plcebo in 6 helthy dult mles who developed fever induced Use cution when dministering cetminophen in ptients with the following conditions: heptic impirment or ctive heptic disese, lcoholism, chronic mlnutrition, severe hypovolemi (e.g., due to dehydrtion or blood loss), or severe renl impirment (cretinine clernce 3 ml/min) Do not exceed the mximum recommended dily dose of cetminophen by ll routes The mximum totl dily dose of OFIRMEV for dults 5 kg is 4 mg by stndrd dose of endotoxin. 5 OFIRMEV 1 g ws shown to be effective in blunting the pek temperture produced by endotoxin nd reducing the fever it produced for period of up to 6 hours. The weighted sum of temperture differences over 6 hours (primry endpoint) ws significntly improved with OFIRMEV 1 g vs plcebo (Tble 5A, P=.1). 5 wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion

19 Men WSTD through 6 h ( C) Men WSTD through 3 h ( C) Importntly, OFIRMEV (cetminophen) injection 1 g demonstrted rpid onset of ction nd showed sttisticlly significnt temperture differences from bseline vs plcebo, strting 3 minutes fter endotoxin dministrtion (15 minutes fter completing the infusion) (P=.85). Sttisticlly significnt reductions in temperture t ech time point from 3 minutes through 5.5 hours were observed for subjects who received OFIRMEV 1 g vs plcebo (Figure 5U). 5 Men temperture (ºC) mitt, modified intention-to-tret. 5 Tble 5A. Weighted sum of temperture differences (WSTD) from bseline (T) 5 OFIRMEV 1 g (n=31) Plcebo (n=29) Figure 5U. Significnt reduction in men temperture (mitt popultion) Time (min) P vlue P=.1 P<.1 OFIRMEV 1 g (n=31) Plcebo (n=29) P< Kett t l. A phse 3, rndomized, double-blind, plcebo-controlled, singledose, single-center US study evluting the efficcy nd sfety of 1 g IV cetminophen in the tretment of endotoxin-induced fever in helthy dult mles. Subjects experienced elevted body temperture following dministrtion of reference stndrd endotoxin nd received either IV cetminophen (n=31) or plcebo (n=29). The primry endpoint of the study ws the weighted sum of temperture differences from bseline through 6 hours. Kett t l. A phse 3, rndomized, double-blind, plcebo-controlled, single-dose, single-center US study evluting the efficcy nd sfety of 1 g IV cetminophen in the tretment of endotoxin-induced fever in helthy dult mles. Subjects experienced elevted body temperture following dministrtion of reference stndrd endotoxin nd received either IV cetminophen (n=31) or plcebo (n=29). The primry endpoint of the study ws the weighted sum of temperture differences from bseline through 6 hours. Pecock et l: A rndomized, double-blind, double-shm, prllel-group study tht evluted the rpidity of onset of ntipyretic effect of single dose of OFIRMEV 1 g vs orl cetminophen 1 g in 81 helthy dult mles who developed fever induced by stndrd dose of endotoxin. 59 Compred with orl cetminophen 1 g, OFIRMEV 1 g rpidly reduced the pek temperture fter endotoxin induction. Results fvored OFIRMEV vs orl cetminophen (P=.39) regrding the weighted sum of temperture differences from bseline through 2 hours (primry endpoint) (Tble 5B). 59 Men (ºC) Medin (ºC) mitt, modified intention-to-tret. P vlue Tble 5B. Significntly reduced verge temperture (mitt popultion) 59 Furthermore, sttisticlly significnt (P<.5) reductions in men body temperture were observed t time point T3 minutes (15 minutes fter completing the IV infusion) nd t every ssessment time point therefter to T9 minutes (Figure 5V). 59 Men body temperture (ºC) OFIRMEV 1 g (n=36) OFIRMEV 1 g (n=45) Orl cetminophen (n=36) P< P=.39 Orl cetminophen 1 g (n=45) Figure 5V. Significnt reduction in men temperture (mitt popultion) mitt, modified intention-to-tret. Time (min) Acetminophen is contrindicted in ptients with: known hypersensitivity to cetminophen or to ny of the excipients in the intrvenous (IV) formultion severe heptic impirment or severe ctive liver disese 12 Pecock et l. A rndomized, double-blind, double-shm, single-dose, single-institution study evluting the sfety nd efficcy of 1 g IV cetminophen vs 1 g orl cetminophen in helthy dult mles. Subjects received dose of stndrd endotoxin nd were rndomized to receive IV cetminophen nd orl plcebo (n=54) or orl cetminophen nd IV plcebo (n=51). The primry endpoint ws the weighted sum of temperture differences from bseline through 12 minutes. Pecock et l. A rndomized, double-blind, double-shm, single-dose, single-institution study evluting the sfety nd efficcy of 1 g IV cetminophen vs 1 g orl cetminophen in helthy dult mles. Subjects received dose of stndrd endotoxin nd were rndomized to receive IV cetminophen nd orl plcebo (n=54) or orl cetminophen nd IV plcebo (n=51). The primry endpoint ws the weighted sum of temperture differences from bseline through 12 minutes. wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion

20 6. CLINICAL SAFETY The sfety of OFIRMEV (cetminophen) injection hs been estblished by n extensive clinicl tril dt set comprising 12 dult ptients who received OFIRMEV in clinicl trils, including 37.3% (n=38) who received 5 or more doses nd 17.% (n=173) who received more thn 1 doses. Most dult ptients, 86.9% (n=886), were treted with IV cetminophen 1 g q6h. A totl of 13.1% (n=134) received IV cetminophen 65 mg q4h. 1,2 The most common tretment-emergent dverse rections occurring in t lest 3% of dult ptients treted with IV cetminophen nd t greter frequency thn plcebo in repeted-dose studies were nuse, vomiting, hedche, nd insomni (Tble 6A). 1 The incidence of pyrexi ws 5% (n=22) for IV cetminophen ptients nd 14% (n=52) for plcebo ptients. Helth cre prctitioners should be wre tht the ntipyretic effects of IV cetminophen my msk fever in ptients treted for postsurgicl pin. 1 Tretment-emergent dverse event Nuse 138 (34) 119 (31) Vomiting 62 (15) 42 (11) Pyrexi 22 (5) 52 (14) Insomni Tble 6A. Tretment-emergent dverse events occurring in t lest 3% of dults receiving OFIRMEV nd t greter frequency thn plcebo in repeted-dose studies 1 OFIRMEV (n=42) n (%) Hedche 39 (1) 33 (9) 3 (7) Plcebo (n=379) n (%) Pyrexi dverse rection frequency dt is included in order to lert helth cre prctitioners tht the ntipyretic effects of OFIRMEV my msk fever. A totl of 355 peditric ptients (47 neontes, 64 infnts, 171 children, nd 73 dolescents) hve received OFIRMEV in ctive-controlled (n=25) nd open-lbel (n=225) clinicl trils, including 59.7% (n=212) who received 5 or more doses nd 43.1% (n=153) who received more thn 1 doses. Peditric ptients received OFIRMEV doses up to 15 mg/kg on q4h, q6h, or q8h schedule. The mximum exposure ws 7.7, 6.4, 6.8, nd 7.1 dys in neontes, infnts, children, nd dolescents, respectively. 1 The most common dverse rections in dult ptients treted with OFIRMEV (incidence 5% nd greter thn plcebo) were nuse, vomiting, hedche, nd insomni. The most common dverse rections (incidence 5%) in peditric ptients treted with OFIRMEV were nuse, vomiting, constiption, pruritus, gittion, nd telectsis (5) Mximum dily dose (4 mg) The FDA-pproved mximum recommended dosing of cetminophen for dults is 4 mg per dy. The mximum recommended dily dose includes ll routes of dministrtion nd ll cetminophen-contining products dministered, including combintion products. 1 OFIRMEV contins cetminophen. Acetminophen hs been ssocited with cses of cute liver filure, t times resulting in liver trnsplnt nd deth. Most of the cses of liver injury re ssocited with the use of cetminophen t doses tht exceed the recommended mximum dily limits nd often involve more thn one cetminophen-contining product. 1 Acetminophen is contrindicted in ptients with known hypersensitivity to cetminophen or to ny of the excipients in the IV formultion, or with severe heptic impirment or severe ctive liver disese. 1 Heptotoxicity in clinicl trils Within therpeutic dosing, dt demonstrte tht the incidence of liver elevtions during tretment ws comprble to plcebo (Tble 6B). 2 Hospitliztion my be contributing fctor in low-level elevtions of liver function test vlues (more thn 3 times the upper limit of norml [ULN]). 65 These re not reflective of significnt heptic compromise but represent typicl mild perturbtions tht commonly occur post nesthesi nd post surgery. 2,66-69 ALT AST Tble 6B. Pek ALT nd AST vlues postbseline: Percent of ptients in ll repeted-dose, plcebo-controlled, ll-dult-ptient studies 2 >3 ULN >5 ULN >3 ULN >5 ULN IV cetminophen (n=42) 1.1% (n=4).3% (n=1) 1.% (n=4).5% (n=2) ALT, lnine minotrnsferse; AST, sprtte minotrnsferse; ULN, upper limit of norml. Dt from pooled nlysis of 5 repeted-dose clinicl studies involving dult ptients. Plcebo (n=379) 1.7% (n=6).6% (n=2) 1.1% (n=4).8% (n=3) Heptotoxicity ws lso ssessed using Hy s Lw nlysis. Hy s Lw sttes tht the combintion of elevted bilirubin nd trnsminse levels results in t lest 1% chnce of severe liver injury nd ws incorported in the FDA s July 29 Guidnce for Industry Drug-Induced Liver Injury: Premrketing Clinicl Evlution. 7 Using the dt from the OFIRMEV clinicl development progrm, sctterplot of pek lnine minotrnsferse (ALT) vs pek totl bilirubin (TBL) vlues for the OFIRMEV-treted, plcebo-controlled dult sfety popultion (n=1329) ws generted (Figure 6A). This study pool included single- nd repeted-dose, plcebo-controlled studies. wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion

21 The distribution of these TBL nd ALT postbseline vlues shows similr overlp between OFIRMEV (cetminophen) injection (n=824) nd plcebo (n=55) groups. Note lso tht there were no Hy s Lw cses (s defined by 2 TBL nd 3 ALT vlues bove bseline with no other known cuses) seen in this study pool. Bsed on these dt, there ws no evidence of serious drug-induced heptotoxicity signl during the OFIRMEV clinicl development progrm. 2 Tble 6C. Incidence of heptotoxicity of IV cetminophen in Europe, 22 through 21 (of pproximtely 65 million ptient exposures) 2 Heptic event Incidence Figure 6A. Sctterplot of pek ALT vs pek TBL vlues (ll-dult plcebo-controlled ptient studies pool [OFIRMEV sfety popultion]) 2 Totl mediclly significnt heptic dverse events.3% Pek bilirubin ( ULNR) OFIRMEV (n=824) Plcebo (n=55) Ftl events Drug-induced liver injury Contrindictions.3%.6% OFIRMEV is contrindicted in ptients with 1 Known hypersensitivity to cetminophen or to ny of the excipients in the IV formultion Severe heptic impirment or severe ctive liver disese.1.1 norml rnge Pek ALT ( ULNR) ALT, lnine minotrnsferse; TBL, totl bilirubin; ULNR, upper limit of norml rnge. Heptotoxicity in clinicl use From the time IV cetminophen ws first mrketed (s Perflgn ) in 22 through 21, over 4 million units were distributed for use, nd pproximtely 65 million ptients were treted. The incidence of heptic-relted dverse rections noted in postmrketing surveillnce reports is summrized in Tble 6C. 2 The 8-yer dt showed 212 reports of mediclly significnt heptic dverse rections ssocited with IV cetminophen without regrd to cuslity ssessment. Among 21 ftlities reported, 15 were considered possibly relted to IV cetminophen use through temporl ssocition. The nlysis found tht other etiologies lso were present. There were totl of 44 cses in which there ws some evidence of drug-induced liver injury (DILI). However, in the mjority of these, the dt were considered incomplete for evlution of the role of cetminophen. A totl of 8 cses of DILI were ftl, of which 3 were ssessed s relted to cetminophen exposure nd 5 were considered possibly relted to cetminophen only due to temporl ssocition. In ech of these cses, there were other etiologies present tht my hve cused or contributed to the heptic events. Six of the suspect cses of DILI were reported s hving received doses in excess of the recommended dosing regimens in the Bristol-Myers Squibb core dt sheet, either s IV cetminophen lone or in combintion with orl cetminophen or IV propcetmol. 2 Wrnings nd precutions Heptic injury Administrtion of cetminophen in doses higher thn recommended my result in heptic injury, including the risk of liver filure nd deth. Do not exceed the mximum recommended dily dose of cetminophen. The mximum recommended dily dose of cetminophen includes ll routes of cetminophen nd ll cetminophen-contining products dministered, including combintion products. 1 Use cution when dministering cetminophen in ptients with the following conditions: heptic impirment or ctive heptic disese, lcoholism, chronic mlnutrition, severe hypovolemi (eg, due to dehydrtion or blood loss), or severe renl impirment (cretinine clernce 3 ml/min). 1 Serious skin rections Rrely, cetminophen my cuse serious skin rections such s cute generlized exnthemtous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), nd toxic epiderml necrolysis (TEN), which cn be ftl. Ptients should be informed bout the signs of serious skin rections, nd use of the drug should be discontinued t the first ppernce of skin rsh or ny other sign of hypersensitivity. 1 wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion. 4 41

22 Risk of mediction errors Tke cre when prescribing, prepring, nd dministering OFIRMEV (cetminophen) injection in order to void dosing errors, which could result in ccidentl overdose nd deth. In prticulr, be creful to ensure tht 1 the dose in milligrms (mg) nd milliliters (ml) is not confused; the dosing is bsed on weight for ptients under 5 kg; infusion pumps re properly progrmmed; nd the totl dily dose of cetminophen from ll sources does not exceed mximum dily limits. Allergy nd hypersensitivity There hve been postmrketing reports of hypersensitivity nd nphylxis ssocited with the use of cetminophen. Clinicl signs included swelling of the fce, mouth, nd throt; respirtory distress; urticri; rsh; nd pruritus. There were infrequent reports of life-thretening nphylxis requiring emergent medicl ttention. Discontinue OFIRMEV immeditely if symptoms ssocited with llergy or hypersensitivity occur. Do not use OFIRMEV in ptients with cetminophen llergy. 1 Adverse rections Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes observed cnnot be directly compred with rtes in other clinicl trils nd my not reflect the rtes observed in prctice. 1 Adult popultion A totl of 12 dult ptients hve received OFIRMEV in clinicl trils, including 37.3% (n=38) who received 5 or more doses nd 17.% (n=173) who received more thn 1 doses. Most ptients were treted with OFIRMEV 1 mg q6h. A totl of 13.1% (n=134) received OFIRMEV 65 mg q4h. 1 All dverse rections tht occurred in dult ptients treted with either OFIRMEV or plcebo in repeted-dose, plcebocontrolled clinicl trils t n incidence 3% nd t greter frequency thn plcebo re listed in Tble 6D. The most common dverse rections in dult ptients treted with OFIRMEV (incidence 5% nd greter thn plcebo) were nuse, vomiting, hedche, nd insomni. 1 Tble 6D. Tretment-emergent dverse rections occurring in 3% of ptients receiving OFIRMEV nd t greter frequency thn plcebo in plcebo-controlled, repeted-dose studies 1 System Orgn Clss Preferred Term Gstrointestinl disorders Nuse Vomiting Generl disorders nd dministrtion site conditions Pyrexi Nervous system disorders Hedche Psychitric disorders Insomni OFIRMEV (n=42) n (%) 138 (34) 62 (15) Plcebo (n=379) n (%) 119 (31) 42 (11) 22 (5) 52 (14) 39 (1) 33 (9) 3 (7) 21 (5) Pyrexi dverse rection frequency dt is included in order to lert helth cre prctitioners tht the ntipyretic effects of OFIRMEV my msk fever. The following dditionl tretment-emergent dverse rections occurred in dult ptients treted with OFIRMEV in ll clinicl trils (n=12) t n incidence of t lest 1% nd t frequency greter thn plcebo (n=525): blood disorders nd lymphtic system disorders (nemi); generl disorders nd dministrtion site conditions (ftigue, infusion-site pin, nd peripherl edem); bnorml investigtion results (sprtte minotrnsferse increse nd bnorml breth sounds); metbolism nd nutrition disorders (hypoklemi); musculoskeletl nd connective tissue disorders (muscle spsms, trismus); psychitric disorders (nxiety); respirtory, thorcic, nd medistinl disorders (dyspne); nd vsculr disorders (hypertension, hypotension). 1 Peditric popultion A totl of 355 peditric ptients (47 neontes, 64 infnts, 171 children, nd 73 dolescents) hve received OFIRMEV in ctive-controlled (n=25) nd open-lbel (n=225) clinicl trils, including 59.7% (n=212) who received 5 or more doses nd 43.1% (n=153) who received more thn 1 doses. Peditric ptients received OFIRMEV doses up to 15 mg/kg on q4h, q6h, or q8h schedule. The mximum exposure ws 7.7, 6.4, 6.8, nd 7.1 dys in neontes, infnts, children, nd dolescents, respectively. 1 The most common dverse rections (incidence 5%) in peditric ptients treted with OFIRMEV were nuse, vomiting, constiption, pruritus, gittion, nd telectsis. 1 wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion

23 The following dditionl tretment-emergent dverse rections occurred in peditric ptients treted with OFIRMEV (cetminophen) injection (n=355) t n incidence of t lest 1%: blood nd lymphtic system disorders (nemi); crdic disorders (tchycrdi); gstrointestinl disorders (bdominl pin nd dirrhe); generl disorders nd dministrtion site conditions (injection site pin, peripherl edem, nd pyrexi); bnorml investigtion results (heptic enzyme increse); metbolism nd nutrition disorders (hypolbuminemi, hypoklemi, hypomgnesemi, hypophosphtemi, nd hypervolemi); musculoskeletl nd connective tissue disorders (muscle spsm nd pin in extremity); nervous system disorders (hedche); psychitric disorders (insomni); renl nd urinry disorders (oliguri); respirtory, thorcic, nd medistinl disorders (pulmonry edem, hypoxi, pleurl effusion, stridor, nd wheezing); skin nd subcutneous tissue disorders (periorbitl edem nd rsh); nd vsculr disorders (hypertension nd hypotension). 1 Use in specific popultions Pregnncy Ctegory C There re no studies of IV cetminophen in pregnnt women; however, epidemiologicl dt on orl cetminophen use in pregnnt women show no incresed risk of mjor congenitl mlformtions. Animl reproduction studies hve not been conducted with IV cetminophen, nd it is not known whether OFIRMEV cn cuse fetl hrm when dministered to pregnnt womn. OFIRMEV should be given to pregnnt womn only if clerly needed. 1 The results from lrge popultion-bsed prospective cohort, including dt from 26,424 women with live-born singletons who were exposed to orl cetminophen during the first trimester, indicte no incresed risk for congenitl mlformtions compred with control group of unexposed children. 1 The rte of congenitl mlformtions (4.3%) ws similr to the rte in the generl popultion. A popultion-bsed, cse-control study from the Ntionl Birth Defects Prevention Study showed tht 11,61 children with prentl exposure to orl cetminophen during the first trimester hd no incresed risk of mjor birth defects compred with 45 children in the control group. Other epidemiologicl dt showed similr results. 1 While niml reproduction studies hve not been conducted with IV cetminophen, studies in pregnnt rts tht received orl cetminophen during orgnogenesis t doses up to.85 times the mximum humn dily dose (MHDD; 4 mg/dy, bsed on body surfce re) showed evidence of fetotoxicity (reduced fetl weight nd length) nd dose-relted increse in bone vritions (reduced ossifiction nd rudimentry rib chnges). Offspring hd no evidence of externl, viscerl, or skeletl mlformtions. When pregnnt rts received orl cetminophen throughout gesttion t doses of 1.2 times the MHDD, bsed on body surfce comprison, res of necrosis occurred in both the liver nd kidney of pregnnt rts nd fetuses. These effects did not occur in nimls tht received orl cetminophen t doses.3 times the MHDD, bsed on body surfce re comprison. 1 In continuous breeding study, pregnnt mice received.25%,.5%, or 1.% cetminophen vi the diet (357, 715, or 143 mg/kg/dy). These doses re pproximtely.43,.87, nd 1.7 times the MHDD, respectively, bsed on body surfce re comprison. A dose-relted reduction in body weights of fourth- nd fifth-litter offspring of the treted mting pir occurred during lcttion nd postwening t ll doses. Animls in the high-dose group hd reduced number of litters per mting pir, mle offspring with n incresed percentge of bnorml sperm, nd reduced birth weights in the next-genertion pups. 1 Lbor nd delivery There re no dequte nd well-controlled studies with OFIRMEV during lbor nd delivery; therefore, it should be used in such settings only fter creful benefit-risk ssessment. 1 Nursing mothers While studies with OFIRMEV hve not been conducted, cetminophen is secreted in humn milk in smll quntities fter orl dministrtion. Bsed on dt from more thn 15 nursing mothers, the clculted infnt dily dose of cetminophen is pproximtely 1%-2% of the mternl dose. 1 There is one well-documented report of rsh in brestfed infnt tht resolved when the mother stopped cetminophen use nd recurred when she resumed cetminophen use. Cution should be exercised when OFIRMEV is dministered to nursing womn. 1 Peditric use The sfety nd effectiveness of OFIRMEV for the tretment of cute pin nd fever in peditric ptients 2 yers of ge is supported by evidence from dequte nd well-controlled studies of OFIRMEV in dults. Additionl sfety nd phrmcokinetic dt were collected in 355 ptients cross the full peditric ge strt, from premture neontes ( 32 weeks postmenstrul ge) to dolescents. The effectiveness of OFIRMEV for the tretment of cute pin nd fever hs not been studied in peditric ptients <2 yers of ge. 1 Geritric use Of the totl number of subjects in clinicl studies of OFIRMEV, 15% were ge 65 yers nd over, while 5% were ge 75 yers nd over. No overll differences in sfety or effectiveness were observed between these subjects nd younger subjects, nd other reported clinicl experience hs not identified differences in responses between the elderly nd younger ptients, but greter sensitivity of some older individuls cnnot be ruled out. 1 Ptients with heptic impirment Acetminophen is contrindicted in ptients with severe heptic impirment or severe ctive liver disese nd should be used with cution in ptients with heptic impirment or ctive liver disese. A reduced totl dily dose of cetminophen my be wrrnted. 1 Ptients with renl impirment In cses of severe renl impirment (cretinine clernce 3 ml/min), longer dosing intervls nd reduced totl dily dose of cetminophen my be wrrnted. 1 wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion

24 Drug interctions Effects of other substnces on cetminophen Substnces tht induce or regulte heptic cytochrome enzyme CYP2E1 my lter the metbolism of cetminophen nd increse its heptotoxic potentil. The clinicl consequences of these effects hve not been estblished. Effects of ethnol re complex, becuse excessive lcohol usge cn induce heptic cytochromes, but ethnol lso cts s competitive inhibitor of the metbolism of cetminophen. 1 Anticogulnts Chronic orl cetminophen use t dose of 4 mg/dy hs been shown to cuse n increse in interntionl normlized rtio (INR) in some ptients who hve been stbilized on sodium wrfrin s n nticogulnt. As no studies hve been performed evluting the short-term use of OFIRMEV (cetminophen) injection in ptients on orl nticogulnts, more frequent ssessment of INR my be pproprite in such circumstnces DOSING OFIRMEV is dministered s 15-minute infusion nd my be given s single or repeted dose for the tretment of cute pin or fever (Tble 7A). No dose djustment is required when converting between orl cetminophen nd OFIRMEV dosing in dults nd dolescent ptients weighing 5 kg. Clculted mximum dily dose of cetminophen is bsed on ll routes of dministrtion (ie, IV, orl, nd rectl) nd ll products contining cetminophen. Exceeding the mximum dily dose of cetminophen s described in Tble 7A my result in heptic injury, including the risk of liver filure nd deth. To void the risk of overdose, ensure tht the totl mount of cetminophen from ll routes nd from ll sources does not exceed the mximum recommended dose. 1 Age group Adults nd dolescents (13 yers nd older) weighing 5 kg Adults nd dolescents (13 yers nd older) weighing <5 kg Children 2 to 12 yers of ge 8. ADMINISTRATION Tble 7A. Recommended dosing of OFIRMEV for dults, dolescents, nd children 2 yers of ge 1 Dose given every 4 hours 65 mg 12.5 mg/kg Dose given every 6 hours 1 mg 15 mg/kg Instructions for IV dministrtion Mximum single dose 1 mg 15 mg/kg (up to 75 mg) Mximum totl dily dose of cetminophen (by ll routes) 4 mg in 24 hours 75 mg/kg in 24 hours (up to 375 mg) For dult nd dolescent ptients weighing 5 kg requiring 1-mg doses of OFIRMEV, dminister the dose by inserting vented IV set through the septum of the 1-mL vil. OFIRMEV my be dministered without further dilution. Exmine the vil contents before dose preprtion or dministrtion. DO NOT USE if prticulte mtter or discolortion is observed. Administer the contents of the vil intrvenously over 15 minutes. Use septic technique when prepring OFIRMEV for IV infusion. Do not dd other medictions to the OFIRMEV vil or infusion device. 1 Adults nd dolescents ( 13 yers of ge) For dults nd dolescents weighing 5 kg, the recommended dosge of OFIRMEV is 1 mg q6h or 65 mg q4h, with mximum single dose of OFIRMEV of 1 mg, minimum dosing intervl of 4 hours, nd mximum dily dose of cetminophen of 4 mg per dy (includes ll routes of dministrtion nd ll cetminophen-contining products, including combintion products). 1 For dults nd dolescents weighing <5 kg, the recommended dosge of OFIRMEV is 15 mg/kg q6h or 12.5 mg/kg q4h, with mximum single dose of OFIRMEV of 15 mg/kg, minimum dosing intervl of 4 hours, nd mximum dily dose of cetminophen of 75 mg/kg per dy (includes ll routes of dministrtion nd ll cetminophencontining products, including combintion products). 1 Children 2 yers of ge For children 2 to 12 yers of ge, the recommended dosge of OFIRMEV is 15 mg/kg q6h or 12.5 mg/kg q4h, with mximum single dose of OFIRMEV of 15 mg/kg, minimum dosing intervl of 4 hours, nd mximum dily dose of cetminophen of 75 mg/kg per dy. 1 1 Use septic technique to prepre the vil nd IV line 2 On flt surfce, insert vented IV set; open vent 3 Hng bottle; djust flow for 15-minute infusion wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion

25 For doses less thn 1 mg, the pproprite dose must be withdrwn from the vil nd plced into seprte continer prior to dministrtion. Using septic technique, withdrw the pproprite dose (65 mg or weight bsed) from n intct seled OFIRMEV (cetminophen) injection vil nd plce the mesured dose in seprte, empty sterile continer (eg, glss bottle, plstic IV continer, or syringe) for IV infusion to void the indvertent delivery nd dministrtion of the totl volume of the commercilly vilble continer. The entire 1-mL vil of OFIRMEV is not intended for use in ptients weighing <5 kg. OFIRMEV is single-use vil, nd the unused portion must be discrded. 1 Plce smll-volume peditric doses, up to 6 ml in volume, in syringe nd dminister over 15 minutes using syringe pump. 1 Monitor the end of the infusion in order to prevent the possibility of n ir embolism, especilly in cses where the OFIRMEV infusion is the primry infusion. 1 Once the vcuum sel of the glss vil hs been penetrted, or the contents trnsferred to nother continer, dminister the dose of OFIRMEV within 6 hours. 1 Do not dd other medictions to the OFIRMEV solution. Dizepm nd chlorpromzine hydrochloride re physiclly incomptible with OFIRMEV; therefore, do not dminister simultneously. 1 Storge nd hndling OFIRMEV is supplied in 1-mL glss vil contining 1 mg of cetminophen (1 mg/ml). OFIRMEV should be stored t 2 C-25 C (68 F-77 F). Do not refrigerte or freeze CONCLUSIONS Although there hve been mny developments nd n incresed emphsis on cute pin mngement over the pst 2 decdes, reltively little hs chnged with regrd to the incidence of postsurgicl pin or ptients perceptions of their pin mngement. 21 Postopertive pin continues to be indequtely controlled, nd opioid monotherpy continues to be prevlent. In 214 study nlyzing dt from 2,853,632 hospitl inptients, 73% of ptients treted with IV pin mediction received IV nrcotic monotherpy. 19 Ptient stisfction is n incresingly importnt outcome when considering periopertive nlgesic regimens, nd HCAHPS scores re becoming the bsis for vlue-bsed incentive pyments. There is strong correltion between pin control nd ptient stisfction. Ptients who gve high scores on HCAHPS survey questions relted to pin mngement lso gve high scores for other HCAHPS components. 71 It is therefore criticl to develop effective solutions for mnging cute pin while lso mintining level of comfort for ptients. Multimodl nlgesi represents shifting prdigm in periopertive pin mngement nd hs grnered the support of numerous professionl orgniztions, including the ASA, ASPAN, AGS, SCCM, ASPMN, AHRQ, nd The Joint Commission. 22,28-31 The ASA guidelines recommend tht, unless contrindicted, cetminophen, COXIBs, or NSAIDs be considered s prt of multimodl nlgesic regimen. 22 Thus, opioid monotherpy should no longer be viewed s n dequte strtegy for periopertive pin mngement. 2,21 OFIRMEV is the first nd only IV formultion of cetminophen vilble in the United Sttes, offering n IV nlgesic tretment option when n IV route of dministrtion nd/or rpid onset of ction re desirble. OFIRMEV is indicted for the mngement of mild to moderte pin, mngement of moderte to severe pin with djunctive opioid nlgesics, nd reduction of fever. 1 IV cetminophen hs been studied in published RCTs cross ll surgicl contexts, from minor outptient to complicted or mjor inptient surgery Additionlly, OFIRMEV hs n estblished sfety profile nd ws well tolerted in clinicl trils. Given its documented efficcy in wide rnge of surgeries nd well-understood sfety profile, OFIRMEV cn help fill n unmet medicl need for n effective nd well-tolerted non-opioid nd non-nsaid nlgesic. Only OFIRMEV provides the option to use cetminophen s prt of multimodl IV nlgesic regimen to improve pin relief, reduce opioid consumption, nd increse ptient stisfction with cute pin tretment cross the periopertive setting. 1-13,22 The clinicl benefit of reduced opioid consumption with OFIRMEV hs not been evluted or demonstrted. Serious dverse rections my include heptic injury, serious skin rections, hypersensitivity, nd nphylxis Common dverse rections in dults include nuse, vomiting, hedche, nd insomni. Common dverse rections in peditric ptients include nuse, vomiting, constiption, pruritus, gittion, nd telectsis wrning, on pges 5-51 nd in the ccompnying Full Prescribing Informtion