Support for Acetaminophen 1000 mg Over-the-Counter Dose:

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2 Support for Acetaminophen 1000 mg Over-the-Counter Dose: The Dental Impaction Pain Model and Efficacy and Safety Results from McNeil Randomized, Double-Blind, Single-Dose Study of Acetaminophen 1000 mg, Acetaminophen 650 mg, and Placebo in Postoperative Dental Pain McNeil Consumer Healthcare, Division of McNeil-PPC, Inc., 7050 Camp Hill Road, Fort Washington, PA , December 12,

3 TABLE OF CONTENTS McNeil Consumer Healthcare Page 1 KEY POINTS INTRODUCTION DENTAL IMPACTION PAIN MODEL MCNEIL STUDY ACEPAI Study Design Statistical Methods for Efficacy Analysis Study Results Disposition, Demographics, and Baseline Characteristics Efficacy Weighted Sum of the Pain Intensity Difference (PID) and Pain Relief (PAR) Scores Over Six Hours (SPRID6) - Primary Endpoint Weighted Sum of the Pain Intensity Difference from Baseline Scores Over Six Hours (SPID6) Weighted Sum of the Pain Relief Scores Over Six Hours (TOTPAR6) Percentage of Subjects with >50% of the Maximum Possible TOTPAR6 Score Time to Rescue Rescue Rates Time to Confirmed Perceptible Pain Relief Time to Meaningful Pain Relief Assessments of Overall Impression of Study Medication (Global) Efficacy Conclusions Safety Safety Conclusions SUMMARY CONCLUSIONS REFERENCE LIST...52 December 12,

4 1 KEY POINTS The dental impaction pain model is an accepted, validated, standardized model used to demonstrate the acute pain relief and duration of analgesia provided by analgesics, including acetaminophen. Results from dental impaction pain studies can be generalized to other acute pain states. The model has been an important basis for approval of numerous prescription and non-prescription analgesic drug product NDAs, such as ibuprofen (Motrin IB and Advil ) and Ultracet, both in the US and globally. McNeil Study ACEPAI demonstrated that acetaminophen 1000 mg provided clinically meaningful and statistically significantly greater efficacy in treating postoperative dental pain compared with acetaminophen 650 mg and placebo through six hours. For the primary endpoint of the weighted sum of the pain intensity difference (PID) and pain relief (PAR) scores over six hours (SPRID6), the least squares mean was statistically significantly greater for subjects treated with acetaminophen 1000 mg (529.4) compared to acetaminophen 650 mg (427.3), demonstrating a 24% improvement. Greater overall pain relief was observed with acetaminophen 1000 mg compared to acetaminophen 650 mg for all summary measures (SPRID6, SPID6, and TOTPAR6) and for PID, PAR, and PRID from 75 minutes through six hours. Both acetaminophen 1000 mg and acetaminophen 650 mg had similar times to onset of confirmed perceptible pain relief and meaningful pain relief. The duration of analgesia was longer with acetaminophen 1000 mg compared to acetaminophen 650 mg as demonstrated by a longer time to use of rescue medication and a smaller percentage of subjects requiring rescue medication. McNeil Study ACEPAI2001 demonstrated that a significantly larger percentage of subjects obtained pain relief with acetaminophen 1000 mg compared with acetaminophen 650 mg. A statistically significantly larger percentage of subjects completed the six-hour study without rescuing in the acetaminophen 1000 mg group (70.7%) compared with the acetaminophen 650 mg group (54.4%). In addition, a statistically significantly larger percentage of subjects had greater than 50% of the maximum possible TOTPAR6 score in the acetaminophen 1000 mg group (56.9%) compared with the acetaminophen 650 mg group (44.4%). Finally, a larger percentage of subjects rated the study medication as a pain reliever as good, very good, or excellent in the acetaminophen 1000 mg group (78.2%) compared with the acetaminophen 650 mg group (65.6%). 1 The McNeil study evaluated immediate-release formulations of acetaminophen, ie, two 500 mg caplets for the 1000 mg dose and two 325 mg tablets for the 650 mg dose. December 12,

5 The results of McNeil s study are consistent with those of a recent similar study using the dental impaction pain model (Study A ) conducted by GlaxoSmithKline Consumer Healthcare (GSKCH). Both studies evaluated immediate-release formulations of acetaminophen using the same primary endpoint, ie, sum of pain relief and pain intensity differences over the six-hour period after treatment (SPRID 6h ), and demonstrated statistically significantly superior dental pain relief efficacy for acetaminophen 1000 mg compared with acetaminophen 650 mg. These studies demonstrated the superior efficacy (McNeil ACEPAI2001 and GSKCH A ) and duration of analgesia (McNeil ACEPAI2001) of acetaminophen 1000 mg compared with acetaminophen 650 mg. These studies add to the body of existing data and provide additional and sufficient support to maintain the current over-the-counter availability of acetaminophen 1000 mg single adult dose when marketed under the Tentative Final Monograph for Internal Analgesic, Antipyretic and Antirheumatic Drug Products for Over-the-Counter Human Use. 2 INTRODUCTION McNeil Consumer Healthcare Division of McNeil-PPC, Inc. (McNeil) is a major manufacturer of over-the-counter (OTC) drug products, including Tylenol and Motrin IB analgesic and antipyretic products. The Food and Drug Administration (FDA) held a public joint meeting of the Drug Safety and Risk Management Advisory Committee, Nonprescription Drugs Advisory Committee, and the Anesthetic and Life Support Drugs Advisory Committee on June 29 and 30, The relative efficacy of acetaminophen 1000 mg compared with acetaminophen 650 mg was discussed at the meeting. McNeil provided a review of company and published data on this topic in our background package for the meeting [1] and presented results on this topic at the meeting. Following the June 2009 meeting, McNeil conducted a randomized, double-blind, controlled trial including a direct comparison of acetaminophen 1000 mg, acetaminophen 650 mg, and placebo. A summary of the findings from this study that was conducted using the dental impaction pain model are provided in Section 4 of this document. A brief description of the attributes and benefits of the dental impaction pain model is provided in Section 3. 3 DENTAL IMPACTION PAIN MODEL The dental impaction pain model is an established and proven acute pain model that was developed in its modern form in the mid 1970s [2]. The model is widely used to evaluate the December 12,

6 analgesic efficacy of drugs, especially those with a relatively short time to onset of action such as acetaminophen [2, 3]. It is a validated and standardized model that can be used to establish analgesic efficacy compared with placebo, onset of pain relief, and duration of analgesia for a range of doses [2, 4]. The following beneficial characteristics of the model have been reported [2, 3, 4, 5, 6, 7]: Patients studied are generally young and healthy with no preexisting pain This young and healthy population is large and relatively homogeneous The surgical procedure of third molar extraction is elective, standardized, of short duration, and results in reproducible trauma Standardized, reproducible trauma results in consistent and sufficient postoperative baseline pain level Postoperative pain is most intense a few hours after surgery as anesthesia wears off; pain remains fairly constant for the next 12 hours Low placebo response Provides reproducible results across studies Studies can be conducted in an outpatient setting The two-stopwatch method can be used to establish the onset of analgesia using the time to perceptible pain relief and the time to meaningful pain relief The generalizability of analgesic efficacy results from studies using the dental impaction pain model to other pain states has been established. In 1994, Urquhart reported that the dental pain impaction model provided valuable information on the treatment of acute pain in general, since the pathophysiology of the dental pain model has shared elements with other pain states, including acute trauma and postoperative pain [4]. In 1998, Norholt reported that the dental pain impaction model was a valid predictor of efficacy for treating other conditions of acute pain [3]. Cooper and Desjardins recently reported that results from the dental impaction pain model were generalizable to other pain states. Cooper and Desjardins compared results of pain relief for the same products across multiple pain states (dental vs general postoperative pain, dental vs obstetrics-gynecology surgical pain, and dental vs bunionectomy pain) and found similar results for analgesics across these models [2]. Similarly, Barden et al [8] conducted a meta-analysis of studies that evaluated pain and analgesic response after third molar extraction and other postsurgical pain and concluded that it was legitimate to extrapolate analgesic efficacy from one pain state to another. In addition, Barden concluded that when studies were conducted according to high standards and where systematic bias had been avoided, that data from different pain models could be December 12,

7 combined to calculate the number needed to treat (NNT) for the outcome of half pain relief over four to six hours. In addition, different doses of a specific analgesic have been evaluated and differentiated using this model. For example, the model has been used to compare the efficacy of valdicoxib doses of 10, 20, 40, and 80 mg [2]. Similarly, comparative analgesic efficacy for different doses of ibuprofen ranging from 50 mg to 400 mg have been evaluated and reported using the dental pain impaction model [9, 10, 11, 12, 13]. In summary, the dental impaction pain model is an accepted model used to demonstrate acute pain relief provided by analgesics, including acetaminophen. Results from the dental impaction pain studies can be generalized to other acute pain states and can be used to evaluate, demonstrate, and differentiate clinically meaningful pain relief for different analgesics and for different doses of an analgesic. 4 MCNEIL STUDY ACEPAI Study Design This was a randomized, double-blind, single-center, single-dose, placebo-controlled study of acetaminophen 1000 mg and acetaminophen 650 mg. A sufficient number of healthy volunteers 16 to 50 years old that required extraction of a minimum of three third molars were enrolled to ensure 540 were randomized into the study. There were two study visits planned. These were to occur on the same day, or on two separate dates depending on when the dental procedure was scheduled. In the event two visits were required, the second visit must have occurred within 21 days after Visit 1, and inclusion/exclusion criteria were reassessed. Subjects who were enrolled in the study remained at the research site for approximately six hours after the dental extraction (observation period) regardless of whether they took study medication or rescue. The total study duration on the day of dental procedure was approximately 12 hours (ie, from the time the dental procedure was performed, to the time the last study assessment was collected). The subjects underwent dental extraction of a minimum of three third molars. The mandibular extractions required by each subject must have met one of the following scenarios and must not have resulted in a trauma rating of severe (from a scale of mild, moderate, or severe): Two full bony impactions Two partial bony impactions One full bony impaction in combination with a partial bony impaction One full bony impaction in combination with a soft tissue impaction One full bony impaction in combination with an erupted third molar December 12,

8 Maxillary third molars were removed regardless of impaction level. McNeil Consumer Healthcare Subjects who met the randomization criteria (reported postoperative pain of moderate or severe intensity (score of 2 or 3) on the four-point categorical pain scale [no pain (0), mild (1), moderate (2), and severe (3)], and at least a 50 on the visual analog scale (0-100 mm VAS) within four hours (+15 minutes) after the dental extractions) were assigned to one of three treatment groups (239 subjects to acetaminophen 1000 mg, 241 subjects to acetaminophen 650 mg, and 60 subjects to placebo). Subjects were randomized based on stratification of self-reported categorical baseline pain rating (moderate or severe). Self-reported pain intensity scores were collected at baseline (time 0) and pain intensity and pain relief relative to baseline intensity at 15, 30, 45, 60, 75, and 90 minutes, and at 2, 3, 4, 5, and 6 hours (± 5 minutes) postdose administration using a mm VAS. After ingestion of investigational product, the exact time of first perceptible pain relief and meaningful pain relief were collected using two separate stopwatches. At the time when meaningful pain relief was achieved by the subject, pain relief and pain intensity VAS scores were assessed. Subjects who did not experience an analgesic response, were encouraged, but not required, to wait for at least one and one half hours (90 minutes) prior to rescuing. At the end of the six hour rating, or at the time of rescuing, whichever came first, a subjective patient global assessment of the investigational product was collected. No interim analyses were performed. The protocol was amended seven weeks after the study started. At the time of protocol amendment, 74 subjects were enrolled and randomized. The primary purpose of the amendment was to ensure the enrollment of subjects with the appropriate amount of pain. It was amended to change the inclusion criteria from extraction of up to four third molars to extraction of a minimum of three third molars that did not result in a trauma rating of severe using a scale of mild, moderate or severe. Originally, mandibular extractions were to include one of the following: one full bony impaction alone, one full bony impaction in combination with a partial bony impaction, one full bony impaction in combination with a soft tissue impaction, or one full bony impaction in combination with an erupted third molar. After amendment of the protocol, the mandibular extractions were to include one of the following: two full bony impactions, two partial bony impactions, one full bony impaction in combination with a partial bony impaction, one full bony impaction in combination with a soft tissue impaction, one full bony impaction in combination with an erupted third molar. Other changes included modification of the definition of the intent-to-treat set by additionally limiting it to those subjects who did not vomit within 60 minutes post dosing; reassessment of height, weight and BMI at Visit 2 (prior to surgery) if dental extractions were performed after Visit 1; and modification from 30 minutes to 60 minutes for the occurrence of vomiting December 12,

9 which would result in discontinuation of further pain assessments and recording of the event as an adverse event. 4.2 Statistical Methods for Efficacy Analysis The efficacy analysis was based on the intent-to-treat analysis set. To protect the type I error rate, a closed testing procedure on the primary endpoint was followed, with testing in the following order. First test H1: acetaminophen 1000 mg vs placebo at the alpha = one-tail level If H1 was rejected then, o Test H2: acetaminophen 1000 mg vs acetaminophen 650 mg and o Test H3: acetaminophen 650 mg vs placebo H2 and H3 were each tested at the alpha = one-tail level. A comparison was only considered to be significant at if the current and previous comparison in the hierarchy was SPRID6 was analyzed with an analysis of variance with treatment and categorical baseline pain rating in the model. Treatments were compared using the pairwise comparisons of the least squares means from this model. A model that included the interaction term of treatment and baseline pain was also examined for the primary endpoint SPRID6. TOTPAR6 and SPID6 were analyzed with an analysis of variance with treatment and categorical baseline pain rating in the model. Pairwise comparisons of the least squares means were made using this model. Pain intensity difference from baseline, pain relief, and PRID were analyzed at each time point with an analysis of variance with treatment and categorical baseline pain rating in the model. Pairwise comparisons of the least squares means were made using this model. Treatments were compared for both time to confirmed perceptible pain relief and time to meaningful pain relief using the Wilcoxon test (from the SAS LIFETEST procedure). Kaplan-Meier estimates of the cumulative percent of subjects having relief over the six-hour period of the trial were provided. Subjects who did not have relief by six hours were censored at six hours. Kaplan-Meier estimates of the cumulative percent of subjects rescuing were presented by treatment group in tabular and graphical formats. Time to rescue was compared using the log-rank test (from the SAS LIFETEST procedure). The proportion of subjects rescuing over four and six hours was compared using general association from the Cochran-Mantel- Haenszel (CMH) test stratified by categorical baseline pain rating. Treatments were compared on the proportion of subjects with >50% of the maximum possible TOTPAR6 score using general association from the CMH test stratified by the categorical baseline pain rating (moderate or severe). December 12,

10 Patient global evaluation was analyzed with an analysis of variance with categorical baseline pain rating and treatment in the model. Pairwise comparisons of the least squares means were made using this model. 4.3 Study Results Disposition, Demographics, and Baseline Characteristics Overall, 540 subjects were randomized to double-blind study treatment: 239 received acetaminophen 1000 mg, 241 received acetaminophen 650 mg, and 60 received placebo. No subjects withdrew from the study. The demographic and baseline characteristics for all subjects included in the intent-to-treat set are provided in Table 1. The mean age of the study population was 18.4 years, 95.4% of subjects were white, and 47.8% of subjects were male. The mean BMI at both the screening and surgery visits was 23.1 kg/m 2. Mean systolic blood pressure, diastolic blood pressure, and pulse were mm Hg, 70.8 mm Hg, and 68.9 beats per minute, respectively, for all groups combined. Overall, 81.5% of subjects had four third molars extracted, 77.4% had four impacted third molars extracted, 93.1% had two maxillary third molars extracted, and 87.6% had two mandibular third molars extracted. Overall, the most frequent types of impacted mandibular molar were two full bony impactions (62.2%), one full bony impaction in combination with a partial bony impaction (13.1%), and one full bony impaction alone (12.4%). The mean length of surgery was 10.7 minutes. The percentage of subjects with a surgical trauma rating of moderate was 100%, 99.5%, and 100% in the acetaminophen 1000 mg, acetaminophen 650 mg, and placebo groups, respectively. An almost equal distribution in the percentage of subjects with a baseline pain severity categorical scale rating of moderate and severe was observed. The mean visual analog scale score for baseline pain severity was 77.6, 78.6, and 78.0 mm in the acetaminophen 1000 mg, acetaminophen 650 mg, and placebo groups, respectively. There were no clinically important differences among treatment groups for any of the demographic or baseline characteristics. Information was not collected for or used to calculate the following demographic and baseline characteristics for 74 subjects enrolled before the date of the protocol amendment: weight at surgery visit, height at surgery visit, body mass index at surgery visit, total number of maxillary third molars extracted, the number of full bony impaction third molars extracted, and the surgical trauma rating. Information for the 466 subjects enrolled after the protocol amendment is presented for these variables. December 12,

11 Table 1. Demographics, Vital Signs, and Baseline Characteristics (Subjects in Intent-to-Treat Analysis Set) (Page 1 of 6) ======================================================================================================================= APAP 1000 mg APAP 650 mg Placebo Total (N=239) (N=241) (N=60) (N=540) Age (year) N Mean S.D Median Min,Max (16,30) (16,27) (16,26) (16,30) Race, n(%) White 227(95.0%) 232(96.3%) 56(93.3%) 515(95.4%) Black or African American 2(<1.0%) 0 0 2(<1.0%) Asian 2(<1.0%) 3( 1.2%) 1( 1.7%) 6( 1.1%) Native Hawaiian or Other Pacific Islander 0 1(<1.0%) 0 1(<1.0%) American Indian or Alaska Native 0 1(<1.0%) 0 1(<1.0%) Other 8( 3.3%) 4( 1.7%) 3( 5.0%) 15( 2.8%) Total 239( 100%) 241( 100%) 60( 100%) 540( 100%) Sex, n (%) Male 108(45.2%) 121(50.2%) 29(48.3%) 258(47.8%) Female 131(54.8%) 120(49.8%) 31(51.7%) 282(52.2%) Total 239( 100%) 241( 100%) 60( 100%) 540( 100%) Weight at Screening Visit (lbs) N Mean S.D Median Min,Max (101,224) (104,226) (109,202) (101,226) Height at Screening Visit (in) N Mean S.D Median Min,Max (58,77) (59,81) (60,75) (58,81) [1] Information was not collected for subjects enrolled before the date of protocol Amendment 1, August 13, Seventy-four subjects enrolled before Protocol Amendment 1 are excluded from the total count. [2] Includes data from screening visit for those who had screening and surgical procedure conducted in one visit. December 12,

12 Table 1. Demographics, Vital Signs, and Baseline Characteristics (Subjects in Intent-to-Treat Analysis Set) (Page 2 of 6) ======================================================================================================================= APAP 1000 mg APAP 650 mg Placebo Total (N=239) (N=241) (N=60) (N=540) Body Mass Index at Screening Visit (kg/m2) N Mean S.D Median Min,Max (18.2,29.9) (18.1,29.8) (18.9,29.7) (18.1,29.9) Weight at Surgery Visit (lbs) [1] [2] N Mean S.D Median Min,Max (102,225) (105,227) (113,205) (102,227) Height at Surgery Visit (in) [1] [2] N Mean S.D Median Min,Max (59,77) (59,81) (62,75) (59,81) Body Mass Index at Surgery Visit (kg/m2) [1] [2] N Mean S.D Median Min,Max (18.2,29.6) (18.0,29.9) (18.5,29.9) (18.0,29.9) Systolic Blood Pressure (mmhg) N Mean S.D Median Min,Max (90,145) (92,145) (87,134) (87,145) [1] Information was not collected for subjects enrolled before the date of protocol Amendment 1, August 13, Seventy-four subjects enrolled before Protocol Amendment 1 are excluded from the total count. [2] Includes data from screening visit for those who had screening and surgical procedure conducted in one visit. December 12,

13 Table 1. Demographics, Vital Signs, and Baseline Characteristics (Subjects in Intent-to-Treat Analysis Set) (Page 3 of 6) ======================================================================================================================= APAP 1000 mg APAP 650 mg Placebo Total (N=239) (N=241) (N=60) (N=540) Diastolic Blood Pressure (mmhg) N Mean S.D Median Min,Max (51,95) (52,96) (56,88) (51,96) Pulse (beats/min) N Mean S.D Median Min,Max (46,97) (44,100) (47,98) (44,100) Respiration Rate (per min) N Mean S.D Median Min,Max (12,20) (12,20) (12,18) (12,20) Temperature (F) N Mean S.D Median Min,Max (97,99) (97,99) (97,99) (97,99) [1] Information was not collected for subjects enrolled before the date of protocol Amendment 1, August 13, Seventy-four subjects enrolled before Protocol Amendment 1 are excluded from the total count. [2] Includes data from screening visit for those who had screening and surgical procedure conducted in one visit. December 12,

14 Table 1. Demographics, Vital Signs, and Baseline Characteristics (Subjects in Intent-to-Treat Analysis Set) (Page 4 of 6) ======================================================================================================================= APAP 1000 mg APAP 650 mg Placebo Total (N=239) (N=241) (N=60) (N=540) Total Number of Third Molars Extracted, n (%) One 1(<1.0%) 1(<1.0%) 0 2(<1.0%) Two 28(11.7%) 25(10.4%) 6(10.0%) 59(10.9%) Three 11( 4.6%) 18( 7.5%) 8(13.3%) 37( 6.9%) Four 198(82.8%) 196(81.3%) 46(76.7%) 440(81.5%) Five 0 1(<1.0%) 0 1(<1.0%) Six 1(<1.0%) 0 0 1(<1.0%) Total 239( 100%) 241( 100%) 60( 100%) 540( 100%) Total Number of Impacted Third Molars Extracted, n (%) One 3( 1.3%) 4( 1.7%) 0 7( 1.3%) Two 31(13.0%) 31(12.9%) 7(11.7%) 69(12.8%) Three 14( 5.9%) 22( 9.1%) 8(13.3%) 44( 8.1%) Four 190(79.5%) 183(75.9%) 45(75.0%) 418(77.4%) Five 0 1(<1.0%) 0 1(<1.0%) Six 1(<1.0%) 0 0 1(<1.0%) Total 239( 100%) 241( 100%) 60( 100%) 540( 100%) Total Number of Maxillary Third Molars Extracted [1], n (%) One 9( 4.4%) 15( 7.2%) 6(11.5%) 30( 6.4%) Two 195(95.1%) 193(92.3%) 46(88.5%) 434(93.1%) Three 0 1(<1.0%) 0 1(<1.0%) Four 1(<1.0%) 0 0 1(<1.0%) Total 205( 100%) 209( 100%) 52( 100%) 466( 100%) Total Number of Mandibular Third Molars Extracted, n (%) One 31(13.0%) 29(12.0%) 7(11.7%) 67(12.4%) Two 208(87.0%) 212(88.0%) 53(88.3%) 473(87.6%) Total 239( 100%) 241( 100%) 60( 100%) 540( 100%) [1] Information was not collected for subjects enrolled before the date of protocol Amendment 1, August 13, Seventy-four subjects enrolled before Protocol Amendment 1 are excluded from the total count. [2] Includes data from screening visit for those who had screening and surgical procedure conducted in one visit. December 12,

15 Table 1. Demographics, Vital Signs, and Baseline Characteristics (Subjects in Intent-to-Treat Analysis Set) (Page 5 of 6) ======================================================================================================================= APAP 1000 mg APAP 650 mg Placebo Total (N=239) (N=241) (N=60) (N=540) Type of Impacted Mandibular Molars, n (%) One full bony impaction alone 31(13.0%) 29(12.0%) 7(11.7%) 67(12.4%) One full bony impaction in combination 37(15.5%) 28(11.6%) 6(10.0%) 71(13.1%) with a partial bony impaction One full bony impaction in combination 5( 2.1%) 10( 4.1%) 0 15( 2.8%) with a soft tissue impaction One full bony impaction in combination with an erupted third molar Two full bony impactions 147(61.5%) 149(61.8%) 40(66.7%) 336(62.2%) Two partial bony impactions 19( 7.9%) 25(10.4%) 7(11.7%) 51( 9.4%) Other Total 239( 100%) 241( 100%) 60( 100%) 540( 100%) Number of Full Bony Impaction Third Molar Extracted [1], n (%) Zero 16( 7.8%) 19( 9.1%) 6(11.5%) 41( 8.8%) One 2(<1.0%) 2(<1.0%) 1( 1.9%) 5( 1.1%) Two 46(22.4%) 60(28.7%) 16(30.8%) 122(26.2%) Three 29(14.1%) 31(14.8%) 8(15.4%) 68(14.6%) Four 111(54.1%) 97(46.4%) 21(40.4%) 229(49.1%) Six 1(<1.0%) 0 0 1(<1.0%) Total 205( 100%) 209( 100%) 52( 100%) 466( 100%) Surgical Trauma Rating [1], n (%) Mild 0 1(<1.0%) 0 1(<1.0%) Moderate 205( 100%) 208(99.5%) 52( 100%) 465(99.8%) Severe Total 205( 100%) 209( 100%) 52( 100%) 466( 100%) Length of Surgery (min) N Mean S.D Median Min,Max (3,37) (3,26) (4,20) (3,37) [1] Information was not collected for subjects enrolled before the date of protocol Amendment 1, August 13, Seventy-four subjects enrolled before Protocol Amendment 1 are excluded from the total count. [2] Includes data from screening visit for those who had screening and surgical procedure conducted in one visit. December 12,

16 Table 1. Demographics, Vital Signs, and Baseline Characteristics (Subjects in Intent-to-Treat Analysis Set) (Page 6 of 6) ======================================================================================================================= APAP 1000 mg APAP 650 mg Placebo Total (N=239) (N=241) (N=60) (N=540) Baseline Pain Severity Categorical Scale, n (%) Moderate 124(51.9%) 124(51.5%) 31(51.7%) 279(51.7%) Severe 115(48.1%) 117(48.5%) 29(48.3%) 261(48.3%) Total 239( 100%) 241( 100%) 60( 100%) 540( 100%) Visual Analog Scale (mm) N Mean S.D Median Min,Max (52,100) (50,100) (52,100) (50,100) ======================================================================================================================= [1] Information was not collected for subjects enrolled before the date of protocol Amendment 1, August 13, Seventy-four subjects enrolled before Protocol Amendment 1 are excluded from the total count. [2] Includes data from screening visit for those who had screening and surgical procedure conducted in one visit. December 12,

17 4.3.2 Efficacy Efficacy results for the study are summarized in Table 2 and discussed in the sections that follow. Table 2. Primary and Secondary Efficacy Endpoints Intent-to-Treat Analysis Set Endpoint Primary Efficacy Endpoint APAP 1000 mg (N=239) APAP 650 mg (N=241) Placebo (N=60) 1000 mg vs Pbo p-values 1000 mg vs 650 mg 650 mg vs Pbo SPRID6, LSM a < <0.001 Secondary Efficacy Endpoints SPID6, LSM a < <0.001 TOTPAR6, LSM a < <0.001 Percentage of Subjects with >50% of Maximum < <0.001 Possible TOTPAR6 Score b Median time to rescue c, min Rescue rate through four hours b, % Rescue rate through six hours b, % Median time to confirmed perceptible pain relief c, min Median time to meaningful pain relief c, min Patient global evaluation a, LSM NE NE 99.5 <0.001 <0.001 < < < <0.001 <0.001 < NE < < NE < < < <0.001 a: p-values were based on pairwise comparison of the Least Squares Means from an ANOVA model with treatment and baseline categorical pain rating as factors. b: p-values are based on the Cochran-Mantel-Haenszel test (CMH) of general association stratified by categorical baseline pain (moderate or severe). c: p-values are based on the log-rank test (time to rescue) or Wilcoxon test (time to confirmed perceptible or meaningful pain relief) from PROC LIFETEST comparing survival curves. Abbreviations: APAP = acetaminophen, LSM = least squares mean, NE = not estimable, Pbo = placebo December 12,

18 Weighted Sum of the Pain Intensity Difference (PID) and Pain Relief (PAR) Scores Over Six Hours (SPRID6) - Primary Endpoint The results for the primary endpoint of the weighted sum of the pain intensity difference (PID) and pain relief (PAR) scores over six hours (SPRID6) are shown in Table 3. The least squares mean SPRID6 was 529.4, 427.3, and 60.0 for subjects treated with acetaminophen 1000 mg, acetaminophen 650 mg, and placebo, respectively. The least squares mean SPRID6 was statistically significantly greater for subjects treated with acetaminophen 1000 mg compared with subjects treated with placebo (p<0.001) or acetaminophen 650 mg (p=0.001). Acetaminophen 1000 mg demonstrated a 24% improvement compared to acetaminophen 650 mg (529.4 vs 427.3; p=0.001). In addition, the least squares mean SPRID6 was statistically significantly greater for subjects treated with acetaminophen 650 mg compared with subjects treated with placebo (p<0.001). Subjects treated with acetaminophen 1000 mg had significantly greater PRID scores compared with subjects treated with placebo beginning at 15 minutes (p=0.027) and continuing through six hours and compared with subjects treated with acetaminophen 650 mg beginning at 75 minutes (p=0.043) and continuing through six hours. Subjects treated with acetaminophen 650 mg had significantly greater PRID scores compared with subjects treated with placebo beginning at 15 minutes (p=0.005) and continuing through six hours. Figure 1 summarizes the sum of pain relief and pain intensity difference from baseline at each time point. An incremental benefit was observed over time with acetaminophen 1000 mg compared to acetaminophen 650 mg. The curves for mean PRID were almost identical for acetaminophen 1000 mg and acetaminophen 650 mg for the first 45 minutes at which time they began to separate from one another. The degree of separation between the curve for acetaminophen 1000 mg and the curve for acetaminophen 650 mg remained relatively constant between two and six hours. Treatment by baseline pain intensity (moderate or severe) interaction was examined for the primary endpoint SPRID6. There was no interaction identified (p=0.859). A post-hoc analysis for sensitivity was performed on PRID and SPRID6 using baseline pain intensity carried forward and pain relief set to zero for subjects who rescued. In the analysis outlined in the statistical analysis plan, the last reported pain score or baseline pain score, whichever was worse, was carried forward to the remaining time points and pain relief scores after rescue were set to zero for subjects who rescued. As shown in Table 4, results from the sensitivity analysis demonstrated almost identical levels of significance for the pairwise comparison of treatments as in the original analysis. PRID scores for subjects treated with placebo were greater from 120 minutes onwards in this analysis compared to PRID scores for subjects treated with placebo in the planned analysis. December 12,

19 Table 3. Summary Statistics and Treatment Comparisons for Sum of Pain Relief and Pain Intensity Difference from Baseline at Each Time Point (PRID) and Weighted Sum Over Six Hours (SPRID6) (Subjects in ITT Analysis Set) ====================================================================================================================================== Assessment Time Points (Minutes) Treatment SPRID APAP 1000 mg (N=239) Mean SD LS Mean SE APAP 650 mg (N=241) Mean SD LS Mean SE Placebo (N=60) Mean SD LS Mean SE Pairwise Comparisons - p-value APAP 1000 mg vs. Placebo <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 APAP 1000 mg vs. APAP 650 mg <0.001 < APAP 650 mg vs. Placebo <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 Root MSE ====================================================================================================================================== P-values (presented as two-sided) are based on pairwise comparison of the Least Squares Means from an ANOVA model with treatment and baseline categorical pain rating as factors. December 12,

20 Figure 1. Sum of Pain Relief and Pain Intensity Difference (PRID ± SEM) from Baseline at Each Time Point (Subjects in ITT Analysis Set) December 12,

21 Table 4. Sensitivity Analysis - Summary Statistics and Treatment Comparisons for Sum of Pain Relief and Pain Intensity Difference from Baseline at Each Time Point (PRID) and Weighted Sum Over Six Hours (SPRID6) a (Subjects in ITT Analysis Set) ====================================================================================================================================== Assessment Time Points (Minutes) Treatment SPRID APAP 1000 mg (N=239) Mean SD LS Mean SE APAP 650 mg (N=241) Mean SD LS Mean SE Placebo (N=60) Mean SD LS Mean SE Pairwise Comparisons - p-value APAP 1000 mg vs. Placebo <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 APAP 1000 mg vs. APAP 650 mg <0.001 < APAP 650 mg vs. Placebo <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 Root MSE ====================================================================================================================================== a: For subjects taking rescue medication, baseline pain scores are carried forward for the remaining measurement timepoints. P-values (presented as two-sided) are based on pairwise comparison of the Least Squares Means from an ANOVA model with treatment and baseline categorical pain rating as factors. December 12,

22 Weighted Sum of the Pain Intensity Difference from Baseline Scores Over Six Hours (SPID6) Table 5 provides the results of the weighted sum of the pain intensity difference from baseline scores over six hours (SPID6). The least squares mean SPID6 was 222.5, 174.3, and -4.2 for subjects treated with acetaminophen 1000 mg, acetaminophen 650 mg, and placebo, respectively. The least squares mean SPID6 was statistically significantly greater for subjects treated with acetaminophen 1000 mg compared with subjects treated with placebo (p<0.001) or acetaminophen 650 mg (p=0.001). Furthermore, the least squares mean SPID6 was statistically significantly greater for subjects treated with acetaminophen 650 mg compared with subjects treated with placebo (p<0.001). Subjects treated with acetaminophen 1000 mg had significantly greater PID scores compared with subjects treated with placebo beginning at 15 minutes (p=0.037) and continuing through six hours and compared with subjects treated with acetaminophen 650 mg beginning at 75 minutes (p=0.041) and continuing through six hours. Subjects treated with acetaminophen 650 mg had significantly greater PID scores compared with subjects treated with placebo beginning at 15 minutes (p=0.006) and continuing through six hours. Figure 2 summarizes the pain intensity difference from baseline at each time point. An incremental benefit was observed over time with acetaminophen 1000 mg compared to acetaminophen 650 mg. The curves for mean PID were almost identical for acetaminophen 1000 mg and acetaminophen 650 mg for the first 45 minutes at which time they began to separate from one another. The degree of separation between the curve for acetaminophen 1000 mg and the curve for acetaminophen 650 mg remained relatively constant between two and six hours. A post-hoc analysis for sensitivity was performed on PID and SPID6 using baseline pain intensity carried forward for subjects who rescued. In the analysis outlined in the statistical analysis plan, the last reported pain score or baseline pain score, whichever was worse, was carried forward to the remaining time points for subjects who rescued. As shown in Table 6, results from the sensitivity analysis demonstrated almost identical levels of significance for the pairwise comparison of treatments as in the original analysis. PID scores for subjects treated with placebo were greater from 120 minutes onwards in this analysis compared to PID scores for subjects treated with placebo in the planned analysis.. December 12,

23 Table 5. Summary Statistics and Treatment Comparisons for Pain Intensity Difference From Baseline at Each Time Point (PID) and Weighted Sum Over Six Hours (SPID6) (Subjects in ITT Analysis Set) ====================================================================================================================================== Assessment Time Points (Minutes) Treatment SPID APAP 1000 mg (N=239) Mean SD LS Mean SE APAP 650 mg (N=241) Mean SD LS Mean SE Placebo (N=60) Mean SD LS Mean SE Pairwise Comparisons - p-value APAP 1000 mg vs. Placebo <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 APAP 1000 mg vs. APAP 650 mg <0.001 < APAP 650 mg vs. Placebo <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 Root MSE ====================================================================================================================================== P-values (presented as two-sided) are based on pairwise comparison of the Least Squares Means from an ANOVA model with treatment and baseline categorical pain rating as factors. December 12,

24 Figure 2. Pain Intensity Difference from Baseline (PID ± SEM) at Each Time Point (Subjects in ITT Analysis Set) December 12,

25 Table 6. Sensitivity Analysis - Summary Statistics and Treatment Comparisons for Pain Intensity Difference From Baseline at Each Time Point (PID) and Weighted Sum Over Six Hours (SPID6) a (Subjects in ITT Analysis Set) ====================================================================================================================================== Assessment Time Points (Minutes) Treatment SPID APAP 1000 mg (N=239) Mean SD LS Mean SE APAP 650 mg (N=241) Mean SD LS Mean SE Placebo (N=60) Mean SD LS Mean SE Pairwise Comparisons - p-value APAP 1000 mg vs. Placebo <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 APAP 1000 mg vs. APAP 650 mg < <0.001 < APAP 650 mg vs. Placebo <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 Root MSE ====================================================================================================================================== a: For subjects taking rescue medication, baseline pain scores are carried forward for the remaining measurement timepoints. P-values (presented as two-sided) are based on pairwise comparison of the Least Squares Means from an ANOVA model with treatment and baseline categorical pain rating as factors. December 12,

26 Weighted Sum of the Pain Relief Scores Over Six Hours (TOTPAR6) Table 7 provides the results of the weighted sum of the pain relief scores over six hours (TOTPAR6). The least squares mean TOTPAR6 was 306.9, 253.0, and 64.3 for subjects treated with acetaminophen 1000 mg, acetaminophen 650 mg, and placebo, respectively. The least squares mean TOTPAR6 was statistically significantly greater for subjects treated with acetaminophen 1000 mg compared with subjects treated with placebo (p<0.001) or acetaminophen 650 mg (p=0.002). In addition, the least squares mean TOTPAR6 was statistically significantly greater for subjects treated with acetaminophen 650 mg compared with subjects treated with placebo (p<0.001). Subjects treated with acetaminophen 1000 mg had significantly greater PAR scores compared with subjects treated with placebo beginning at 15 minutes (p=0.028) and continuing through six hours and compared with subjects treated with acetaminophen 650 mg beginning at 75 minutes (p=0.050) and continuing through six hours. Subjects treated with acetaminophen 650 mg had significantly greater PAR scores compared with subjects treated with placebo beginning at 15 minutes (p=0.008) and continuing through six hours. Figure 3 summarizes the pain relief at each time point. An incremental benefit was observed over time with acetaminophen 1000 mg compared to acetaminophen 650 mg. The curves for mean pain relief were almost identical for acetaminophen 1000 mg and acetaminophen 650 mg for the first 45 minutes at which time they began to separate from one another. The degree of separation between the curve for acetaminophen 1000 mg and the curve for acetaminophen 650 mg remained relatively constant between two and six hours. December 12,

27 Table 7. Summary Statistics and Treatment Comparisons for Pain Relief at Each Time Point and Weighted Sum Over Six Hours (TOTPAR6) (Subjects in ITT Analysis Set) ====================================================================================================================================== Assessment Time Points (Minutes) Treatment TOTPAR APAP 1000 mg (N=239) Mean SD LS Mean SE APAP 650 mg (N=241) Mean SD LS Mean SE Placebo (N=60) Mean SD LS Mean SE Pairwise Comparisons - p-value APAP 1000 mg vs. Placebo <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 APAP 1000 mg vs. APAP 650 mg <0.001 < APAP 650 mg vs. Placebo <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 Root MSE ====================================================================================================================================== P-values (presented as two-sided) are based on pairwise comparison of the Least Squares Means from an ANOVA model with treatment and baseline categorical pain rating as factors. December 12,

28 Figure 3. Pain Relief (± SEM) at Each Time Point (Subjects in ITT Analysis Set) December 12,

29 Percentage of Subjects with >50% of the Maximum Possible TOTPAR6 Score Table 8 provides the results for the percentage of subjects with >50% of the maximum possible TOTPAR6 score. These results show that 56.9% of subjects treated with acetaminophen 1000 mg, 44.4% of subjects treated with acetaminophen 650 mg, and 6.7% of subjects treated with placebo had >50% of the maximum possible TOTPAR6 score. A statistically significant difference in the percentage of subjects with >50% of the maximum possible TOTPAR6 score was observed in favor of acetaminophen 1000 mg compared with placebo (p<0.001) or acetaminophen 650 mg (p=0.006). In addition, acetaminophen 650 mg was statistically significantly superior to placebo (p<0.001). December 12,

30 Table 8. Summary and Treatment Comparison for Percentage of Subjects with >50% of the Maximum Possible TOTPAR6 Score (Subjects in ITT Analysis Set) ==================================================================================================== APAP 1000 mg APAP 650 mg Placebo (N=239) (N=241) (N=60) Percentage of Subjects with >50% of the Maximum Possible TOTPAR6 Score [1], n(%) 136(56.9%) 107(44.4%) 4(6. 7%) Comparisons vs. Placebo P-value <0.001 <0.001 Comparison vs. APAP 650 mg P-value ==================================================================================================== [1] The Maximum Possible TOTPAR6 Score is 600. P-values are based on the Cochran-Mantel-Haenszel test (CMH) of general association stratified by categorical baseline pain (moderate or severe). December 12,

31 Time to Rescue Table 9 provides the distribution of cumulative percentage of subjects rescuing by time interval and the median time until subjects rescued. The median time to rescue was not estimable for subjects treated with acetaminophen 1000 mg or acetaminophen 650 mg since fewer than 50% of these subjects rescued and was 99.5 minutes for subjects treated with placebo. Statistically significant differences were observed in favor of subjects treated with acetaminophen 1000 mg compared to subjects treated with placebo (p<0.001) or acetaminophen 650 mg (p<0.001) and in favor of subjects treated with acetaminophen 650 mg compared to subjects treated with placebo (p<0.001). Figure 4 presents Kaplan-Meier estimates of the cumulative percentage of subjects rescuing. December 12,

32 Table 9. Distribution of Cumulative Percentage of Subjects Rescuing by Time Interval and Median Time to Rescue (Subjects in ITT Analysis Set) ====================================================================================================================================== Time Interval (hrs) postdose Median Time to Rescue Treatment (Minutes) APAP 1000 mg (N=239) Percent 0.0% 0.4% 0.4% 9.6% 14.2% 20.1% 23.0% 29.3% NE n APAP 650 mg (N=241) Percent 0.0% 0.0% 0.0% 12.9% 24.9% 32.4% 39.8% 45.6% NE n Placebo (N=60) Percent 0.0% 0.0% 0.0% 61.7% 76.7% 80.0% 80.0% 80.0% 99.5 n Survival Distribution Pairwise Comparison - p-value APAP 1000 mg vs. Placebo <0.001 APAP 1000 mg vs. APAP 650 mg <0.001 APAP 650 mg vs. Placebo <0.001 ====================================================================================================================================== P-values are based on the log-rank test from PROC LIFETEST comparing survival curves. Abbreviation: NE = Not Estimable. December 12,

33 Figure 4. Kaplan-Meier Estimates of the Cumulative Percentage of Subjects Rescuing (Subjects in ITT Analysis Set) December 12,

34 Rescue Rates Table 10 provides the results for the percentage of subjects rescuing through four and six hours. The percentage of subjects rescuing through four hours was 20.1%, 32.4%, and 80.0% for subjects treated with acetaminophen 1000 mg, acetaminophen 650 mg, and placebo, respectively. A statistically significantly smaller percentage of subjects treated with acetaminophen 1000 mg rescued through four hours compared to subjects treated with placebo (p<0.001) or acetaminophen 650 mg (p=0.002). In addition, a statistically significantly smaller percentage of subjects treated with acetaminophen 650 mg rescued through four hours compared to subjects treated with placebo (p<0.001). The percentage of subjects rescuing through six hours was 29.3%, 45.6%, and 80.0% for subjects treated with acetaminophen 1000 mg, acetaminophen 650 mg, and placebo, respectively. A statistically significantly smaller percentage of subjects treated with acetaminophen 1000 mg rescued through six hours compared to subjects treated with placebo (p<0.001) or acetaminophen 650 mg (p<0.001). In addition, a statistically significantly smaller percentage of subjects treated with acetaminophen 650 mg rescued through six hours compared to subjects treated with placebo (p<0.001). December 12,

35 Table 10. Rescue Rates Through Four and Six Hours (Subjects in ITT Analysis Set) =================================================================================================================== APAP 1000 mg APAP 650 mg Placebo (N=239) (N=241) (N=60) Number and Percent Rescued <= 4 Hours, n(%) 48(20.1%) 78(32.4%) 48(80.0%) Comparisons vs. Placebo P-value <0.001 <0.001 Comparison vs. APAP 650 mg P-value Number and Percent Rescued <= 6 Hours, n(%) 70(29.3%) 110(45.6%) 48(80.0%) Comparisons vs. Placebo P-value <0.001 <0.001 Comparison vs. APAP 650 mg P-value <0.001 =================================================================================================================== P-values are based on the Cochran-Mantel-Haenszel test (CMH) of general association stratified by categorical baseline pain (moderate or severe). December 12,

36 Time to Confirmed Perceptible Pain Relief McNeil Consumer Healthcare Table 11 provides the results of the time to confirmed perceptible pain relief which was defined as follows: Subjects who indicated they had perceptible pain relief and also indicated that they obtained meaningful pain relief, or Subjects who indicated they had perceptible pain relief, but not meaningful pain relief, however, at the time point right after perceptible pain relief, the pain relief was at least 10 or the pain intensity was at least 10 less than baseline (using the mm VAS) The median time to confirmed perceptible pain relief was 22.2 minutes for subjects treated with acetaminophen 1000 mg, 22.2 minutes for subjects treated with acetaminophen 650 mg, and was not estimable for subjects treated with placebo since fewer than 50% of the subjects obtained confirmed perceptible pain relief. The time to confirmed perceptible pain relief was statistically significantly shorter for subjects treated with acetaminophen 1000 mg compared with subjects treated with placebo (p<0.001) and was numerically, but not significantly, favored for acetaminophen 1000 mg when compared with subjects treated with acetaminophen 650 mg. A statistically significantly shorter time to confirmed perceptible pain relief was also demonstrated for subjects treated with acetaminophen 650 mg compared with subjects treated with placebo (p<0.001). Figure 5 presents the Kaplan- Meier estimates of the cumulative percentage of subjects with confirmed perceptible pain relief. December 12,

37 Table 11. Kaplan-Meier Estimates of Time to Confirmed Perceptible Pain Relief - Cumulative Percentage of Subjects with Confirmed Perceptible Pain Relief (Subjects in ITT Analysis Set) ====================================================================================================================================== APAP 1000 mg APAP 650 mg Placebo (N=239) (N=241) (N=60) Minutes After Dosing 0 0.0% 0.0% 0.0% 5 0.8% 0.4% 1.7% % 5.8% 8.3% % 26.6% 16.7% % 44.0% 23.3% % 55.2% 25.0% % 69.3% 30.0% % 79.3% 33.3% % 80.9% 36.7% % 82.2% 36.7% % 82.2% 36.7% % 83.0% 36.7% % 83.0% 36.7% % 83.4% 36.7% % 83.4% 38.3% % 83.4% 38.3% % 83.4% 38.3% % 83.4% 38.3% N Median NE Comparisons vs. Placebo p-value <0.001 <0.001 Comparison vs. APAP 650 mg p-value ====================================================================================================================================== P-values are based on the Wilcoxon test from PROC LIFETEST comparing survival curves. Abbreviation: NE = Not Estimable. December 12,

38 Figure 5. Kaplan-Meier Estimates of Time to Confirmed Perceptible Pain Relief - Cumulative Percentage of Subjects with Confirmed Perceptible Pain Relief (Subjects in ITT Analysis Set) December 12,

39 Time to Meaningful Pain Relief Table 12 provides the results of the time to meaningful pain relief. The median time to meaningful pain relief was 53.7 minutes for subjects treated with acetaminophen 1000 mg, 56.1 minutes for subjects treated with acetaminophen 650 mg, and was not estimable for subjects treated with placebo since fewer than 50% of the subjects obtained meaningful pain relief. The time to meaningful pain relief was statistically significantly shorter for subjects treated with acetaminophen 1000 mg compared with subjects treated with placebo (p<0.001) and was numerically, but not significantly, favored for acetaminophen 1000 mg when compared with subjects treated with acetaminophen 650 mg. A statistically significantly shorter time to meaningful pain relief was also demonstrated for subjects treated with acetaminophen 650 mg compared with subjects treated with placebo (p<0.001). Figure 6 presents the Kaplan-Meier estimates of the cumulative percentage of subjects with meaningful pain relief. December 12,

40 Table 12. Kaplan-Meier Estimates of Time to Meaningful Pain Relief Cumulative Percentage of Subjects with Meaningful Pain Relief (Subjects in ITT Analysis Set) ====================================================================================================================================== APAP 1000 mg APAP 650 mg Placebo (N=239) (N=241) (N=60) Minutes After Dosing 0 0.0% 0.0% 0.0% 5 0.0% 0.0% 0.0% % 0.0% 0.0% % 0.0% 0.0% % 3.3% 0.0% % 10.0% 0.0% % 18.3% 1.7% % 42.7% 5.0% % 53.1% 5.0% % 57.7% 8.3% % 61.0% 11.7% % 61.8% 13.3% % 63.9% 16.7% % 65.6% 18.3% % 66.8% 20.0% % 68.9% 21.7% % 70.1% 23.3% % 70.1% 23.3% N Median NE Comparisons vs. Placebo p-value <0.001 <0.001 Comparison vs. APAP 650 mg p-value ====================================================================================================================================== P-values are based on the Wilcoxon test from PROC LIFETEST comparing survival curves. Abbreviation: NE = Not Estimable. December 12,

41 Figure 6. Kaplan-Meier Estimates of Time to Meaningful Pain Relief - Cumulative Percentage of Subjects with Meaningful Pain Relief (Subjects in ITT Analysis Set) December 12,

42 Assessments of Overall Impression of Study Medication (Global) Table 13 provides the distribution and means of the subject s rating of overall impression of study medication by treatment group. The least squares mean rating was 2.28, 1.95, and 0.60 for subjects treated with acetaminophen 1000 mg, acetaminophen 650 mg, and placebo, respectively. A statistically significantly higher rating was reported by subjects treated with acetaminophen 1000 mg compared with subjects treated with placebo (p<0.001) or acetaminophen 650 mg (p=0.001). Subjects treated with acetaminophen 650 mg had a statistically significantly higher rating compared with subjects treated with placebo (p<0.001). The percentage of subjects who rated their overall impression of study medication as good, very good or excellent was 78.2%, 65.6%, and 16.7% for subjects treated with acetaminophen 1000 mg, acetaminophen 650 mg, and placebo, respectively. December 12,

43 Table 13. Distribution of Subject s Rating of Overall Impression of Study Medication (Subjects in ITT Analysis Set) ======================================================================================================== APAP 1000 mg APAP 650 mg Placebo (N=239) (N=241) (N=60) How Would You Rate the Study Medication You Received as a Pain Reliever, n (%) Poor (0) 27(11.3%) 31(12.9%) 37(61.7%) Fair (1) 25(10.5%) 52(21.6%) 13(21.7%) Good (2) 70(29.3%) 75(31.1%) 8(13.3%) Very Good (3) 87(36.4%) 63(26.1%) 1( 1.7%) Excellent (4) 30(12.6%) 20( 8.3%) 1( 1.7%) N Mean S.D LSMean S.E Comparisons vs. Placebo P-value <0.001 <0.001 Difference of LSMeans S.E. of difference % C.I. [1.4, 2.0] [1.0, 1.7] Comparison vs. APAP 650 mg P-value Difference of LSMeans 0.33 S.E. of difference % C.I. [0.1, 0.5] ======================================================================================================== P-values are based on pairwise comparisons of the Least Squares Means from an ANOVA model with Treatment and baseline categorical pain as factors. December 12,

44 Efficacy Conclusions This study demonstrated that acetaminophen 1000 mg provided clinically meaningful and statistically significantly greater efficacy in treating postoperative dental pain compared with acetaminophen 650 mg and placebo. This study also demonstrated the significantly superior efficacy of acetaminophen 650 mg compared to placebo in treating postoperative dental pain. Greater overall pain relief was observed with acetaminophen 1000 mg compared to acetaminophen 650 mg for all summary measures (SPRID6, SPID6, and TOTPAR6) and for PID, PAR, and PRID from 75 minutes through six hours. Both acetaminophen 1000 mg and acetaminophen 650 mg had similar times to onset of confirmed perceptible pain relief and meaningful pain relief. The duration of analgesia was longer with acetaminophen 1000 mg compared to acetaminophen 650 mg as demonstrated by a longer time to use of rescue medication and a smaller percentage of subjects requiring rescue medication. The primary endpoint of the weighted sum of pain intensity difference (PID) and pain relief (PAR) scores over six hours (SPRID6) was statistically significantly superior for acetaminophen 1000 mg compared with placebo or acetaminophen 650 mg and for acetaminophen 650 mg compared with placebo. Results for SPID6 and TOTPAR6 demonstrated statistically significant superiority of acetaminophen 1000 mg compared to placebo or acetaminophen 650 mg and statistically significant superiority of acetaminophen 650 mg compared to placebo. Statistically significantly greater PID, PAR, and PRID scores were observed for acetaminophen 1000 mg and acetaminophen 650 mg compared to placebo beginning at 15 minutes, and for acetaminophen 1000 mg compared to acetaminophen 650 mg beginning at 75 minutes and continuing through six hours for all comparisons. Results for the percentage of subjects with >50% of the maximum possible TOTPAR6 score demonstrated statistically significant differences in favor of acetaminophen 1000 mg compared to placebo or acetaminophen 650 mg and in favor of acetaminophen 650 mg compared to placebo. The time to rescue and the rescue rate through four and six hours demonstrated statistically significant differences in favor of acetaminophen 1000 mg compared to placebo or acetaminophen 650 mg and in favor of acetaminophen 650 mg compared to placebo. For the time to confirmed perceptible pain relief and the time to meaningful pain relief, acetaminophen 1000 mg and acetaminophen 650 mg were statistically significantly superior to placebo. December 12,

45 The global assessment of study medication as a pain reliever was statistically significantly greater for subjects treated with acetaminophen 1000 mg compared with those treated with placebo or acetaminophen 650 mg and for acetaminophen 650 mg compared with placebo Safety No deaths or other serious adverse events were reported, and no subjects withdrew from the study due to adverse events. The number and percent of subjects with adverse events by system organ class and MedDRA preferred term and treatment group are shown in Table 14. One or more adverse events were reported by 45 (18.8%) subjects treated with acetaminophen 1000 mg, 42 (17.4%) subjects treated with acetaminophen 650 mg, and 13 (21.7%) subjects treated with placebo. The most commonly reported system organ classes were gastrointestinal disorders and nervous system disorders. The most commonly reported adverse events were nausea, vomiting, and dizziness. All of these adverse events were reported at similar frequencies among the three treatment groups. Two subjects (one treated with acetaminophen 1000 mg and one treated with acetaminophen 650 mg) experienced syncope and one subject treated with acetaminophen 1000 mg reported passing out, which was coded to a MedDRA preferred term of loss of consciousness. It appears that all three subjects experienced very similar events even though two events were coded as syncope and one as loss of consciousness. All adverse events were of mild or moderate severity except for one adverse event of dizziness reported by a subject treated with acetaminophen 1000 mg. December 12,

46 Table 14. Summary of Adverse Events [1] by System Organ Class and MedDRA Preferred Term (Subjects in the Safety Analysis Set) (Page 1 of 2) ================================================================================================================================ APAP 1000 mg APAP 650 mg Placebo Total (N=239) (N=241) (N=60) (N=540) System Organ Class [2] Preferred Term n (%) n (%) n (%) n (%) Subjects with At Least One AE 45(18.8%) 42(17.4%) 13(21.7%) 100(18.5%) Gastrointestinal disorders 31(13.0%) 27(11.2%) 9(15.0%) 67(12.4%) Nausea 29(12.1%) 26(10.8%) 9(15.0%) 64(11.9%) Vomiting 11( 4.6%) 11( 4.6%) 4( 6.7%) 26( 4.8%) Abdominal discomfort 1(<1.0%) 0 0 1(<1.0%) Hypoaesthesia oral 1(<1.0%) 0 0 1(<1.0%) Nervous system disorders 19( 7.9%) 16( 6.6%) 6(10.0%) 41( 7.6%) Dizziness 10( 4.2%) 8( 3.3%) 4( 6.7%) 22( 4.1%) Headache 6( 2.5%) 8( 3.3%) 2( 3.3%) 16( 3.0%) Syncope 1(<1.0%) 1(<1.0%) 0 2(<1.0%) Tremor 1(<1.0%) 1(<1.0%) 0 2(<1.0%) Loss of consciousness 1(<1.0%) 0 0 1(<1.0%) Presyncope 1(<1.0%) 0 0 1(<1.0%) General disorders and administration site conditions 4( 1.7%) 7( 2.9%) 0 11( 2.0%) Feeling hot 3( 1.3%) 5( 2.1%) 0 8( 1.5%) Feeling cold 1(<1.0%) 1(<1.0%) 0 2(<1.0%) Chills 0 1(<1.0%) 0 1(<1.0%) Skin and subcutaneous tissue disorders 1(<1.0%) 3( 1.2%) 2( 3.3%) 6( 1.1%) Hyperhidrosis 1(<1.0%) 3( 1.2%) 2( 3.3%) 6( 1.1%) Respiratory, thoracic and mediastinal disorders 2(<1.0%) 1(<1.0%) 0 3(<1.0%) Dyspnoea 1(<1.0%) 0 0 1(<1.0%) Epistaxis 1(<1.0%) 0 0 1(<1.0%) Tachypnoea 0 1(<1.0%) 0 1(<1.0%) Vascular disorders 0 2(<1.0%) 0 2(<1.0%) Pallor 0 2(<1.0%) 0 2(<1.0%) Ear and labyrinth disorders 1(<1.0%) 0 0 1(<1.0%) Ear pain 1(<1.0%) 0 0 1(<1.0%) [1] Subjects are counted only once for each system organ class and preferred term. [2] Listed in descending order of frequency reported by all subjects. December 12,

47 Table 14. Summary of Adverse Events [1] by System Organ Class and MedDRA Preferred Term (Subjects in the Safety Analysis Set) (Page 2 of 2) ================================================================================================================================ APAP 1000 mg APAP 650 mg Placebo Total (N=239) (N=241) (N=60) (N=540) System Organ Class [2] Preferred Term n (%) n (%) n (%) n (%) Eye disorders 0 1(<1.0%) 0 1(<1.0%) Vision blurred 0 1(<1.0%) 0 1(<1.0%) Immune system disorders 1(<1.0%) 0 0 1(<1.0%) Drug hypersensitivity 1(<1.0%) 0 0 1(<1.0%) Injury, poisoning and procedural complications 0 1(<1.0%) 0 1(<1.0%) Operative haemorrhage 0 1(<1.0%) 0 1(<1.0%) Musculoskeletal and connective tissue disorders 0 1(<1.0%) 0 1(<1.0%) Myalgia 0 1(<1.0%) 0 1(<1.0%) Psychiatric disorders 1(<1.0%) 0 0 1(<1.0%) Emotional disorder 1(<1.0%) 0 0 1(<1.0%) ================================================================================================================================ [1] Subjects are counted only once for each system organ class and preferred term. [2] Listed in descending order of frequency reported by all subjects. December 12,

48 Safety Conclusions All study medications were well tolerated and no safety issues were identified. The severity and nature of adverse events were similar among groups. Overall, 18.5% of subjects reported adverse events; event rates were similar across treatment groups. The most commonly reported adverse events were nausea, vomiting, and dizziness and were reported by 11.9%, 4.8%, and 4.1%, respectively, of study subjects. Event rates were similar across treatment groups. No deaths or other serious adverse events were reported, and no subjects withdrew from the study due to adverse events. 5 SUMMARY The objective of McNeil study ACEPAI2001 was to assess the relative efficacy of acetaminophen 1000 mg versus acetaminophen 650 mg over a six-hour period in subjects experiencing at least moderate postoperative dental pain. The assessment of postoperative pain after removal of impacted third molars is a well-recognized pain model that is often used to evaluate the relative efficacy of acute pain medications. The protocol-specified primary efficacy endpoint was the weighted sum of pain intensity difference (PID) and pain relief (PAR) scores over six hours (SPRID6). The least squares mean SPRID6 was 529.4, 427.3, and 60.0 for subjects treated with acetaminophen 1000 mg, acetaminophen 650 mg, and placebo, respectively. The least squares mean SPRID6 was statistically significantly greater for subjects treated with acetaminophen 1000 mg compared with subjects treated with placebo (p<0.001) or acetaminophen 650 mg (p=0.001). Acetaminophen 1000 mg demonstrated a 24% improvement compared to acetaminophen 650 mg. In addition, the least squares mean SPRID6 was statistically significantly greater for subjects treated with acetaminophen 650 mg compared with subjects treated with placebo (p<0.001). Results for the two secondary measures of the weighted sum of the pain intensity difference from baseline scores over six hours (SPID6) and the weighted sum of the pain relief scores over six hours (TOTPAR6) were consistent with the primary endpoint. The least squares mean SPID6 and mean TOTPAR6 were statistically significantly greater for subjects treated with acetaminophen 1000 mg compared with subjects treated with placebo (p<0.001) or acetaminophen 650 mg (p 0.002). Furthermore, the least squares mean SPID6 and mean TOTPAR6 were statistically significantly greater for subjects treated with acetaminophen 650 mg compared with subjects treated with placebo (p<0.001). December 12,

49 Statistically significantly greater PID, PAR, and PRID scores were observed with acetaminophen 1000 mg compared to placebo beginning at 15 minutes, with acetaminophen 1000 mg compared to acetaminophen 650 mg beginning at 75 minutes, and with acetaminophen 650 mg compared to placebo beginning at 15 minutes and continuing through six hours for all comparisons. The percentage of subjects with >50% of the maximum TOTPAR6 score was significantly greater for subjects treated with acetaminophen 1000 mg compared to subjects treated with placebo (p<0.001) or acetaminophen 650 mg (p=0.006) and for subjects treated with acetaminophen 650 mg compared to subjects treated with placebo (p<0.001). The duration of analgesic effect as estimated by the elapsed time to rescue medication was statistically significantly greater for subjects treated with acetaminophen 1000 mg compared to subjects treated with placebo (p<0.001) or acetaminophen 650 mg (p<0.001) and for subjects treated with acetaminophen 650 mg compared to subjects treated with placebo (p<0.001). A statistically significantly smaller percentage of subjects treated with acetaminophen 1000 mg rescued through four and six hours compared to subjects treated with placebo (p<0.001) or acetaminophen 650 mg (p 0.002). In addition, a statistically significantly smaller percentage of subjects treated with acetaminophen 650 mg rescued through four hours compared to subjects treated with placebo (p<0.001). The median time to confirmed perceptible pain relief was 22.2 minutes for subjects treated with acetaminophen 1000 mg, 22.2 minutes for subjects treated with acetaminophen 650 mg, and was not estimable for subjects treated with placebo since fewer than 50% of the subjects obtained confirmed perceptible pain relief. The time to confirmed perceptible pain relief was statistically significantly shorter for subjects treated with acetaminophen 1000 mg compared with subjects treated with placebo (p<0.001). A statistically significantly shorter time to confirmed perceptible pain relief was also demonstrated for subjects treated with acetaminophen 650 mg compared with subjects treated with placebo (p<0.001). The median time to meaningful pain relief was 53.7 minutes for subjects treated with acetaminophen 1000 mg, 56.1 minutes for subjects treated with acetaminophen 650 mg, and was not estimable for subjects treated with placebo since fewer than 50% of the subjects obtained meaningful pain relief. The time to meaningful pain relief was statistically significantly shorter for subjects treated with acetaminophen 1000 mg compared with subjects treated with placebo (p<0.001) and numerically, but not significantly, favored for acetaminophen 1000 mg when compared with subjects treated with acetaminophen 650 mg. A statistically significantly shorter time to meaningful pain December 12,

50 relief was also demonstrated for subjects treated with acetaminophen 650 mg compared with subjects treated with placebo (p<0.001). The statistically significant superiority of acetaminophen 1000 mg compared with placebo (p<0.001) or acetaminophen 650 mg (p=0.001) and of acetaminophen 650 mg compared with placebo (p<0.001) was also demonstrated for the patient global evaluation. The percentage of subjects that rated their overall impression of study medication as good, very good or excellent was 78.2%, 65.6%, and 16.7% for subjects treated with acetaminophen 1000 mg, acetaminophen 650 mg, and placebo, respectively. This study demonstrated that acetaminophen 1000 mg provided clinically meaningful and statistically significantly greater efficacy in treating postoperative dental pain compared with acetaminophen 650 mg and placebo. This study also demonstrated the significantly superior efficacy of acetaminophen 650 mg compared to placebo in treating postoperative dental pain. Greater overall pain relief was observed with acetaminophen 1000 mg compared to acetaminophen 650 mg for all summary measures (SPRID6, SPID6, and TOTPAR6) and for PID, PAR, and PRID from 75 minutes through six hours. Both acetaminophen 1000 mg and acetaminophen 650 mg had similar times to onset of confirmed perceptible pain relief and meaningful pain relief. The duration of analgesia was longer with acetaminophen 1000 mg compared to acetaminophen 650 mg as demonstrated by a longer time to use of rescue medication and a smaller percentage of subjects requiring rescue medication. The results of McNeil s study were consistent with those of a recent similar study (Study A ) conducted by GlaxoSmithKline Consumer Healthcare (GSKCH). Study A was single-center, single-dose, randomized (stratified at baseline for pain intensity), placebo-controlled, double-blind, double-dummy, parallel group trial similar in design to McNeil study ACEPAI2001. Results of Study A were submitted as part of a citizen petition submitted by GSKCH on March 14, 2011 [14]. The citizen petition requested that the FDA Commissioner maintain the current OTC availability of acetaminophen 1000 mg single adult dose, pursuant to the Tentative Final Monograph (TFM) for Internal Analgesic, Antipyretic and Antirheumatic Drug Products for Over-the- Counter Human Use (Docket No. 77N-0094). Study A was one of two clinical efficacy and safety studies provided in support of this citizen petition. The second clinical efficacy and safety study (A ) included in the citizen petition was a study that compared acetaminophen 1000 mg to acetaminophen 500 mg and placebo. Study A used the same primary endpoint as the McNeil study, ie, sum of pain relief and pain intensity differences over the six-hour period after treatment (SPRID 6h ). Results from Study A were similar to that of the McNeil study in that superior December 12,

51 dental pain relief efficacy was demonstrated for acetaminophen 1000 mg compared with acetaminophen 650 mg (p=0.0009) [15]. In addition, superior efficacy of acetaminophen 1000 mg compared with acetaminophen 650 mg was demonstrated for the following secondary endpoints in Study A : sum of pain relief and pain intensity differences over the two-hour and four-hour period after treatment (SPRID 2h and SPRID 4h ), total pain relief over the two-hour, four-hour, and six-hour period after treatment (TOTPAR 2h, TOTPAR 4h, and TOTPAR 6h ), sum of the pain intensity difference over the two-hour, four-hour, and six-hour period after treatment (SPID 2h, SPID 4h, and SPID 6h ), and global evaluation of pain relief [15]. On July 6, 2011, FDA notified GSKCH that due to other priorities FDA was unable to provide a response to the petition at that time [16]. These studies demonstrated the superior efficacy (McNeil ACEPAI2001 and GSKCH A ) and duration of analgesia (McNeil ACEPAI2001) of acetaminophen 1000 mg compared with acetaminophen 650 mg. These studies add to the body of existing data and provide additional and sufficient support to maintain the current OTC availability of acetaminophen 1000 mg single adult dose when marketed under the TFM for Internal Analgesic, Antipyretic and Antirheumatic Drug Products for Over-the-Counter Human Use. 6 CONCLUSIONS The dental impaction pain model is an accepted, validated, standardized model used to demonstrate the acute pain relief and duration of analgesia provided by analgesics, including acetaminophen. Results from dental impaction pain studies can be generalized to other acute pain states. The model has been an important basis for approval of numerous prescription and non-prescription analgesic drug product NDAs, such as ibuprofen (Motrin IB and Advil ) and Ultracet, both in the US and globally. McNeil Study ACEPAI2001 demonstrated that acetaminophen 1000 mg provided clinically meaningful and statistically significantly greater efficacy in treating postoperative dental pain compared with acetaminophen 650 mg and placebo through six hours. For the primary endpoint of the weighted sum of the pain intensity difference (PID) and pain relief (PAR) scores over six hours (SPRID6), the least squares mean was statistically significantly greater for subjects treated with acetaminophen 1000 mg (529.4) compared to acetaminophen 650 mg (427.3), demonstrating a 24% improvement. Greater overall pain relief was observed with acetaminophen 1000 mg compared to acetaminophen 650 mg for all summary December 12,

52 measures (SPRID6, SPID6, and TOTPAR6) and for PID, PAR, and PRID from 75 minutes through six hours. Both acetaminophen 1000 mg and acetaminophen 650 mg had similar times to onset of confirmed perceptible pain relief and meaningful pain relief. The duration of analgesia was longer with acetaminophen 1000 mg compared to acetaminophen 650 mg as demonstrated by a longer time to use of rescue medication and a smaller percentage of subjects requiring rescue medication. McNeil Study ACEPAI2001 demonstrated that a significantly larger percentage of subjects obtained pain relief with acetaminophen 1000 mg compared with acetaminophen 650 mg. A statistically significantly larger percentage of subjects completed the six-hour study without rescuing in the acetaminophen 1000 mg group (70.7%) compared with the acetaminophen 650 mg group (54.4%). In addition, a statistically significantly larger percentage of subjects had greater than 50% of the maximum possible TOTPAR6 score in the acetaminophen 1000 mg group (56.9%) compared with the acetaminophen 650 mg group (44.4%). Finally, a larger percentage of subjects rated the study medication as a pain reliever as good, very good, or excellent in the acetaminophen 1000 mg group (78.2%) compared with the acetaminophen 650 mg group (65.6%). The results of McNeil s study are consistent with those of a recent similar study using the dental impaction pain model (Study A ) conducted by GlaxoSmithKline Consumer Healthcare (GSKCH). Both studies evaluated immediate-release formulations of acetaminophen using the same primary endpoint, ie, sum of pain relief and pain intensity differences over the six-hour period after treatment (SPRID 6h ), and demonstrated statistically significantly superior dental pain relief efficacy for acetaminophen 1000 mg compared with acetaminophen 650 mg. These studies demonstrated the superior efficacy (McNeil ACEPAI2001 and GSKCH A ) and duration of analgesia (McNeil ACEPAI2001) of acetaminophen 1000 mg compared with acetaminophen 650 mg. These studies add to the body of existing data and provide additional and sufficient support to maintain the current over-the-counter availability of acetaminophen 1000 mg single adult dose when marketed under the Tentative Final Monograph for Internal Analgesic, Antipyretic and Antirheumatic Drug Products for Over-the-Counter Human Use. December 12,

53 7 REFERENCE LIST 1. McNeil Consumer Healthcare. Briefing Materials for June 29-30, 2009 Joint Meeting of the Drug Safety and Risk Management Advisory Committee with the Anesthetic and Life Support Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee. Available at: /Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM pdf. Accessed on November 2, Cooper SA, Desjardins PJ. The value of the dental impaction pain model in drug development. In: Szallasi A, ed. Analgesia: Methods and Protocols, Methods in Molecular Biology; 2010:617: Norholt SE. Treatment of acute pain following removal of mandibular third molars. Use of the dental pain model in pharmacological research and development of a comparable animal model. Int J Oral Maxilofac Surg 1998;27 (Suppl 1): Urquhart E. Analgesic agents and strategies in the dental pain model. J Dent 1994;22: Cooper SA. Models for clinical assessment of oral analgesics. Am J Med 1983;75: Malmstrom K, Kotey P, McGratty M, et al. Dental impaction pain model as a potential tool to evaluate drugs with efficacy in neuropathic pain. J Clin Pharmacol 2006;46: Edelman DA, Loose LD. Considerations in the design and analysis of postoperative dental pain studies. Drug Information Journal 2002;36: Barden J, Edwards JE, McQuay HJ, et al. Pain and analgesic response after third molar extraction and other postsurgical pain. Pain 2004:107: Desjardins P, Black P, Papageorge M, et al. Ibuprofen arginate provides effective relief from postoperative dental pain with a more rapid onset of action than ibuprofen. Eur J Clin Pharmacol 2002;58: Black P, Max MB, Dejardins P, et al. A randomized, double-blind, placebocontrolled comparison of the analgesic efficacy, onset of action, and tolerability of ibuprofen arginate and ibuprofen in postoperative dental pain. Clin Ther 2002;24: Mehlisch DR, Ardia A, Pallotta T. A controlled comparative study of ibuprofen arginate versus conventional ibuprofen in the treatment of postoperative dental pain. J Clin Pharmacol 2002;42: December 12,

54 12. Hersh EV, Levin LM, Cooper SA, et al. Ibuprofen liquigel for oral surgery pain. Clin Ther 2000;22: Schou S, Nielsen H, Nattestad A, et al. Analgesic dose-response relationship of ibuprofen 50, 100, 200, and 400 mg after surgical removal of third molars: a single-dose, randomized, placebo-controlled, and double-blind study of 304 patients. J Clin Pharmacol 1998;38: GlaxoSmithKline Consumer Healthcare (GSKCH) - Citizen Petition: Submission of Clinical Efficacy Data to Suport Acetaminophen 1,000 mg Dose Over-the- Counter. March 14, Available at Accessed November 3, GlaxoSmithKline Consumer Healthcare (GSKCH) - Citizen Petition: Attachment 2. Synopsis Report, Study Number A : A study to compare the analgesic efficacy of two different paracetamol doses as measured by post-operative dental pain relief. Available at: N Accessed November 3, FDA letter dated July 6, 2011 to GlaxoSmithKline Consumer Healthcare concerning their March 14, 2011 citizen petition. Available at: Accessed November 3, December 12,

55 Chapter 15 The Value of the Dental Impaction Pain Model in Drug Development Stephen A. Cooper and Paul J. Desjardins Abstract The modern version of the Dental Impaction Pain Model (DIPM) was developed in the mid-1970s. Since that time, several hundred studies have been conducted by numerous investigators. Today it is arguably the most utilized of all the acute pain models. Its popularity is due to the success rate of the studies, fast subject entry, and cost effectiveness. The surgical procedure is extremely standardized, and the surgery requires either minimal or no use of CNS depressant anesthetics. The methodology is similar to that utilized in other acute pain models; however, the DIPM is much more versatile than most other models. The model can be easily adapted to perform multiple-dose studies, pharmacokinetics/pharmacodynamics (PK/PD) correlations, preemptive interventions, and sleep pain studies. A few investigators have even developed microdialysis techniques, wherein they insert probes into extraction sockets to collect exudates for measuring biochemical mediators of pain or drug levels at the site of injury. In many instances, an accomplished site can complete a study of several hundred subjects in approximately 3 months. There are studies in the literature that have incorporated up to six treatment arms in one study and clearly separated the drugs from each other. The exquisite assay sensitivity is due to the homogeneity of the study population, the predictable level and appropriate intensity of the postsurgical pain, and the minimizing of variability by using only one or two study centers. The DIPM has been employed to evaluate NSAIDs (both nonselective and selective Cox inhibitors), opioids and combination analgesics, as well as some investigational drugs with unique mechanisms of action. The model is particularly useful for proof-of-concept studies that require dose-ranging and profiling the time effect curve for efficacy including onset, peak effect, and duration of analgesic activity. Key words: Acute pain, Dental impaction pain, First perceptible relief, Meaningful relief, Visual analog pain score 1. Introduction During my training in dental school, I became curious as to why almost every patient with a traumatic procedure received the same analgesic prescription. Even in this early stage of my career, Arpad Szallasi (ed.), Analgesia: Methods and Protocols, Methods in Molecular Biology, vol. 617, DOI / _15, Springer Science + Business Media, LLC

56 176 Cooper and Desjardins I suspected that treating pain was far more complex and more deserving than this simplistic approach. This led to my interest in pharmacology and eventual pursuit of an NIDR fellowship under the mentorship of Dr. William T. Beaver. Dr. Beaver, Emeritus Professor at Georgetown University, Department of Pharmacology, is one of the world s leading experts in analgesic methodology and the conduct of clinical trials in cancer and postsurgical pain. In 1971, with my background in dentistry and his expertise in Analgesiology, we embarked on the development of the Dental Impaction Pain Model. Today, there are literally hundreds of published studies utilizing this model, and it still remains one of the most widely used models for studying acute pain drugs. Since the initial studies published in the mid-1970s, Paul Desjardins, Raymond Dionne, Kenneth Hargreaves, Elliot Hersh, Abraham Sunshine, and several other investigators have contributed to the growth and development of this model. This paper covers the following topics: Characteristics of the Dental Impaction Pain Model (DIPM) Early studies that established the DIPM Studies that demonstrate the versatility of the DIPM Methodology Extrapolating the results from the DIPM to other pain conditions Debunking some myths about the DIPM 2. Characteristics of the Dental Impaction Pain Model How does a symptom like pain from a dental surgical procedure become transformed into a validated, standardized pain model? To be considered a representative model for acute pain, the experimental model should have assay sensitivity to discriminate against placebo as well to explore the full range of dosages for the control and experimental drugs. The ability to demonstrate efficacy across a broad spectrum of prototype analgesics determines the overall utility of the model. In addition, the model must have reproducible results, a low placebo response, and results that can be generalized across a variety of pain states. The ideal acute pain model characterizes the onset, peak effect, and duration of effect of the experimental drug across a range of dosages. As we will see, the DIPM meets all these criteria and the results from studies have clearly predicted the ultimate treatment regimens for many experimental drugs that were eventually approved for treating acute pain by the FDA and other international regulatory bodies

57 The Value of the Dental Impaction Pain Model in Drug Development 177 It is also important to define the limitations of any acute pain model. They do not predict long-term toxicity, rare adverse events, or efficacy beyond the scope of acute pain. The efficacy results from acute pain studies are just one key aspect in assembling the puzzle of a full analgesic development program. There are several demographic factors that make the DIPM an ideal model. The study subjects are young, healthy adults with impacted third molars commonly called wisdom teeth. The population of subjects is large in number and very homogeneous. Usually, the subjects are not even aware of their condition until a dentist makes the diagnosis from a radiographic exam. Given this demographic profile, the population rarely has any preexisting pain or complicating medical illnesses involving confounding medications. The surgical procedure is elective, relatively short (less than 30 min), and very standardized. Unlike many other surgical interventions, the procedure requires minimal sedation or anesthesia and is often performed with just a local anesthetic. Avoiding the carry-over effects of general anesthesia is an important advantage in that subjects are alert and ambulatory with no memory impairment or druginduced nausea. Most important, the surgical procedure results in an intensity level of postoperative pain that optimizes assay sensitivity. The pain is sufficiently intense that placebo is virtually ineffective; while drugs like aspirin, ibuprofen, and codeine-like opioids have only modest analgesic activity. This results in the ideal situation of both optimal downside and upside assay sensitivity (Fig. 1). Setting the Pain Bar & Choosing the Right Controls NSAIDs Narcotic Combinations Fig. 1. Assay sensitivity the model must be able to separate active drug from placebo as well as more efficacious drugs from less efficacious drugs