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For patients undergoing partial large or small bowel resection surgery with primary anastomosis‌

The first and only FDA-approved agent indicated to accelerate the time to upper and lower GI recovery following partial large or small bowel resection surgery with primary anastomosis

Opioids Can Delay Patients’ GI Recovery1-3 Opioids impact both the central nervous system (CNS) and the gastrointestinal (GI) tract1,2 • Opioids bind to CNS μ-opioid receptors for pain control1 • Opioids also bind to GI tract μ-opioid receptors, impairing motility1,2

Slow return of GI motility is…

– A potential cause of hospital discharge delay after bowel resection surgery until its resolution2,3

– A contributor to certain postop symptoms, which may include2,4: • Delayed passage of flatus/stool

• Inability to tolerate solid food

Important Safety Information • There were more reports of myocardial infarctions in patients treated with alvimopan 0.5 mg twice daily compared with placebo-treated patients in a 12-month study of patients treated with opioids for chronic pain. In this study, the majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of alvimopan, including studies of patients undergoing bowel resection surgery who received alvimopan 12 mg twice daily for up to 7 days. A causal relationship with alvimopan has not been established 2

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ENTEREG Accelerates GI Recovery 2 ENTEREG achieves selective GI opioid antagonism without reversing the central analgesic effects of μ-opioid agonists2 • Blocks the peripheral effects of opioids on GI motility and secretion by competitively binding to GI tract μ-opioid receptors, without reversing centrally mediated analgesia2 • This antagonism was evident in guinea pig ileum2 ENTEREG is a peripherally acting μ-opioid receptor antagonist 2

Opioids ENTEREG

GI μ-opioid receptors

ENTEREG did not reverse opioid analgesia in clinical trials, as measured by visual analog scale pain intensity scores and/or amount of postop opioids administered 2

WARNING: FOR SHORT-TERM HOSPITAL USE ONLY ENTEREG is available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have registered in and met all of the requirements for the ENTEREG Access Support & Education (E.A.S.E.™) Program may use ENTEREG.

Please see accompanying full Prescribing Information for ENTEREG. 3

The first and only FDA-approved agent indicated to accelerate the time to upper and lower GI recovery following partial large or small bowel resection surgery with primary anastomosis

ENTEREG Improved Time to GI Recovery 2 Improved mean time to GI recovery by up to 1 day 2,5-10 (GI recovery=toleration of solid food and first bowel movement)

Büchler et al5 Delaney et al6 Viscusi et al7 Ludwig et al8 Wolff et al9 ENTEREG (n=239) ENTEREG (n=98) ENTEREG (n=139) ENTEREG (n=317) ENTEREG (n=160) Placebo (n=229) Placebo (n=99) Placebo (n=142) Placebo (n=312) Placebo (n=142) HR=1.3 (CI=1.1-1.6) HR=1.4 (CI=1.0-1.9) HR=1.4 (CI=1.1-1.8) HR=1.5 (CI=1.3-1.8) HR=1.6 (CI=1.3-2.1)

Mean improvement in GI recovery time vs placebo (hours)

30 24

26

18

20

12 6 0

11

HOURS FASTER

13

HOURS FASTER

14

HOURS FASTER

HOURS FASTER

HOURS FASTER

HR=hazard ratio; CI=95% confidence interval.

ENTEREG vs placebo

The studies conducted by Ludwig et al 8 and Wolff et al 9 contained the largest number of bowel resection patients in the United States.

Important Safety Information • ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG • Overall, the incidence of adverse reactions in short-term surgical clinical trials was similar between patients receiving either ENTEREG or placebo. Most common adverse reactions (incidence ≥3% and ≥1% placebo) in patients undergoing bowel resection were anemia, dyspepsia, hypokalemia, back pain, and urinary retention 4

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All Study Arms Were Managed With a Standardized, Accelerated Postop Care Pathway, Including2: Removal of nasogastric tube before first postop dose Early ambulation Early feeding

Additional phase 3 study design features • Data are from multicenter, randomized, double-blind, placebo-controlled studies in patients undergoing bowel resection with primary anastomosis. Patients were administered ENTEREG 12 mg or placebo 30 minutes to 5 hours prior to surgery and twice daily after surgery until discharge, for a maximum of 7 days • Patients who received more than 3 doses of an opioid (regardless of route) during the 7 days prior to surgery and patients with complete bowel obstruction or who were scheduled for a total colectomy, colostomy, or ileostomy were excluded • The study conducted by Büchler et al was a non-US study; the use of nonopioid analgesics was substantially higher compared with the US studies for both treatment groups5

Please see accompanying full Prescribing Information, including Boxed Warning regarding short-term hospital use only and the ENTEREG Access Support & Education (E.A.S.E.™) Program.

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The first and only FDA-approved agent indicated to accelerate the time to upper and lower GI recovery following partial large or small bowel resection surgery with primary anastomosis

ENTEREG Reduced Time to 2 Discharge Order Written (DOW) Mean improvement in time to DOW approximately 13 to 21 hours2,6-10 Delaney et al6

Viscusi et al7

Ludwig et al8

Wolff et al9

ENTEREG (n=98) Placebo (n=99) HR=1.3 (CI=1.0-1.7)

ENTEREG (n=139) Placebo (n=142) HR=1.6 (CI=1.2-2.0)

ENTEREG (n=317) Placebo (n=312) HR=1.4 (CI=1.2-1.6)

ENTEREG (n=160) Placebo (n=142) HR=1.4 (CI=1.1-1.8)

21

HOURS FASTER

Mean improvement to DOW vs placebo (hours)

0

6

13

HOURS FASTER 12

18

18

HOURS FASTER

19

HOURS FASTER

24

HR=hazard ratio; CI=95% confidence interval.

ENTEREG vs placebo

Data are from 4 multicenter, randomized, double-blind, placebo-controlled pivotal US trials of patients undergoing bowel resection with primary anastomosis.

Patient management in all study arms included a standardized, accelerated postop care pathway2

Important Safety Information • ENTEREG should be administered with caution to patients receiving more than 3 doses of an opioid within the week prior to surgery. These patients may be more sensitive to ENTEREG and may experience GI side effects (eg, abdominal pain, nausea and vomiting, diarrhea) • ENTEREG is not recommended for use in patients with severe hepatic impairment, end-stage renal disease, or in patients undergoing surgery for correction of complete bowel obstruction 6

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Make ENTEREG Part of Your Routine Proactive dosing prior to surgery2 (Not actual size)

PREOPERATIVELY One ENTEREG 12-mg Capsule orally 30 minutes to 5 hours prior to surgery

POSTOPERATIVELY Continue ENTEREG 12-mg Capsule orally twice daily beginning the day after surgery for a maximum of 7 days or until discharge

• ENTEREG is for hospital use only • Patients should not receive more than 15 total doses of ENTEREG • ENTEREG is available only to hospitals that enroll in the E.A.S.E. Program

Please see accompanying full Prescribing Information, including Boxed Warning regarding short-term hospital use only and the ENTEREG Access Support & Education (E.A.S.E.™) Program.

7

The first and only FDA-approved agent indicated to accelerate the time to upper and lower GI recovery following partial large or small bowel resection surgery with primary anastomosis

Important Safety Information WARNING: FOR SHORT-TERM HOSPITAL USE ONLY ENTEREG is available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have registered in and met all of the requirements for the ENTEREG Access Support & Education (E.A.S.E.™) Program may use ENTEREG. Contraindications • ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG Warnings and precautions • There were more reports of myocardial infarctions in patients treated with alvimopan 0.5 mg twice daily compared with placebo-treated patients in a 12-month study of patients treated with opioids for chronic pain. In this study, the majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of alvimopan, including studies of patients undergoing bowel resection surgery who received alvimopan 12 mg twice daily for up to 7 days. A causal relationship with alvimopan has not been established • ENTEREG should be administered with caution to patients receiving more than 3 doses of an opioid within the week prior to surgery. These patients may be more sensitive to ENTEREG and may experience GI side effects (eg, abdominal pain, nausea and vomiting, diarrhea) • ENTEREG is not recommended for use in patients with severe hepatic impairment, end-stage renal disease, or in patients undergoing surgery for correction of complete bowel obstruction

Distribution Program for ENTEREG ENTEREG is available only to hospitals that enroll in the E.A.S.E. Program. To enroll in the E.A.S.E. Program, the hospital must acknowledge that: • Hospital staff who prescribe, dispense, or administer ENTEREG have been provided the educational materials on the need to limit use of ENTEREG to short-term, inpatient use • Patients will not receive more than 15 doses of ENTEREG • ENTEREG will not be dispensed to patients after they have been discharged from the hospital For more information on the E.A.S.E. Program, contact Adolor Corporation at 1.866.4ADOLOR (1.866.423.6567) or visit www.entereg.com.

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UNLOCK THE POTENTIAL

Adverse Reactions Observed 2 in Clinical Studies Treatment-emergent adverse reactions* Bowel resection patients

All surgical patients

Placebo (n=986)

ENTEREG (n=999)

Placebo (n=1365)

ENTEREG (n=1650)

Anemia

4.2%

5.2%

5.4%

5.4%

Constipation

3.9%

4.0%

7.6%

9.7%

Dyspepsia

4.6%

7.0%

4.8%

5.9%

Flatulence

4.5%

3.1%

7.7%

8.7%

Hypokalemia

8.5%

9.5%

7.5%

6.9%

Back pain

1.7%

3.3%

2.6%

3.4%

Urinary retention

2.1%

3.2%

2.3%

3.5%

Adverse reaction

*Reported in ≥3% of either bowel resection patients treated with ENTEREG or all surgical patients treated with ENTEREG and for which the rate for ENTEREG was ≥1% than placebo.

Drug interactions2 • Low probability of drug interactions with ENTEREG when coadministered with CYP450 and P-glycoprotein substrates, inducers, or inhibitors • No dosage adjustments necessary with concomitant use of acid blockers or antibiotics References: 1. Gutstein HB, Akil H. Opioid analgesics. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: The McGraw-Hill Companies, Inc; 2006:547-590. 2. ENTEREG Prescribing Information. Exton, PA: Adolor Corporation; 2009. 3. Person B, Wexner SD. The management of postoperative ileus. Curr Probl Surg. 2006;43:12-65. 4. Senagore AJ. Pathogenesis and clinical and economic consequences of postoperative ileus. Am J Health-Syst Pharm. 2007;64(suppl 13):S3-S7.

5. Büchler MW, Seiler CM, Monson JRT, et al. Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study. Aliment Pharmacol Ther. 2008;28:312-325 (Study 5). 6. Delaney CP, Weese JL, Hyman NH, et al. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005;1114-1129 (Study 4). 7. Viscusi ER, Goldstein S, Witkowski T, et al. Alvimopan, a peripherally acting mu-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery: results of a randomized, double-blind, controlled study. Surg Endosc. 2006;20:64-70 (Study 3). 8. Ludwig K, Enker WE, Delaney CP, et al. Gastrointestinal tract recovery in patients undergoing bowel resection: results of a randomized trial of alvimopan and placebo with a standardized accelerated postoperative care pathway. Arch Surg. 2008;143(11):1098-1105 (Study 1). 9. Wolff BG, Michelassi F, Gerkin TM, et al. Alvimopan, a novel, peripherally acting μ opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004;240:728-735 (Study 2).

10. Data on file. Adolor Corporation.

Please see accompanying full Prescribing Information for ENTEREG. 9

The first and only FDA-approved agent indicated to accelerate the time to upper and lower GI recovery following partial large or small bowel resection surgery with primary anastomosis

Make ENTEREG a key part of your preop and postop routine • Improvement in mean time to GI recovery by up to 1 day (11 to 26 hours faster)2 • Reduced mean time to DOW by approximately 13 to 21 hours2

Preop and postop dosing to accelerate GI recovery 2 PREOPERATIVELY One ENTEREG 12-mg Capsule orally 30 minutes to 5 hours prior to surgery

POSTOPERATIVELY Continue ENTEREG 12-mg Capsule orally twice daily beginning the day after surgery for a maximum of 7 days or until discharge

Important Safety Information WARNING: FOR SHORT-TERM HOSPITAL USE ONLY ENTEREG is available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have registered in and met all of the requirements for the ENTEREG Access Support & Education (E.A.S.E.™) Program may use ENTEREG. • ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG • There were more reports of myocardial infarctions in patients treated with alvimopan 0.5 mg twice daily compared with placebo-treated patients in a 12-month study of patients treated with opioids for chronic pain.

In this study, the majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of alvimopan, including studies of patients undergoing bowel resection surgery who received alvimopan 12 mg twice daily for up to 7 days. A causal relationship with alvimopan has not been established

Please see accompanying full Prescribing Information for ENTEREG. ENTEREG is a registered trademark and E.A.S.E. is a trademark of Adolor Corporation. © 2010 Adolor Corporation. All rights reserved.

Printed in USA. ETG393R0 February 2010