General Information

Entereg is an oral, peripherally-acting, mu-opioid receptor (PAMOR) antagonist. Following oral administration, alvimopan antagonizes the peripheral effects of opioids on gastrointestinal motility and secretion by competitively binding to gastrointestinal tract mu-opioid receptors.

Entereg is specifically indicated to accelerate the time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis.

Entereg is supplied as a tablet designed for oral administration. The recommended initial dose of the drug is 12 mg administered 30 minutes to 5 hours prior to surgery followed by 12 mg twice daily beginning the day after surgery for a maximum of 7 days or until discharge. Patients should not receive more than 15 doses of Entereg.

Clinical Results

FDA Approval
FDA approval of Entereg is based on the results of five multicenter, randomized, double-blind, parallel-group, placebo-controlled studies: four in the US and one ex-US. The trials enrolled over 2,000 adult subjects undergoing partial large or small bowel resection surgery with primary anastomosis or total abdominal hysterectomy under general anesthesia. The subjects were randomly assigned to receive oral doses of Entereg 12 mg or matching placebo. The initial dose was administered at least 30 minutes and up to 5 hours prior to the scheduled start of surgery for most patients, and subsequent doses were administered twice daily beginning on the first postoperative day and continued until hospital discharge or a maximum of 7 days. There were no limitations on the type of general anesthesia used, but intrathecal or epidural opioids or anesthetics were prohibited. All patients in the US studies were scheduled to receive intravenous patient-controlled opioid analgesia, while in the non-US study, patients were scheduled to receive opioids either by intravenous patient-controlled opioid analgesia or bolus parenteral administration. There were no restrictions on the type or duration of opioid use. Subjects who received more than 3 doses of an opioid (regardless of route) during the 7 days prior to surgery were excluded. The primary endpoint was time to achieve resolution of postoperative ileus, defined as a composite measure of both upper and lower gastrointestinal recovery. This was based on two components: GI2-toleration of solid food and first bowel movement.

Study One- In the Entereg arm the mean number of hours to GI2 was 92.0 hours versus 111.8 hours in the placebo arm (Hazard Ratio 1.533; 95% CI). Study Two- Mean number of hours to GI2 was 105.9 in the Entereg arm and 132.0 in the placebo arm (Hazard ratio 1.625; 95% CI). Study Three- In the Entereg arm the mean number of hours to GI2 was 116.4 verses 130.3 hours in the placebo arm (Hazard Ratio 1.365; 95% CI). Study Four- The mean number of hours to GI2 in the Entereg arm was 106.7 versus 119.9 hours in the placebo arm (Hazard ratio 1.400; 95% CI). Study Five- In the Entereg arm the mean number of hours to GI2 was 98.8 versus 109.5 hours in the placebo arm (Hazard Ratio 1.299; 95% CI). In addition, across studies 1-4, subjects receiving Entereg had their discharge order written approximately 13 to 21 hours sooner compared to subjects receiving placebo. The incidence of anastomotic leak was low and comparable in subjects receiving either Entereg or placebo (0.8% and 1.1%, respectively). Entereg did not reverse opioid analgesia as measured by visual analog scale pain intensity scores and/or amount of postoperative opioids administered across all 5 studies.

Bowel Resection
The efficacy of Entereg following total abdominal hysterectomy has not been established. Therefore, the following data are for the bowel resection population only. A total of 1,877 subjects underwent bowel resection. In the non-US study (Study 5), average daily postoperative opioid consumption was approximately 50% lower and the use of non-opioid analgesics substantially higher, as compared with the US studies (Studies 1-4) for both treatment groups. During the first 48 hours postoperatively, the use of non-opioid analgesics was 69% compared with 4% for the non-US and US studies, respectively. In each of the 5 studies, Entereg accelerated the time to recovery of gastrointestinal function, as measured by the composite endpoint GI2, and time to discharge order written as compared with placebo.

Ongoing Study Commitments

Adolor has agreed to conduct a study of Entereg for the acceleration of gastrointestinal recovery in pediatric patients age greater than 1 month up to 16 years undergoing bowel resection surgery. The study will measure the time to first tolerated feed, population pharmacokinetic parameters, the proportion of postoperative days with stool passed while in hospital, length of hospital stay, the need for postoperative nasogastric tube insertion for symptoms of postoperative ileus, and safety.
Protocol Submission: December 2012
Study Start: June 2013
Final Report Submission: June 2016

Adolor has agreed to conduct a study of Entereg for the acceleration of gastrointestinal recovery in pediatric patients age 0 to 1 month undergoing bowel resection surgery. The study will measure population pharmacokinetic parameters, safety, and time to first tolerated feed while in the hospital.
Protocol Submission: December 2016
Study Start: June 2017
Final Report Submission: June 2019

Adolor has agreed to a multi-center, double-blind, placebo-controlled, parallel group clinical trial of Entereg for the management or postoperative ileus in patients undergoing radical cystectomy.
Protocol Submission: June 2008
Trial Start: March 2009
Final Report Submission: June 2012

Literature References

Foss JF, Fisher DM, Schmith VD Pharmacokinetics of alvimopan and its metabolite in healthy volunteers and patients in postoperative ileus trials. Clinical Pharmacology and Therapeutics 2008 May;83(5):770-6

Büchler MW, Seiler CM, Monson JR, Flamant Y, Thompson-Fawcett MW, Byrne MM, Mortensen ER, Altman JF, Williamson R Clinical trial: alvimopan for the management of postoperative ileus after abdominal surgery: results of an international randomised, double-blind, multicentre, placebo-controlled clinical study. Alimentary Pharmacology & Therapeutics 2008 Mar 28

Webster L, Jansen JP, Peppin J, Lasko B, Irving G, Morlion B, Snidow J, Pierce A, Mortensen E, Kleoudis C, Carter E Alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: Results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain. Pain 2007 Dec 28

Wolff BG, Viscusi ER, Delaney CP, Du W, Techner L Patterns of gastrointestinal recovery after bowel resection and total abdominal hysterectomy: pooled results from the placebo arms of alvimopan phase III North American clinical trials. Journal of the American College of Surgeons 2007 Jul;205(1):43-51

Fukuda H, Suenaga K, Tsuchida D, Mantyh CR, Pappas TN, Hicks GA, Dehaven-Hudkins DL, Takahashi T The selective mu opioid receptor antagonist, alvimopan, improves delayed GI transit of postoperative ileus in rats. Brain Research 2006 Aug 2;1102(1):63-70

Delaney CP, Weese JL, Hyman NH, Bauer J, Techner L, Gabriel K, Du W, Schmidt WK, Wallin BA; Alvimopan Postoperative Ileus Study Group Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Diseases of the Colon and Rectum 2005 Jun;48(6):1114-25; discussion 1125-6; author reply 1127-9

Paulson DM, Kennedy DT, Donovick RA, Carpenter RL, Cherubini M, Techner L, Du W, Ma Y, Schmidt WK, Wallin B, Jackson D Alvimopan: an oral, peripherally acting, mu-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction--a 21-day treatment-randomized clinical trial. The Journal of Pain : official journal of the American Pain Society 2005 Mar;6(3):184-92

Wolff BG, Michelassi F, Gerkin TM, Techner L, Gabriel K, Du W, Wallin BA; Alvimopan Postoperative Ileus Study Group Alvimopan, a novel, peripherally acting mu opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Annals of Surgery 2004 Oct;240(4):728-34